AVEO Pharmaceuticals

fromPatent rights
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended: December 31, 2021
Or
☐
TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the transition period from to
Commission file number: 001-34655
AVEO PHARMACEUTICALS, INC.
(Exact Name of Registrant as Specified in Its Charter)
Delaware
 
04-3581650
(State or Other Jurisdiction of
Incorporation or Organization)
 
(I.R.S. Employer
Identification No.)
 30 Winter Street
Boston, Massachusetts
02108
(Address of Principal Executive Offices)
 (zip code)
Registrant’s telephone number, including area code: (857) 400-0101
Securities registered pursuant to Section 12(b) of the Act:
Title of each class
Trading Symbol(s)
Name of each exchange on which registered
Common Stock, $0.001 par value
AVEO
Nasdaq Capital Market
Securities registered pursuant to Section 12(g) of the Act:
None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes ☐ No ☒
Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter period
that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days. Yes ☒ No ☐
Indicate by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the
preceding 12 months (or for such shorter period that the registrant was required to submit such files). Yes ☒ No ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company, or emerging growth company. See definitions of “large accelerated
filer,” “accelerated filer,” “smaller reporting company,” and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer
☐
Accelerated filer
☐
Non-accelerated filer
☒
Smaller reporting company
☒
Emerging growth company
☐
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided
pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b) of the
Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting firm that prepared or issued its audit report. ☒
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act). Yes ☐ No ☒
The aggregate market value of the registrant’s common stock, $0.001 par value per share, held by non-affiliates of the registrant, based on the last reported sale price of the common stock on the Nasdaq Capital
Market at the close of business on June 30, 2021, was $199.9 million.
The number of shares outstanding of the registrant’s Common Stock as of March 9, 2022 was 34,474,710.
Documents incorporated by reference:
Portions of our definitive proxy statement for our 2022 annual meeting of stockholders are incorporated by reference into Part III of this Annual Report on Form 10-K.

AVEO PHARMACEUTICALS, INC.
TABLE OF CONTENTS
Page
No.
 
PART I
6
Item 1.
Business
7
Item 1A.
Risk Factors
43
Item 1B.
Unresolved Staff Comments
83
Item 2.
Properties
83
Item 3.
Legal Proceedings
83
Item 4.
Mine Safety Disclosures
83
PART II
83
Item 5.
Market for Registrants Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities
83
Item 6.
Reserved
84
Item 7.
Management's Discussion and Analysis of Financial Condition and Results of Operations
85
Item 8.
Financial Statements and Supplementary Data
103
Item 9.
Changes in and Disagreements with Accountants on Accounting and Financial Disclosure
141
Item 9A.
Controls and Procedures
141
Item 9B.
Other Information
143
Item 9C.
Disclosure Regarding Foreign Jurisdictions that Prevent Inspections
145
Part III
145
Item 10.
Directors, Executive Officers and Corporate Governance
145
Item 11.
Executive Compensation
146
Item 12.
Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters
146
Item 13.
Certain Relationships and Related Person Transactions and Director Independence
147
Item 14.
Principal Accountant Fees and Services
147
PART IV
147
Item 15.
Exhibits, Financial Statement Schedules
147
Item 16.
Form 10-K Summary
147
SIGNATURES
151
2

References to AVEO
Throughout this Form 10-K, the words “we,” “us,” “our” and “AVEO”, except where the context requires otherwise, refer to AVEO Pharmaceuticals, Inc. and its consolidated subsidiaries, and
“our board of directors” refers to the board of directors of AVEO Pharmaceuticals, Inc.
Cautionary Note Regarding Forward-Looking Statements and Industry Data
This Annual Report on Form 10-K contains forward-looking statements within the meaning of the U.S. Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties.
All statements other than statements of historical fact contained in this report are statements that could be deemed forward-looking statements, including without limitation statements with respect to
the plans, strategies and objectives of management for future operations; statements concerning product research, development and commercialization plans, timelines and anticipated results;
statements of expectation or belief; statements with respect to clinical trials and studies; statements with respect to the therapeutic potential of product candidates; any expectations of revenue,
expenses, earnings or losses from operations, or other financial results; and statements of assumptions underlying any of the foregoing. Without limiting the foregoing, the words “anticipates”,
“believes”, “could”, “estimates”, “expects”, “intends”, “may”, “plans”, “seeks”, “will”, “strategy”, “potential”, “should”, “would” and other similar language, whether in the negative or affirmative,
are intended to identify forward-looking statements, although not all forward-looking statements contain these identifying words. Forward-looking statements may include, but are not limited to,
statements about:
•
our plans to commercialize FOTIVDA;
•
our manufacturing, marketing and sales capabilities and strategy;
•
the rate and degree of market acceptance and clinical utility of our products;
•
our plans to develop our clinical stage assets and commercialize our product candidates;
•
the initiation, timing, progress and results of future clinical trials, and our development programs;
•
our ability to secure new collaborations, maintain existing collaborations or obtain additional funding;
•
the potential of ficlatuzumab, AV-380 or other product candidates that we in-license, or may elect to in-license, or may acquire in the future;
•
impacts resulting from the COVID-19 pandemic and responsive actions relating thereto;
•
the timing or likelihood of regulatory filings and approvals;
•
the implementation of our business model, strategic plans for our business, product candidates and technology;
•
our competitive position;
•
developments and projections relating to our competitors and our industry;
•
our intellectual property position;
•
our estimates of the period in which we anticipate that existing cash, cash equivalents and investments will enable us to fund our current and planned operations; and
•
our estimates regarding expenses, future revenue, capital requirements and needs for additional financing.
Our actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors. We therefore caution you against relying on any of
these forward-looking statements. Important factors that could cause actual results to differ materially from those in these forward-looking statements include the factors discussed below under the
heading “Risk Factor Summary,” and the risk factors detailed further in Item 1A., “Risk Factors” of Part I of this report and in our U.S. Securities and Exchange Commission reports filed after this
report.
This report also includes statistical and other industry and market data that we obtained from industry publications and research, surveys and studies conducted by third parties as well as our
own estimates. All the market data used in this report involve a number of assumptions and limitations, and you are cautioned not to give undue weight to such data. Industry publications and third-
party research, surveys and studies generally indicate that their information has been obtained from sources believed to be reliable, although they do not guarantee the accuracy or completeness of
such information. Our estimates of the potential market opportunities for our product candidates include several key assumptions based on our industry knowledge, industry publications, third-party
research and other surveys, which may be based on a small sample size and may fail to accurately reflect market opportunities. While we believe that our internal assumptions are reasonable, no
independent source has verified such assumptions.
The forward-looking statements included in this annual report represent our estimates as of the filing date of this annual report. We specifically disclaim any obligation to update these forward-
looking statements in the future. These forward-looking statements should not be relied upon as representing our estimates or views as of any date subsequent to the date of this annual report.
3

Risk Factor Summary
Investment in our securities involves risk. You should carefully consider the following summary of what we believe to be the principle risks facing our business, in addition to the risks
described more fully in Item 1A., “Risk Factors” of Part I of this Annual Report on Form 10-K and other information included in this report. The risks and uncertainties described below are not the
only risks and uncertainties we face. Additional risks and uncertainties not presently known to us or that we presently deem less significant may also impair our business operations.
If any of the following risks occur, our business, financial condition and results of operations and future growth prospects could be materially and adversely affected, and the actual outcomes
of matters as to which forward-looking statements are made in this report could be materially different from those anticipated in such forward-looking statements.
•
We have incurred significant operating losses, anticipate that we will continue to incur significant operating expenses for the foreseeable future and may never generate significant
revenue or achieve or sustain profitability.
•
We may require substantial additional funding to advance our pipeline of clinical stage assets, and if we are unable to obtain this necessary capital when needed, we could be forced
to delay, limit, reduce or terminate our research, product development or commercialization efforts.
•
If we fail to comply with the covenants or payment obligations under the 2020 Loan Facility, which could result in an event of default, this could materially and adversely affect our
business and our financial condition.
•
We have only recently transitioned from a development stage biopharmaceutical company to a commercial stage biopharmaceutical company, which may make it difficult for you to
evaluate the success of our business to date and to assess our future viability.
•
We depend heavily on the success of our commercial product, FOTIVDA, and on our clinical stage assets, including tivozanib (in other indications), ficlatuzumab, AV-380 and AV-
203. If we are unable to complete the clinical development of, obtain marketing approval for or successfully commercialize our product candidates, our business will be materially
harmed.
•
The COVID-19 pandemic has adversely disrupted our ability to commercialize FOTIVDA, to manufacture clinical product, and to initiate new trials or complete ongoing clinical
trials and may have other adverse effects on our business and operations.
•
If we or our collaborators experience delays or difficulties in the enrollment of patients in clinical trials, receipt of necessary regulatory approvals could be delayed or prevented.
•
If clinical trials of any product candidates that we, or any collaborators, may develop fail to satisfactorily demonstrate safety and efficacy to the FDA and other regulators, we may
incur additional costs or experience delays in completing, or ultimately be unable to complete, the development and commercialization of these product candidates.
•
We face substantial competition from existing approved products and our competitors may also discover, develop or commercialize new competing products before, or more
successfully, than we do.
•
Adverse events or undesirable side effects caused by, or other unexpected properties of, product candidates that we develop may be identified during development and could delay
or prevent their marketing approval or limit their use.
•
We rely in part on third parties to produce our preclinical and clinical product candidate supplies and to conduct clinical trials of our internally-developed product candidates, and
those third parties may not perform satisfactorily, including by failing to deliver supplies on time or to meet deadlines for the completion of such trials, research or testing.
•
We rely on our licensee EUSA, over whom we have little control, for the sales, marketing and distribution efforts associated with the commercialization of FOTIVDA in the
countries in the EUSA territory and any failure by EUSA to devote the necessary resources and attention to market and sell FOTIVDA effectively and successfully may materially
impact our ability to generate revenue from the EUSA licensed territory.
•
Any failure by a third-party manufacturer or a third-party supplier to timely produce or provide required manufacturing supplies for us or to safely store product candidate supplies
and commercial supplies of
4

FOTIVDA may delay or impair our ability to manufacture product, initiate or complete our clinical trials or commercialize our product candidates.
•
We may not be successful in establishing or maintaining strategic partnerships to further the development of our therapeutic programs. Additionally, if any of our current or future
strategic partners fails to perform its obligations or terminates the partnership, the development and commercialization of the product candidates under such agreement could be
delayed or terminated and, such failures or terminations could have a material adverse effect on our operations and business.
•
We could be unsuccessful in obtaining or maintaining adequate patent protection for one or more of our product candidates, or the scope of our patent protection could be
insufficiently broad, which could result in competition and a decrease in the potential market share for our product candidates.
5

PART I
6

ITEM 1.
Business
Overview
We are a commercial stage, oncology-focused biopharmaceutical company committed to delivering medicines that provide a better life for patients with cancer. We currently market
FOTIVDA  (tivozanib) in the United States. FOTIVDA is our first commercial product and was approved by the U.S. Food and Drug Administration, or FDA, for marketing and sale in the United
States on March 10, 2021 for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma, or RCC, following two or more prior systemic therapies. We continue to
develop tivozanib in immuno-oncology combinations in RCC and other indications, and we have other investigational programs in clinical development.
FOTIVDA is an oral, next-generation vascular endothelial growth factor receptor, or VEGFR, tyrosine kinase inhibitor, or TKI. The FDA approval of FOTIVDA is based on our pivotal
Phase 3 randomized, controlled, multi-center, open-label clinical trial comparing tivozanib to an approved therapy, Nexavar  (sorafenib), in RCC patients whose disease had relapsed or become
refractory to two or three prior systemic therapies, which we refer to as the TIVO-3 trial. The approval is also supported by three additional trials in RCC and includes safety data from over 1,000
clinical trial subjects.
FOTIVDA became commercially available in the United States on March 22, 2021 and is available to patients through a network of specialty pharmacies and distributors. We commercialize
FOTIVDA in the United States through the support of approximately 65 field-based employees, which includes approximately 50 oncology sales professionals. The field sales force is supported by
the AVEO ACE Patient Support program, which is an extensive patient and healthcare provider support program designed to optimize patient access and help patients navigate their treatment journey.
To date, we believe we have been very successful in securing payor coverage. Furthermore, the NCCN Clinical Practice Guidelines in Oncology, or the NCCN Guidelines , recommend FOTIVDA as
a subsequent therapy for patients with relapsed or refractory advanced RCC with clear cell histology who received two or more prior systemic therapies.
Restrictions related to the ongoing COVID-19 pandemic have posed challenges for gaining in-person access to customers, prescribers and other healthcare professionals and certain
institutions remain closed to industry representatives. Notwithstanding these challenges, as of December 31, 2021, prescriptions for FOTIVDA and product revenues have increased quarter over
quarter since the beginning of our commercial launch. We aim to continue to deliver quarter over quarter net revenue and underlying prescription demand growth as we continue to execute on our
commercial strategy to support the adoption of FOTIVDA in appropriate patients.
We believe there is significant commercial opportunity for FOTIVDA in RCC in the United States. We estimate that the current U.S. market for relapsed or refractory advanced RCC therapy
is more than $1.7 billion, including $1.3 billion in the second line and $480.0 million in the third and fourth lines. As the TIVO-3 trial is the first positive Phase 3 clinical trial in RCC patients whose
disease had relapsed or become refractory to two or three prior systemic therapies as well as the first Phase 3 clinical trial in RCC to investigate a predefined subpopulation of patients who received
prior immunotherapy, a predominant standard of care for earlier lines of therapy, we believe that FOTIVDA could become a standard of care in the United States in the third and fourth line relapsed
or refractory advanced setting. Further, we intend to pursue opportunities in the second line relapsed or refractory advanced RCC setting. We and our collaboration partners are developing tivozanib
with immune checkpoint inhibitors, or ICIs, and in combination with a hypoxia inducible factor 2α, or HIF2α, inhibitor to support tivozanib's potential utility in this earlier line of RCC therapy.
Based on FOTIVDA’s demonstrated anti-tumor activity, tolerability profile and reduction of regulatory T-cell production, we and our collaboration partners are developing tivozanib in
additional cancer indications with significant unmet medical needs including, hepatocellular carcinoma, or HCC, and tumors that are resistant to immunotherapy, or immunologically cold tumors, in
combination with ICIs. In addition, we are evaluating tivozanib as a monotherapy in ovarian cancer and cholangiocarcinoma, or CCA. We and our collaboration partners or independent investigators
sponsor the development of tivozanib through preclinical studies and clinical trials conducted under collaboration agreements and investigator sponsored trial, or IST, agreements or our Cooperative
Research and Development Agreement, or CRADA, with the National Cancer Institute’s Surgical Oncology Program, or NCI-SOP.
We are also seeking to advance our pipeline of four wholly owned immunoglobulin G1, or IgG1, monoclonal antibody product candidates, ficlatuzumab, AV-380, AV-203 and AV-353. We
aim to leverage our existing collaborations and partnerships and enter into new strategic collaborations and partnerships to continue to advance each of our product candidates.
®
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7

Business Update Regarding COVID-19
The pandemic caused by an outbreak of a new strain of coronavirus and its related variants, or the COVID-19 pandemic, that is affecting the U.S. and global economy and financial markets,
is also impacting our employees, patients, communities and business operations to varying degrees. The extent to which the COVID-19 pandemic will directly or indirectly impact our business,
results of operations and financial condition will depend on future developments that are highly uncertain and cannot be accurately predicted at this time, such as the duration, scope and severity of
the pandemic, the duration and extent of travel restrictions and social distancing in the United States and other countries, business closures and business disruptions, its impact and the economic
impact on local, regional, national and international markets, the effectiveness of actions taken in the United States and other countries to contain and treat the disease, periodic and seasonal spikes in
infection rates, new strains of the virus that cause outbreaks of COVID-19 and the broad availability of effective vaccines and antiviral treatments. In March 2020, we transitioned essentially all of
our business operations to be conducted remotely in response to COVID-19. Although senior management has returned to the office, as of February 2022, the majority of our workforce continues to
work remotely. Management is actively monitoring this situation and the possible effects on our financial condition, liquidity, operations, commercialization, suppliers, manufacturers, industry and
workforce.
Impact on Commercialization of FOTIVDA. COVID-19 related restrictions have posed challenges for gaining in-person access to customers, prescribers and other healthcare professionals
and certain institutions remain closed to industry representatives. We believe these access challenges caused by the COVID-19 pandemic and the emergence of SARs-CoV-2 variants have potentially
slowed the commercial launch trajectory of FOTIVDA delaying our ability to achieve our anticipated market penetration at this stage of our commercial launch. While we have designed our strategic
commercial approach to be optimized for remote as well as in-person customer engagement capabilities and expanded our digital marketing strategies in light of the restrictions necessitated by the
COVID-19 pandemic, changes to standard sales and marketing practices, including the shift from in-person to video and virtual interactions with healthcare professionals, have caused, and may
continue to cause, challenges for the commercialization of FOTIVDA.
Impact on Trial Enrollment and Site Initiations. The COVID-19 pandemic has impacted the initiation, enrollment and completion of certain of our ongoing and planned clinical trials. For
instance, the pandemic partially slowed the enrollment of our open-label, multi-center, randomized Phase 1b/2 clinical trial of tivozanib in combination with AstraZeneca PLC’s, or AstraZeneca,
IMFINZI (durvalumab), which we refer to as the DEDUCTIVE trial, in that it hindered patients' ability to attend routine physical medical assessments with their clinicians resulting in delays in
diagnosis and, at times, treatment of cancer in patients. This is a phenomenon supported by recent studies finding a decline in cancer screening during the pandemic. In addition, our contract research
organization, or CRO, for our Phase 3 clinical trial designed to evaluate the safety and efficacy of tivozanib in combination with nivolumab in RCC patients who have progressed following one or
two lines of prior immunotherapy, which we refer to as our TiNivo-2 trial, informed us that it has been impacted by cancer research staffing shortages related to COVID-19 infections and competition
for staff, among other things, at clinical trial sites resulting in delays to trial site activation, contracting and enrollment. Currently, certain academic institutions have frozen enrollment on all trials or
refused to take on additional clinical trials due to these staffing shortages and these staffing shortages have adversely impacted the DEDUCTIVE trial and the TiNivo-2 trial.
Impact on Manufacturing. The COVID-19 pandemic has, and may continue to, cause delays in the manufacturing of our product candidates ficlatuzumab and AV-380. In 2020, we contracted
with a contract manufacturing organization, or CMO, to manufacture the clinical supply for our potential registrational clinical trial of ficlatuzumab in combination with cetuximab in patients with
human papillomavirus, or HPV, negative recurrent or metastatic, or R/M, head and neck squamous cell carcinoma, or HNSCC, patients. However, in the middle of 2021, our CMO notified us of a
shortage of required key raw materials and manufacturing supplies also used in the COVID-19 vaccine manufacturing process which would delay the delivery of the clinical supply of ficlatuzumab.
We have since secured the required raw materials and manufacturing supplies needed and now plan to manufacture ficlatuzumab Phase 3 clinical supply in the second quarter of 2022.
More recently, another of our CMOs has experienced employee shortages, supply chain issues and other disruptions related to the COVID-19 pandemic which have delayed and may
continue to delay that manufacture of AV-380 preclinical supply.
To date, the COVID-19 pandemic has not had a material impact on our commercial and clinical supply of FOTIVDA (tivozanib) or our clinical supply of AV-203. We currently have a
sufficient commercial and clinical supply of FOTIVDA (tivozanib) and clinical supply of AV-203 that we believe will meet our ongoing needs for more than twelve months from the date of the filing
of this Annual Report on Form 10-K. However, there can be no assurance that future developments do not impact the availability of our commercial and clinical supply of FOTIVDA (tivozanib) or
our clinical supply of AV-203. For additional information on the risks posed by the COVID-19 Pandemic and our reliance on CMOs,
8

please see “Part II, Item 1A. Risk Factors – Risks Related to the COVID-19 Pandemic” and “Part II, Item 1A. Risk Factors Dependence on Third Parties” included elsewhere in this Annual Report on
Form 10-K.
Our Corporate Strategy
Our strategy is to focus our resources toward the development and commercialization of our oncology portfolio in North America, while leveraging partnerships to support the development
and commercialization of our product and product candidates in other geographies and indications outside of oncology. The key elements of this corporate strategy include:
◦
successfully commercialize FOTIVDA in the United States for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic
therapies;
◦
advance life-cycle development for tivozanib to support its potential utility in immuno-oncology and other novel targeted combinations in RCC and other potential indications;
◦
advance the development of our pipeline of four IgG1 monoclonal antibody product candidates, ficlatuzumab, AV-380, AV-203 and AV-353; and
◦
leverage existing collaborations and partnerships and enter into new strategic collaborations and partnerships that can contribute to our ability to efficiently develop our product
candidates to provide a better life for patients with cancer.
Our Marketed Product
FOTIVDA
FOTIVDA is an oral, next-generation VEGFR TKI. FOTIVDA was approved by the FDA for marketing and sale in the United States in March 2021 and is sold for the treatment of adult
patients with relapsed or refractory advanced RCC following two or more prior systemic therapies. FOTIVDA was approved in August 2017 by the European Commission, or EC, and other countries
in the territory of our partner EUSA Pharma (UK) Limited, or EUSA, for the treatment of adult patients with advanced RCC.
FOTIVDA is a potent, selective inhibitor of VEGFRs 1, 2 and 3 with a long half-life. In addition to the inhibition of VEGFR, FOTIVDA has demonstrated the ability to down regulate
regulatory T-cell production in preclinical models. This unique combination of properties is designed to improve efficacy and tolerability of FOTIVDA as a monotherapy or in combination with ICIs
and other emerging cancer targets such as HIF2α relative to earlier generations of VEGFR TKIs.
U.S. Commercialization of FOTIVDA in Relapsed or Refractory Advanced RCC
FOTIVDA became commercially available in the United States on March 22, 2021 and is available to patients through a network of specialty pharmacies and distributors. We commercialize
FOTIVDA in the United States through the support of approximately 65 field-based employees, which includes approximately 50 oncology sales professionals. The field sales force is supported by
the AVEO ACE Patient Support program, which is an extensive patient and healthcare provider support program designed to optimize patient access and help patients navigate their treatment journey.
To date, we believe we have been very successful in securing payor coverage. Furthermore, the NCCN Guidelines  recommend FOTIVDA as a subsequent therapy for patients with relapsed or
refractory advanced RCC with clear cell histology who received two or more prior systemic therapies.
We believe there is significant commercial opportunity for FOTIVDA in RCC in the United States and that FOTIVDA could become a standard of care in the United States in the third and
fourth line relapsed or refractory advanced setting.
Commercialization of FOTIVDA in RCC Outside the United States
FOTIVDA, through EUSA, is also approved for the treatment of adult patients with advanced RCC in the European Union, or the EU, New Zealand and South Africa and is reimbursed in
the United Kingdom, Germany, Spain and certain other countries in EUSA’s territory. FOTIVDA is approved in the EU for the first-line treatment of adult patients with advanced RCC and for adult
patients who are VEGFR and mTOR pathway inhibitor-naïve following disease progression after one prior treatment with cytokine therapy for advanced RCC. FOTIVDA has been commercially
available in the EU since 2017. EUSA is working to secure reimbursement approval in and commercially launch FOTIVDA in additional countries in the EUSA territory. However, there is significant
competition in the first-line RCC setting in the EU
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9

due to the approval of several immunotherapy combinations which have become a standard of care and impacted the market opportunity for monotherapy treatments.
We are entitled to receive milestone payments upon reimbursement approval for RCC, if any, in each of France, Germany, Italy, Spain and the United Kingdom, or, collectively, the EU5.
EUSA has received reimbursement approval for and commercially launched FOTIVDA in Germany, the United Kingdom and Spain and has also received reimbursement approval for and
commercially launched FOTIVDA in additional non-EU5 countries. EUSA is working to secure reimbursement approval in and commercially launch FOTIVDA in additional countries in its licensed
territories. We are eligible to receive milestone payments based upon EUSA obtaining marketing approval for up to three additional indications. We may also receive payments for sales milestones
based on the aggregate global net sales reached in a particular calendar year.
EUSA has reported to us that, to date, it has not experienced any material decrease in sales trends or interruptions in supply or distribution of FOTIVDA during the COVID-19 pandemic;
however, the future impact of the COVID-19 pandemic on FOTIVDA sales in the EUSA territory is difficult to predict. In December 2021, EUSA announced that it had signed an agreement with
Recordati, S.p.A. to be acquired and has indicated that the acquisition is anticipated to close in the first half of 2022.
Our Product Candidates
Tivozanib
Our pipeline includes our lead product tivozanib. We are evaluating tivozanib, both as a monotherapy and in combination with ICIs and other emerging cancer targets such as HIF2α, for the
treatment of RCC, HCC, immunologically cold tumors and CCA. We and our collaboration partners or independent investigators sponsor the development of tivozanib through preclinical studies and
clinical trials conducted under collaboration agreements and IST agreements or our CRADA with NCI-SOP.
We have exclusive rights to develop and commercialize tivozanib in oncology indications in all countries outside of Asia and the Middle East under a license from Kyowa Kirin Co., Ltd.
(formerly Kirin Brewery Co., Ltd.), or KKC. We have sublicensed to EUSA the right to develop and commercialize tivozanib in our licensed territories outside of North America, including Europe
(excluding Russia, Ukraine and the Commonwealth of Independent States), Latin America (excluding Mexico), Africa and Australasia. The EUSA sublicense excludes non-oncologic diseases or
conditions of the eye.
Clinical Development of Tivozanib in RCC
Third-Line and Fourth-Line Phase 3 Clinical Trial (TIVO-3): In May 2016, we initiated enrollment in the TIVO-3 trial. The TIVO-3 trial is the first positive Phase 3 clinical trial in the third-
and fourth-line treatment of patients with relapsed or refractory advanced RCC as well as the first Phase 3 trial in RCC to investigate a predefined subpopulation of patients who received prior
immunotherapy, a predominant standard of care for earlier lines of therapy. Patients were stratified by International Metastatic RCC Database Consortium risk category (favorable, intermediate or
poor) and type of prior therapy (two prior VEGFR TKIs, VEGFR TKI plus checkpoint inhibitor or VEGFR TKI plus any other systemic agent) then randomized 1:1 to receive tivozanib or sorafenib.
In November 2018, we announced that the TIVO-3 trial met its primary endpoint of improving progression free survival, or PFS, with a median PFS in the tivozanib arm of 5.6 months
compared with 3.9 months in the sorafenib arm. Tivozanib demonstrated a 44% improvement in median PFS and 27% reduction in risk of progression or death compared to sorafenib (HR=0.73,
p=0.02). Approximately 26% of patients received checkpoint inhibitor therapy in earlier lines of treatment. Patients who received prior checkpoint inhibitor therapy had exhibited a 45% reduction in
risk of progression or death. The secondary endpoint of objective response rate, or ORR, for patients receiving tivozanib was 18% compared to 8% for patients receiving sorafenib (p=0.02). Median
duration of response in patients receiving tivozanib was not reached and in patients receiving sorafenib was 5.7 months. Tivozanib was generally better tolerated than sorafenib, as indicated by fewer
dose reductions and interruptions. Grade 3 or higher adverse events were consistent with those observed in previous tivozanib trials. Infrequent but severe adverse events reported in greater number in
the tivozanib arm were thrombotic events similar to those observed in previous tivozanib studies. The most common adverse events in patients receiving tivozanib was fatigue and asthenia, adverse
events known to reflect effective VEGF pathway inhibition.
In June 2021, additional analyses and long-term follow up results from the TIVO-3 trial were presented at the 2021 American Society of Clinical Oncology, or ASCO, Annual Meeting. In
February 2022, at the American Society of Clinical Oncology Genitourinary, or ASCO GU, Cancers Symposium, additional long term follow up was presented demonstrating long term PFS benefit
and an improving trend in overall survival, or OS, from the TIVO-3 trial (HR 0.89).
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These landmark long-term PFS rates up to 48-months were higher among patients treated with tivozanib as compared to patients treated with sorafenib (12% vs. 2% and 7.6% vs. 0% at three and four
years, respectively).
RCC PD-1 Phase 3 Combination Clinical Trial with OPDIVO  (TiNivo-2): Based on data from our Phase 1b/2 clinical trial of tivozanib in combination with OPDIVO (nivolumab), or the
TiNivo trial, including data showing few tivozanib dose reductions and additive or synergistic activity for ORR and PFS, we opened enrollment for a Phase 3 clinical trial, which we refer to as the
TiNivo-2 trial, in the third quarter of 2021. We are the sponsor of the trial and Bristol-Myers Squibb Company, or BMS, is supplying OPDIVO (nivolumab), BMS’s antibody directed against
programmed death-1, or PD-1, therapy for the trial. The TiNivo-2 trial is a randomized, open-label, controlled Phase 3 clinical trial designed to evaluate the safety and efficacy of tivozanib in
combination with nivolumab as compared to tivozanib as a monotherapy, in RCC patients who have progressed following one or two lines of prior immunotherapy, one of which must include an ICI.
The TiNivo-2 trial is expected to enroll approximately 326 patients from sites in the United States, Europe and Latin America. Patients will be randomized 1:1 to receive either tivozanib (0.89 mg/QD
for 21 days followed by 7 days off treatment) in combination with nivolumab (480 mg every 4 weeks) or tivozanib as a monotherapy (1.34 mg/QD for 21 days followed by 7 days off treatment). In
February 2022, we amended the protocol to reduce the combination dose of tivozanib to 0.89 mg. The protocol was amended based on (i) emerging evidence that the lower 0.89 mg dose was
effective in combination with an ICI, (ii) that the lower dose may optimize the risk/benefit profile and result in better tolerability for the combination and (iii) the FDA’s recommendation to
investigate an optimal dose of tivozanib in the combination setting under its Project Optimus initiative. We expect TiNivo-2 trial enrollment to be completed in the first half of 2023. The TiNivo-2
trial’s primary endpoint will assess PFS, with secondary endpoints to include OS, ORR, duration of response and safety. The TiNivo-2 trial will seek to further understand the activity and tolerability
of this combination following prior immunotherapy.
RCC HIF2α Phase 2 Clinical Trial with NKT2152: In January 2022, we entered into a clinical trial collaboration and supply agreement with NiKang Therapeutics Inc., or NiKang, to
evaluate tivozanib in combination with NKT2152, NiKang’s small molecule that inhibits HIF2α. The Phase 2 clinical trial is designed to evaluate the safety and efficacy of the combination of
tivozanib and NKT2152 in clear cell RCC, or ccRCC, patients who have not responded to or relapsed from prior therapies. NiKang will sponsor the trial. We are supplying tivozanib at no cost and
will co-fund the trial. We expect the Phase 2 clinical trial to commence in 2022.
Clinical Development of Tivozanib in HCC
HCC PD-L1 Combination Trial with IMFINZI (DEDUCTIVE): We are conducting the DEDUCTIVE trial through a drug supply and cost sharing collaboration with AstraZeneca PLC. The
DEDUCTIVE trial is an open-label, multi-center, randomized Phase 1b/2 clinical trial of tivozanib in combination with AstraZeneca's IMFINZI (durvalumab), a human monoclonal antibody directed
against PD-L1. Enrollment for the first cohort of the trial, which includes patients with advanced, unresectable HCC who have not received prior systemic therapy for metastatic disease, or cohort A,
of the DEDUCTIVE trial is complete and topline results were recently presented at the ASCO Gastrointestinal (GI) Cancers Symposium. Topline efficacy and safety data for cohort A demonstrated
that the combination was well tolerated, with three patients showing Grade 3 treatment related adverse events, or TRAEs, and no Grade 4 TRAEs or treatment-related deaths. Further, the combination
demonstrated a 27.8% partial response, or PR, rate and a disease control rate (PR plus stable disease) of 67.8%, with a median PFS of 7.3 months and a 1-year OS of 76%, which we believe positions
the tivozanib/durvalumab combination well relative to other anti-VEGF ICI combinations in this indication.
The DEDUCTIVE trial was amended in the third quarter of 2021 to include second-line treatment of patients with advanced, unresectable HCC who have progressed after first-line
bevacizumab and atezolizumab treatment, or cohort B. The cohort B Phase 2 portion of the trial is designed to enroll 20 patients and enrollment is now expected to be completed in the second half of
2022, a delay from our previous guidance of the first half of 2022. The DEDUCTIVE trial enrollment has been delayed due to several developments including: developments in the HCC standard of
care that have led to longer treatment in first line therapies and reduced the presence of a sufficient patient pool suitable for the DEDUCTIVE trial; site staffing shortages related to the COVID-19
pandemic and other competitive factors that have led to enrollment delays at trial sites; and the COVID-19 pandemic hindering patients' ability to attend routine physical medical assessments with
their clinicians that resulted in delays in diagnosis and, at times, treatment of cancer in patients.
Clinical Development of Tivozanib in Ovarian Cancer
In June 2019, Dr. Wendy Swetzig at Northwestern University Feinberg School of Medicine presented data at the 2019 ASCO Annual Meeting from an investigator-sponsored Phase 2 clinical
trial of tivozanib in patients with recurrent, platinum-resistant ovarian cancer, including fallopian tube or primary peritoneal cancer. The trial was one of several studies funded by a grant we provided
to the National Comprehensive Cancer Network. The trial was designed to measure the safety and activity of tivozanib in ovarian cancer and enrolled a total of 31 patients, 30 of which were treated
with tivozanib. With four patients showing a partial response and twelve patients with stable disease, the clinical benefit rate
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(partial response plus stable disease) was reported to be 53.3%. The trial data suggests that tivozanib is active in patients with recurrent ovarian cancer, without substantial toxicity.
Clinical Development of Tivozanib in Immunologically Cold Tumors
In September 2021, we entered into an IST Agreement with the University of Florida, or UF, to conduct a Phase 1b/2 clinical trial to evaluate the safety and efficacy of tivozanib in
combination with atezolizumab in immunologically cold tumors. Immunologically cold tumors are solid tumors that lack or have few tumor-infiltrating lymphocytes and remain a clinical challenge.
Clinical Development of Tivozanib in Cholangiocarcinoma
In September 2021, we entered into a CRADA with NCI-SOP to conduct a Phase 1/2 clinical trial designed to evaluate the safety and efficacy of tivozanib in CCA. The Phase 1/2 clinical
trial is an open-label, single-center, non-randomized study which enrolled its first patient in March 2022. CCA is an aggressive biliary tract malignancy that remains a clinical challenge with limited
treatment options and poor survival rates.
Ficlatuzumab
Ficlatuzumab is a potent humanized IgG1 monoclonal antibody that targets hepatocyte growth factor, or HGF. The HGF/cMET pathway is implicated as an escape mechanism for epidermal
growth factor receptor, or EGFR, blockade. Ficlatuzumab has demonstrated differentiated inhibition of HGF/cMET downstream signaling and demonstrated a strong additive anti-tumor effect in
preclinical studies and early clinical trials.
We have previously reported Phase 1/2 clinical data on ficlatuzumab in HNSCC, pancreatic cancer and acute myeloid leukemia, or AML. We continue to evaluate opportunities for the further
clinical development of ficlatuzumab in these and other cancers.
Clinical Development of Ficlatuzumab in HNSCC
We announced results from the randomized Phase 2 clinical trial of ficlatuzumab, or the Phase 2 HNSCC Trial, in combination with ERBITUX (cetuximab), an EGFR, targeted antibody, in
patients with recurrent or metastatic HNSCC who relapsed or were refractory to prior immunotherapy, chemotherapy and cetuximab (pan-refractory) at the 2021 ASCO Annual Meeting. Based on the
Phase 1b and Phase 2 clinical trial results, ficlatuzumab was granted Fast Track designation by the FDA for the evaluation of ficlatuzumab in combination with cetuximab for the treatment of patients
with relapsed or recurrent HNSCC in September 2021.
In support of the proposed Phase 3 clinical trial of ficlatuzumab and cetuximab in patients with HPV negative HNSCC, in January 2022, we entered into a clinical trial collaboration and
supply agreement with Merck KGaA, Darmstadt, Germany, or Merck, to evaluate ficlatuzumab in combination with cetuximab in patients with HPV negative R/M HNSCC. Merck will provide
cetuximab clinical drug supply in all countries outside of the U.S. and Canada for the registrational clinical trial. We expect to continue to discuss potential registrational clinical trial designs with the
FDA and with potential partners. Assuming the timely manufacturing of ficlatuzumab, the availability of financial resources or a strategic partner with adequate funding and the ability to finalize the
trial design with the FDA under the Fast Track designation, we expect to initiate a potential registrational clinical trial of ficlatuzumab in combination with cetuximab in patients with HPV negative
HNSCC patients in the first half of 2023.
In 2020, we contracted with a CMO to manufacture the clinical supply for our potential Phase 3 clinical trial of ficlatuzumab in combination with cetuximab in patients with HPV negative
R/M HNSCC patients. However, a shortage of required raw materials and manufacturing supplies also used in the COVID-19 vaccine manufacturing process delayed the delivery of the clinical
supply of ficlatuzumab. We have secured the required raw materials and manufacturing supplies and now plan to manufacture clinical supply for our potential Phase 3 clinical trial of ficlatuzumab in
the second quarter of 2022.
We continue to evaluate additional opportunities for the further clinical development of ficlatuzumab including in pancreatic cancer, AML and in tumors where EGFR inhibitors are used. The
expansion of the ficlatuzumab clinical program, beyond what we are currently committed to, will require additional manufacturing efforts and costs.
Clinical Development of Ficlatuzumab in Pancreatic Cancer
Kimberly Perez, M.D. at the Dana-Farber Cancer Institute conducted an investigator-sponsored Phase 1b/2 clinical trial of ficlatuzumab in combination with nab-paclitaxel and gemcitabine
in pancreatic cancer. The trial was initiated in December 2017 to test the safety and tolerability of ficlatuzumab in combination with nab-paclitaxel and gemcitabine in previously untreated metastatic
pancreatic ductal cancer, or PDAC. In January 2020, results from the Phase
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1b portion of the trial were presented at the 2020 ASCO GI Cancers Symposium. The trial, which was based on preclinical findings demonstrating a synergistic effect of the combination in a
preclinical model of PDAC, was designed to determine maximum tolerated dose of ficlatuzumab when combined with gemcitabine and nab-paclitaxel. Secondary outcome measures included ORR
and PFS. A total of 24 patients enrolled in the trial. The average number of 28-day treatment cycles received was 7.5 (range 1-15), with three patients remaining on active treatment at the end of the
trial. The combination showed a 29% partial response rate and a 92% disease control rate (partial response plus stable disease), which was promising relative to data observed for gemcitabine and
nab-paclitaxel alone. Treatment with this regimen was associated with significant hypoalbuminemia and edema, and therefore a follow-up safety study is under consideration to evaluate ficlatuzumab
in combination with an alternate cytotoxic regimen.
Clinical Development of Ficlatuzumab in AML
We conducted an investigator-sponsored Phase 1b/2 clinical trial of ficlatuzumab in combination with cytarabine in patients with AML, which we refer to as the CyFi-1 trial, which showed a
complete response rate of 50% in the 18 primary refractory AML patients enrolled in the trial and an acceptable tolerability profile. Based on the promising findings from the CyFi-1 trial, we
designed a randomized Phase 2 clinical trial evaluating ficlatuzumab in combination with high-dose cytarabine versus high-dose cytarabine as a monotherapy in patients with AML, which we
referred to as the CyFi-2 trial. However, in March 2020, we discontinued the CyFi-2 trial prior to the initiation of patient enrollment due to the urgent shift in priorities among clinical trial sites
toward efforts to combat the COVID-19 pandemic, which had impacted the trial enrollment timeline and the feasibility of completing the clinical trial within the shelf-life of the ficlatuzumab clinical
trial drug supply that was available. We are currently considering further clinical development of ficlatuzumab in AML, but have not made any final determinations at this time.
AV-380
AV-380 is a potent humanized IgG1 monoclonal antibody that targets growth differentiation factor 15, or GDF15, which is often associated with poor patient prognosis, the onset and
worsening of cachexia and has been linked to immunosuppression in the tumor microenvironment. We are developing AV-380 for the potential treatment and/or prevention of cancer cachexia.
Cachexia is defined as a multi-factorial syndrome of involuntary weight loss characterized by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed
by conventional nutritional support and leads to progressive functional impairment. It is estimated that cachexia affects approximately 9 million individuals in North America, Europe and Japan.
Cachexia is associated with various cancers, and it is estimated that 50% to 80% of all cancer patients suffer from cachexia and up to 20% of all cancer patients die due to cachexia. We believe AV-
380 has the potential to address a significant unmet medical need. Cachexia also affects patients with chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, anorexia
nervosa, AIDS and other diseases.
In December 2020, the FDA approved our investigational new drug, or IND, application for AV-380 for the potential treatment of cancer cachexia. In October 2021, we completed
enrollment for a Phase 1 clinical trial in healthy subjects. Initial data observed a reduction of GDF15 in subjects and no drug related adverse events were identified. However, operational errors at the
trial site have caused data integrity concerns and we have notified the FDA. We plan to discuss with the FDA the suitability of the data for regulatory purposes and our ability to publish the data from
this trial. We do not expect the data quality issues in the Phase 1 clinical trial to impact our plans to initiate a Phase 1b clinical trial in cancer patients in the second half of 2022.
We believe that AV-380 represents a unique approach to treating cachexia because, in preclinical studies, it has demonstrated the ability to address key mechanisms underlying the syndrome.
Our preclinical research suggests that greater than 70% of cancer patients have increased GDF15 expression, starting at the pre-cachectic stage. If GDF15 inhibitors, such as AV-380, can demonstrate
a clinically meaningful impact on cachexia, we believe there is a significant market opportunity with potential application in multiple tumor types in combination with current standards of care for
oncology. In addition to our patents and patent applications covering our proprietary AV-380 antibody program, we have in-licensed certain patents and patent applications from St. Vincent’s Hospital
Sydney Limited in Sydney, Australia, which we refer to as St. Vincent’s. We have milestone and royalty payment obligations under our license agreement with St. Vincent’s.
AV-203
AV-203 is a potent humanized IgG1 monoclonal antibody that targets ErbB3 (also known as HER3). AV-203 inhibits ErbB3 inducing the internalization and degradation of the surface receptor
and demonstrates a high degree of activity in NRG1+ tumors. AV-203 has also demonstrated a high degree of anti-tumor activity in preclinical models.
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In March 2016, we entered into a collaboration and license agreement with CANbridge Life Sciences Ltd., or CANbridge, which we refer to as the CANbridge Agreement, under which we
granted CANbridge the exclusive right to develop, manufacture and commercialize AV-203 in all countries outside of North America.
In September 2021, we regained worldwide rights to the AV-203 program following CANbridge's' termination of the CANbridge Agreement for convenience. As part of the termination for
convenience, CANbridge transferred to us all of its know-how in the development of AV-203 as well as all manufacturing material. We are exploring AV-203 as a potential oncology treatment and we
expect to reactivate the IND application in the second quarter of 2022.
ErbB3 Antibody Radio-Conjugate
In February 2022, we entered into a research collaboration agreement with Actinium Pharmaceuticals, Inc., or Actinium, to develop and study a first-in-class antibody radio-conjugate, or ARC,
targeting ErbB3, also known as HER3. Actinium plans to utilize its Antibody Warhead Enabling, or AWE, technology platform to conjugate AVEO’s ErbB3 targeted antibody with the potent alpha-
emitting radioisotope Actinium-225, or Ac-225, to form a novel Ac-225 ErbB3 targeted radiotherapy.
AV-353
AV-353 is a preclinical selective and potent IgG1 monoclonal antibody that targets the Notch 3 pathway. The Notch 3 pathway is important in cell-to-cell communication involving gene
regulation mechanisms that control multiple cell differentiation processes during the entire life cycle. Scientific literature has implicated the Notch 3 receptor pathway in multiple diseases, including
cancer, cardiovascular diseases, such as pulmonary arterial hypertension, and neurodegenerative conditions. We are exploring AV-353 as a potential oncology treatment. AV-353 is being studied by
our collaborators at the Mayo Clinic in preclinical studies of triple negative breast cancer.
Competition
The biotechnology and pharmaceutical industries are highly competitive. Our future success depends on our ability to maintain a competitive advantage with respect to our product candidates.
Our core competitors include pharmaceutical and biotech organizations, as well as academic research institutions, clinical research laboratories and government agencies that are pursuing
research activities in the same therapeutic areas as us. Many of our competitors have greater financial, technical and human resources than we do. Additionally, many competitors have greater
experience in oncology commercialization, product discovery and development and obtaining FDA and other regulatory approvals, which may provide them with a competitive advantage.
We believe that our ability to compete will depend on our ability to execute on the following objectives:
•
commercialize products that provide certain advantages over other products in the market in terms of, among other things, safety, efficacy and/or convenience;
•
obtain favorable reimbursement, formulary and guideline status;
•
design and develop products that are superior to other products in the market in terms of, among other things, safety, efficacy and/or convenience;
•
obtain patent and/or other proprietary protection for our processes and product candidates;
•
obtain required regulatory approvals; and
•
collaborate with others in the design, development and commercialization of our products and product candidates.
Established competitors may invest heavily to discover and develop novel compounds that could make our product or our product candidates obsolete. In addition, any new product that
competes with an approved product must demonstrate compelling advantages in efficacy, convenience, tolerability and/or safety in order to obtain approval, to overcome price competition and to be
commercially successful. If we are not able to compete effectively, our business will not grow and our financial condition and operations will suffer.
Tivozanib
The competitive landscape and treatment regimens for RCC and HCC continue to rapidly evolve, particularly given the entrance of ICI combination therapies as well as other novel targets.
The utilization of such regimens may affect sequencing of certain drugs and combinations across different lines of therapy. As such, it is difficult to predict how these developments will impact the
tivozanib competitive landscape in RCC in the future.
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To date, we believe the key competitors for FOTIVDA in relapsed or refractory advanced RCC include the following FDA-approved treatments: Cabometyx (cabozantinib), marketed by
Exelixis, Inc.; Afinitor (everolimus), marketed by Novartis International Pharmaceutical, Ltd., or Novartis; Inlyta (axitinib), marketed by Pfizer Inc.; Opdivo (nivolumab), marketed by BMS, all as
single-agent therapies; along with the combination of Lenvima (lenvatinib), marketed by Eisai Co., Ltd. and Novartis’ Afinitor (everolimus).
The kidney cancer market is very competitive with multiple mechanisms and combinations evolving at a rapid rate. However, we believe we are differentiated among competitors based on
FOTIVDA's product properties and our clinical data set which positions us well in the relapsed or refractory advanced RCC market and supports our belief that FOTIVDA could become a standard of
care in the United States in the third and fourth line relapsed or refractory advanced RCC setting. We are seeking to leverage tivozanib's differentiated product profile in combination with
immunotherapy ICIs and other emerging targets, such as HIF2α, to further our market opportunities in RCC and other indications.
Ficlatuzumab
We believe the products that currently compete with ficlatuzumab are primarily those that are approved and in development that target the HGF/cMET pathway. In particular, we are focused
on targeting the HGF/CMET pathway in the HNSCC setting. To our knowledge, we are the only HNSCC therapy that targets the HGF/CMET pathway focused exclusively on the HPV negative
HNSCC population.
AV-380
We believe the products that currently compete with our AV-380 program are primarily those that target the GDF15/GDNF Family Receptor Alpha Like, or GFRAL, pathway. A number of
agents with unique mechanisms of action are in various stages of clinical development in cancer cachexia or wasting syndrome. We believe the key competitors for our AV-380 program are other
companies pursuing the GDF15/GFRAL pathway for cancer cachexia and/or as an anti-cancer therapeutic, including NGM Biopharmaceuticals Inc., Pfizer and CatalYm GmbH’s clinical GDF15
program.
AV-203
We believe the products that currently compete with our AV-203 program are monoclonal antibodies that specifically target the ErbB3 receptor. The clinical stage agents that are known to
target ErbB3 receptors include Daiichi Sankyo, Inc.’s and Amgen Inc.’s patritumab (AMG-888), Elevation Oncology’s seribantumab, Merus N.V.’s MCLA-128, AstraZeneca’s sapitinib, Celldex
Therapeutics Inc.’s CDX-3379, Sihuan Pharmaceutical Holdings Group Ltd.’s pirotinib and Roche’s duligotuzumab.
AV-353
Currently, we are not aware of any ongoing clinical trials of Notch 3-specific inhibitors, nor any approved Notch 3-specific inhibitors in oncology; however, a number of agents for applications
in oncology are being explored that target the Notch 3 receptor and may inhibit other Notch receptors.
Collaboration Agreements
We have established collaborations with leading pharmaceutical companies for the further development of tivozanib and ficlatuzumab. As part of our corporate strategy, our collaborations
advance life-cycle development for FOTIVDA (tivozanib) to support its potential utility in immuno-oncology and other combinations in RCC and other indications. We expect to continue to leverage
our existing and enter into new strategic collaborations and partnerships that can contribute to our ability to efficiently develop our product candidates to provide a better life for patients with cancer.
Tivozanib
BMS
In January 2021, we entered into a clinical trial collaboration and supply agreement, or the BMS Agreement, with BMS. Under the terms of the BMS Agreement, BMS is supplying
OPDIVO® (nivolumab), its anti-PD-1 therapy, for the TiNivo-2 trial with FOTIVDA® (tivozanib) in RCC patients who have progressed following one or two lines of prior immunotherapy, one of
which must include an ICI. Pursuant to the terms of the BMS Agreement, BMS granted us a non-exclusive, worldwide (other than within certain territories specified therein), non-transferable,
royalty-free license under certain BMS patent rights, technology and regulatory documentation to use nivolumab in research and development, solely to the extent necessary to conduct the TiNivo-2
trial. Additionally, BMS granted us a non-exclusive, worldwide (other than
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within certain territories specified therein), non-transferable, irrevocable, royalty-free license under certain patent rights, technology and regulatory documentation, to seek regulatory approval of
tivozanib for use in a combined therapy in the field, and, upon any such regulatory approval, to market and promote tivozanib solely for use in a combined therapy in the field in any manner that is
consistent with the regulatory approval for tivozanib. Finally, BMS granted us a non-exclusive, worldwide (other than within certain territories specified therein), non-transferable, irrevocable,
royalty-free license in the field under certain inventions and patent rights relating to nivolumab for all purposes in the field except to research, develop, make, have made, use, sell offer for sale,
export or import nivolumab or any biosimilar version. We and BMS shall jointly own all inventions, or the Combined Therapy Inventions, and patent rights, or the Combined Therapy Patent Rights,
relating to the combined therapy used in the TiNivo-2 trial. We and BMS each may freely exploit the Combined Therapy Inventions and Combined Therapy Patent Rights, and the parties will share
equally in costs relating to maintaining and prosecuting the Combined Therapy Patent Rights.
Pursuant to the terms of the BMS Agreement, each party is responsible for expenses relating to the manufacturing and supply of its respective products. For expenses related to conduct of
the TiNivo-2 trial: (i) we will be responsible for all out-of-pocket costs associated with the performance of the TiNivo-2 trial, and (ii) each party will be responsible for its own internal costs
associated with the TiNivo-2 trial. If the conduct of the TiNivo-2 trial requires a third-party license payment, then the party required to make such payment shall be determined in accordance with the
prior sentence.
The term of the BMS Agreement will continue, unless earlier terminated in accordance with the BMS Agreement, until completion of the TiNivo-2 trial by all centers participating in the
TiNivo-2 trial, delivery of all study data, including all completed case report forms, all final analyses and all final clinical study reports contemplated by the TiNivo-2 trial to both parties, and the
completion of any statistical analyses and bioanalyses contemplated by the protocol or otherwise agreed to by the Parties to be conducted under the BMS Agreement.
AstraZeneca
In December 2018, we entered into a clinical supply agreement, the AstraZeneca Agreement, with a wholly owned subsidiary of AstraZeneca to evaluate the safety and efficacy of
AstraZeneca’s IMFINZI (durvalumab), a human monoclonal antibody directed against PD-L1, in combination with tivozanib, in the DEDUCTIVE trial to treat HCC. Under the terms of the clinical
supply agreement, we are the study sponsor and each party contributes the clinical supply of its study drug. Key decisions are made by both parties by consensus and external study costs are
otherwise shared equally.
Ficlatuzumab
Biodesix
In April 2014, we entered into a worldwide co-development and collaboration agreement, or the Biodesix Agreement, with Biodesix to develop and commercialize ficlatuzumab. Under the
terms of the Biodesix Agreement, each party contributed 50% of all clinical, regulatory, manufacturing and other costs to develop ficlatuzumab and to share equally in any future revenue and
development or commercialization. Under the Biodesix Agreement, prior to the first commercial sale of ficlatuzumab, each party had the right to elect to discontinue its funding obligation for further
development or commercialization efforts with respect to ficlatuzumab in exchange for reduced economics in the program, which is referred to as an “Opt-Out.” In September 2020, Biodesix
exercised its "Opt-Out" rights under the Biodesix Agreement and, in December 2020, we regained full global rights to ficlatuzumab.
Pursuant to the terms of the Biodesix Agreement, as a result of Biodesix’s election to Opt-Out, Biodesix will (i) continue to be responsible for reimbursement of development costs with
respect to the ongoing phase 2 investigator-sponsored clinical trial of ficlatuzumab in combination with ERBITUX® (cetuximab) in HNSCC, or the Phase 2 HNSCC Trial, (ii) cease to be entitled to
50% sharing of profits resulting from commercialization of ficlatuzumab, (iii) be entitled to a low double digit royalty on future product sales and 25% of future licensing revenue (excluding
contributions to research and development expenses), less approximately $2.5 million that Biodesix would be required to pay to us pursuant to the October 2016 amendment to the Biodesix
Agreement and (iv) remain responsible for development obligations under the Biodesix Agreement with respect to VeriStrat®.
We and Biodesix also remain obligated to negotiate a commercialization agreement to delineate our respective rights and obligations in the event of any commercialization of VeriStrat® with
ficlatuzumab. As a result of Biodesix’s decision to Opt-Out, we now have worldwide licensing rights and sole decision-making authority with respect to further development and commercialization
of ficlatuzumab. The payment obligations between the parties under the Biodesix Agreement are in effect until completion of the Phase 2 HNSCC Trial.
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License Agreements
As part of our corporate strategy, we have entered into license agreements to develop the programs in our portfolio and commercialize FOTIVDA in the EUSA territory. Under each of our
license agreements, we are entitled to receive or required to pay upfront, milestone payments and/or royalties.
Tivozanib
Kyowa Kirin Co.
In December 2006, we entered into a license agreement with KKC, or the KKC Agreement, under which we obtained an exclusive, sublicensable license to develop, manufacture and
commercialize tivozanib in all territories in the world except for Asia and the Middle East, where KKC retained the rights to tivozanib. Under the KKC Agreement, we obtained exclusive rights to
tivozanib in our territory under certain KKC patents, patent applications and know-how for the diagnosis, prevention and treatment of all human diseases and conditions. In August 2019, we entered
into an amendment to the KKC Agreement pursuant to which KKC repurchased the non-oncology rights to tivozanib in our territory, excluding the rights we have sublicensed to EUSA under the
EUSA Agreement. We have upfront, milestone and royalty payment obligations to KKC under the KKC Agreement, and following the amendment, KKC also has upfront, milestone and royalty
payment obligations to us related to non-oncology development by KKC in our territory. Pursuant to the amendment to the KKC Agreement, KKC was required to make a non-refundable upfront
payment to us in the amount of $25.0 million that we received in September 2019 and KKC waived a one-time milestone payment of $18.0 million otherwise payable by us in March 2021 upon our
obtaining marketing approval for tivozanib in the United States.
If we sublicense any of our rights to tivozanib to a third-party, as we have done with EUSA pursuant to the EUSA Agreement, we are required to pay KKC a fixed 30% of the amounts we
receive from our sublicensees, including upfront license fees, milestone payments and royalties, but excluding amounts we receive in respect of research and development reimbursement payments or
equity investments, subject to certain limitations.
Certain research and development reimbursement payments by EUSA are not subject to sublicense revenue payments to KKC. For example, if EUSA elects to opt-in to the TIVO-3 trial, the
additional research and development reimbursement payment from EUSA of 50% of the total trial costs, up to $20.0 million, would also not be subject to a sublicense revenue payment to KKC,
subject to certain limitations. We would, however, owe KKC 30% of other, non-research and development payments we may receive from EUSA pursuant to the EUSA Agreement, including
reimbursement approvals for RCC in up to five specified EU countries, marketing approvals for RCC in three specified non-EU licensed territories, EU marketing approval filings and corresponding
marketing approvals by the EMA for up to three additional indications beyond RCC, and sales-based milestones and royalties. The $2.0 million milestone payments we earned in each of February
2018, November 2018 and February 2019 upon EUSA’s reimbursement approval for FOTIVDA as a first-line treatment for RCC in the United Kingdom, Germany and Spain, respectively, were
subject to the 30% KKC sublicense fee, or $0.6 million each.
We are also required to pay tiered royalty payments on net sales we make of FOTIVDA in our North American territory, which range from the low to mid-teens as a percentage of net sales.
The royalty rate escalates within this range based on increasing FOTIVDA sales. Our royalty payment obligations in a particular country in our territory begin on the date of the first commercial sale
of FOTIVDA in that country, and end on the later of 12 years after the date of the first commercial sale of FOTIVDA in that country or the date of the last to expire of the patents covering tivozanib
that have been issued in that country.
Pursuant to the amendment to the KKC Agreement, KKC is also required to make milestone payments to us of up to an aggregate of $390.7 million upon the successful achievement of certain
development and sales milestones of tivozanib in non-oncology indications. In August 2020, KKC paid us a $2.8 million development milestone upon acceptance by the Pharmaceuticals and Medical
Devices Agency of Japan of KKC’s IND for a non-oncology formulation of tivozanib. In September 2020, KKC initiated clinical development of KHK4951, the reformulated tivozanib, in healthy
volunteers and patients with Wet AMD.
In addition, KKC is required to make tiered royalty payments to us on net sales of tivozanib in non-oncology indications in our territory, which range from high single digit to low double digits
as a percentage of net sales. The royalty rate escalates within this range based on increasing tivozanib sales, subject to certain adjustments. KKC’s royalty payment obligations in a particular country
in our territory begin on the date of the first commercial sale of tivozanib in that country, and end on the later of the expiration date of the last valid claim of a patent application or patent owned by
KKC covering tivozanib or 10 years after the date of the first commercial sale of tivozanib in non-oncology indications in that country.
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If KKC sublicenses any of its non-oncology rights to tivozanib to a third-party, KKC is required to pay us a percentage of amounts received from the respective sublicensees related to our
territory, including upfront license fees, milestone payments and royalties, but excluding amounts received in respect of research and development reimbursement payments or equity investments,
subject to certain limitations.
We and KKC each have access to and can benefit from the other party’s clinical data and regulatory filings with respect to tivozanib and biomarkers identified in the conduct of activities under
the KKC Agreement, as related to oncology development. Under the KKC Agreement, we are obligated to use commercially reasonable efforts to develop and commercialize tivozanib in our
territory.
The KKC Agreement will remain in effect until the expiration of all of our royalty and sublicense revenue obligations, determined on a product-by-product and country-by-country basis,
unless terminated earlier. If we fail to meet our obligations under the KKC Agreement and are unable to cure such failure within specified time periods, KKC can terminate the KKC Agreement,
resulting in a loss of our rights to tivozanib and an obligation to assign or license to KKC any intellectual property or other rights we may have in tivozanib, including our regulatory filings,
regulatory approvals, patents and trademarks for tivozanib.
EUSA
In December 2015, we entered into the EUSA Agreement under which we granted to EUSA the exclusive, sublicensable right to develop, manufacture and commercialize tivozanib in the
territories of Europe (excluding Russia, Ukraine and the Commonwealth of Independent States), Latin America (excluding Mexico), Africa and Australasia for all diseases and conditions in humans,
excluding non-oncologic diseases or conditions of the eye. EUSA is obligated to use commercially reasonable efforts to seek regulatory approval for and commercialize tivozanib throughout its
licensed territories for RCC. EUSA has responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of tivozanib in its
licensed territories. In December 2021, EUSA announced that it had signed an agreement with Recordati, S.p.A. to be acquired and has indicated that the acquisition is anticipated to close in the first
half of 2022.
We are also eligible to receive a research and development reimbursement payment from EUSA of $20 million of our total TIVO-3 trial costs if EUSA chooses to opt-in to use the TIVO-3
dataset to seek an expanded RCC indication in the EU, or for other regulatory or commercialization purposes. The leadership of EUSA has informed us that it is interested in exercising its opt-in right
with respect to our TIVO-3 data and seeking an expanded label under the EUSA Agreement, but has requested we delay the negotiations regarding the structuring of this payment stream until the
acquisition by Recordati, S.p.A. closes. We cannot be certain that we will arrive at mutually acceptable terms, or that EUSA will ultimately exercise the opt-in.
We are entitled to receive milestone payments of $2.0 million per country upon reimbursement approval, if any, for RCC in each of countries in the EU5 and, to date, we have received
payments upon reimbursement approval for RCC in the UK (February 2018), Germany (November 2018) and Spain (February 2019). We are also entitled to receive $2.0 million for the grant of
marketing approval for RCC, if any, in three of the licensed countries outside of the EU, as mutually agreed by the parties, the first two of which were obtained in New Zealand in July 2019 and in
South Africa in September 2020.
We are also eligible to receive a payment of $2.0 million per indication in connection with a filing by EUSA with the EMA for marketing approval, if any, for tivozanib for the treatment of
each of up to three additional indications and $5.0 million per indication in connection with the EMA’s grant of marketing approval for each of up to three additional indications, as well as up to
$335.0 million upon EUSA’s achievement of certain sales thresholds. Upon commercialization, we are eligible to receive tiered double digit royalties on net sales, if any, of licensed products in its
licensed territories ranging from a low double digit up to mid-twenty percent depending on the level of annual net sales. In November 2017, we began earning sales royalties upon EUSA’s
commencement of the first commercial launch of FOTIVDA (tivozanib) with the initiation of product sales in Germany. EUSA has received reimbursement approval for and commercially launched
FOTIVDA in Germany, the United Kingdom, and Spain as well as in additional non-EU5 countries.
The research and development reimbursement payments under the EUSA Agreement are not subject to the 30% sublicensing payment payable to KKC, subject to certain limitations. We
would, however, owe KKC 30% of other, non-research and development payments we may receive from EUSA pursuant to the EUSA Agreement, including any reimbursement approvals for RCC in
the EU5, marketing approvals for RCC in three specified non-EU licensed territories, EU marketing approval filings and corresponding marketing approvals by the EMA for up to three additional
indications beyond RCC, and sales-based milestones and royalties, as set forth above. The $2.0 million milestone payments we earned in each of February 2018, November 2018 and February 2019
upon EUSA’s reimbursement approval for FOTIVDA in the United Kingdom, Germany and Spain, respectively, were subject to the 30% KKC sublicense fee, or $0.6 million, each.
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The term of the EUSA Agreement continues on a product-by-product and country-by-country basis until the last to occur of (a) the expiration of the last valid patent claim for such product in
such country, (b) the expiration of market or regulatory data exclusivity for such product in such country or (c) the tenth anniversary of the effective date. Either party may terminate the EUSA
Agreement in the event of the bankruptcy of the other party or a material breach by the other party that remains uncured, following receipt of written notice of such breach, for a period of (a) thirty
(30) days in the case of breach for nonpayment of any amount due under the EUSA Agreement, and (b) ninety (90) days in the case of any other material breach. EUSA may terminate the EUSA
Agreement at any time upon one hundred eighty (180) days’ prior written notice. In addition, we may terminate the EUSA Agreement upon thirty (30) days’ prior written notice if EUSA challenges
any of the patent rights licensed under the EUSA Agreement. EUSA has reported to us that, to date, it has not experienced any material decrease in sales trends or interruptions in supply or
distribution of FOTIVDA during the COVID-19 pandemic; however, the future impact of the COVID-19 pandemic on FOTIVDA sales is difficult to predict.
AV-380
St. Vincent’s Hospital
In July 2012, we entered into a license agreement with St. Vincent’s, or the St. Vincent’s Agreement, under which we obtained an exclusive, worldwide sublicensable right to develop,
manufacture and commercialize products for therapeutic applications that benefit from inhibition or decreased expression or activity of MIC-1, which is also known as GDF15. Under the St.
Vincent’s Agreement, we have non-exclusive rights to certain related diagnostic products and research tools and also have a right of first negotiation to obtain an exclusive license to certain
improvements that St. Vincent’s or third parties may make to licensed therapeutic products. We are obligated to use diligent efforts to conduct research and clinical development and commercially
launch at least one licensed therapeutic product.
As of December 31, 2021, we are required to make future milestone payments, up to an aggregate total of $14.4 million, upon the earlier of the achievement of specified development and
regulatory milestones or a specified date for the first indication, and upon the achievement of specified development and regulatory milestones for the second and third indications, for licensed
therapeutic products, some of which payments may be increased by a mid to high double digit percentage rate for milestone payments made after we grant any sublicense, depending on the
sublicensed territory. In February 2022, the Company paid a $2.3 million time-based milestone obligation that became due to St. Vincent’s in January 2022.
The St. Vincent’s Agreement remains in effect until the later of 10 years after the date of first commercial sale of licensed therapeutic products in the last country in which a commercial sale is
made, or expiration of the last-to-expire valid claim of the licensed patents, unless we elect, or St. Vincent’s elects, to terminate the St. Vincent’s Agreement earlier. We have the right to terminate the
St. Vincent’s Agreement on six months’ notice if we terminate our GDF15 research and development programs as a result of the failure of a licensed therapeutic product in preclinical or clinical
development, or if we form the reasonable view that further GDF15 research and development is not commercially viable, and we are not then in breach of any of our obligations under the St.
Vincent’s Agreement.
AV-203
CANbridge
In March 2016, we entered into the CANbridge Agreement under which we granted CANbridge the exclusive right to develop, manufacture and commercialize AV-203, a potent humanized
IgG1 monoclonal antibody that targets ErbB3 (also known as HER3), for the diagnosis, treatment and prevention of disease in all countries outside of North America. In December 2017, CANbridge
filed an IND application with the National Medical Products Administration (formerly, the China Food and Drug Administration), or NMPA, for a clinical study of AV-203 in esophageal squamous
cell carcinoma, or ESCC. In August 2018, CANbridge obtained regulatory approval of its IND application from the NMPA for a clinical study of AV-203 in ESCC. In March 2021, CANbridge
exercised its right to terminate the CANbridge Agreement for convenience. Under the terms of the CANbridge Agreement, the transfer of the AV-203 program was completed in September 2021 and
we regained worldwide rights to the AV-203 program. As part of the transfer, CANbridge transferred to us all of its know-how in the development of AV-203 as well as any remaining manufacturing
material. We expect to reactivate the IND in the second quarter of 2022.
A percentage of any milestone and royalty payments received by us under future partnership agreements related to the AV-203 program, excluding upfront and reimbursement payments, are
due to Biogen Idec International GmbH, or Biogen, as a sublicensing fee under our option and license agreement with Biogen dated March 18, 2009, as amended.
Biogen Idec International GmbH
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In March 2009, we entered into an exclusive option and license agreement with Biogen regarding the development and commercialization of our discovery-stage ErbB3-targeted antibodies,
including AV-203, for the potential treatment and diagnosis of cancer and other diseases outside of North America, or the Biogen Agreement. Under the Biogen Agreement, we are responsible for
developing ErbB3 antibodies through completion of the first Phase 2 clinical trial designed in a manner that, if successful, would generate data sufficient to support advancement to a Phase 3 clinical
trial.
In March 2014, we and Biogen amended the Biogen Agreement, or the Biogen Amendment. Pursuant to the Biogen Amendment, Biogen agreed to the termination of its rights and
obligations under the Biogen Agreement, including Biogen’s option to (i) obtain a co-exclusive (with us) worldwide license to develop and manufacture ErbB3 targeted antibodies and (ii) obtain
exclusive commercialization rights to ErbB3 products in countries in the world other than North America. As a result, we have worldwide rights to AV-203. Pursuant to the Biogen Amendment, we
are obligated to use reasonable efforts to seek a collaboration partner for the purpose of funding further development and commercialization of ErbB3 targeted antibodies. We are also obligated to pay
Biogen a percentage of milestone payments received by us from future partnerships after March 28, 2016 and single digit royalty payments on net sales related to the sale of ErbB3 products, if any,
up to a cumulative maximum amount of $50.0 million.
Intellectual Property Rights
Patent Rights
We continue to build a strong intellectual property portfolio, and, whenever possible, we seek to have multiple tiers of patent protection for our product candidates.
The term of individual patents depends upon the legal term of the patents in the countries in which they are obtained. In most countries in which we file, the patent term is 20 years from the
earliest date of filing a non-provisional patent application. In the United States, a patent’s term may be lengthened by patent term adjustment, which compensates a patentee for administrative delays
by the U.S. Patent and Trademark Office in granting a patent. A U.S. patent term may be shortened, if a patent is terminally disclaimed by its owner, over another patent.
The patent term of a patent that covers an FDA-approved drug may also be eligible for a patent term extension, which permits patent term restoration as compensation for the patent term lost
during the FDA regulatory review process. The Drug Price Competition and Patent Term Restoration Act of 1984, or the Hatch-Waxman Act, permits a patent term extension of up to five years
beyond the expiration of the patent. The length of the patent term extension is related to the length of time the drug is under regulatory review. Patent term extensions cannot extend the remaining
term of a patent beyond a total of 14 years from the date of product approval, and only one patent applicable to an approved drug may be extended. Similar provisions are available in Europe and
other foreign jurisdictions to extend the term of a patent that covers an approved drug. We have applied for patent term extensions on patents covering tivozanib and expect to apply for patent term
extension on patents covering any of our product candidates that may obtain FDA approval in the future.
We rely on, and in the future expect to rely on, a combination of both patent protection and regulatory exclusivities to protect our approved products from generic or biosimilar competition.
With the exception of pediatric exclusivities (a regulatory exclusivity), patent and regulatory exclusivities typically run concurrently with one another. Patents covering our approved products and
product candidates are discussed below. Regulatory exclusivities relating to our approved products are discussed in the following section entitled “Government Regulation and Product Approval –
Generic Drugs.”
Tivozanib
With respect to tivozanib, we have exclusively licensed from KKC its patents that cover the molecule and its therapeutic use for the diagnosis, prevention and treatment of any and all
oncologic diseases and conditions in humans and a crystal form of the molecule. As discussed in “—Strategic Partnerships—Tivozanib–Kyowa Kirin Co. (KKC)” above, pursuant to the amendment
to the KKC Agreement in August 2019, KKC repurchased the non-oncology rights of tivozanib in our licensed territories, excluding the rights which are currently sublicensed to EUSA.
With respect to tivozanib, we have the following in-licensed patents:
•
U.S.: 2 granted patents expiring in 2023
•
Europe: 2 granted patents with expirations ranging from 2022 to 2023
•
Canada: 1 granted patent expiring in 2022
•
Australia: 1 granted patent expiring in 2022
With respect to the U.S. patents, the first patent covers the tivozanib molecule and its therapeutic use and was originally scheduled to expire in April 2022. On January 22, 2022, the United
States Patent and Trademark Office granted a one-year interim patent term extension of this patent until April 2023. If our application for patent term extension is granted, this one year interim
extension will be included in the maximum patent term extension granted for this patent. The second patent covers a crystalline form of tivozanib that is the active pharmaceutical ingredient in our
tivozanib product
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candidate and is expected to expire in November 2023. In view of the length of time that tivozanib has been under regulatory review at the FDA, a patent term extension of up to five years may be
available under the Hatch-Waxman Act. Although we have applied for patent term extensions on each patent, only one patent may be extended, and, when appropriate, we will have to elect which
patent is to be extended. If a five year term extension were to be granted, if applied to the first patent, the term could be extended to April 2027, and if applied to the second patent, the term could be
extended to November 2028.
With respect to the European patents, Supplementary Protection Certificates, or SPCs, have been granted for the European patent covering the tivozanib molecule in Belgium, Finland,
France, Germany, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden, and the United Kingdom extending the term of the patents in each of these countries up to April 2027. An SPC
application is pending in Denmark for the corresponding Danish patent that covers the tivozanib molecule, which, if granted, could extend the term of the patent up to 2027. An SPC has been granted
for the patent covering the crystalline form of tivozanib in Ireland extending the term of that patent to October 2028.
Additionally, we have filed patent applications in the United States and other jurisdictions including Australia, Canada and Europe directed to our clinical protocol for using tivozanib to treat
refractory cancers, including, following therapy with checkpoint inhibitors, which, if granted, would each expire in 2039.
Ficlatuzumab
With respect to our anti-HGF platform, including ficlatuzumab, we have six U.S. patents covering our anti-HGF antibodies, nucleic acids and expression vectors encoding the antibodies,
host cells, methods of making the antibodies, and methods of treatment using the antibodies. In addition, we have filed an international (PCT) application directed to treating head and neck squamous
cell carcinoma (HNSCC) with ficlatuzumab. If nationalized, we expect that a patent granted on a patent application in this family would expire in 2041. With respect to our anti-HGF platform we
have:
•
U.S.: 6 granted patents with expirations ranging from 2027 to 2028
•
Europe: 1 granted patent expiring in 2027
•
Japan: 2 granted patents expiring in 2027
•
Canada: 1 granted patent expiring in 2027
•
Australia: 1 granted patent expiring in 2027
•
PCT: 1 pending PCT application, which if nationalized and granted would expire in 2041
AV-380 Platform
With respect to our anti-GDF15 platform, including AV-380, we have exclusively licensed certain patent rights from St. Vincent’s, which include a granted U.S. patent directed to a method
of increasing appetite and/or body weight upon administering an effective amount of an anti-GDF15 antibody, which is expected to expire in 2029.
With respect to the licensed patent rights, we have:
•
U.S.: 1 granted patent, and 1 pending patent application, if granted, with expirations ranging from 2025 to 2029
•
Europe: 2 granted patents expiring in 2025
•
Japan: 2 granted patents expiring in 2025
•
Canada: 1 granted patent expiring in 2025
•
Australia: 1 granted patent expiring in 2025
Additionally, we own three issued U.S. patents and a pending U.S. patent application covering our anti-GDF15 antibodies and methods of treating cachexia and inhibiting loss of muscle
mass associated with cachexia using our anti-GDF15 antibodies. These patents and patent application, if granted, would be expected to expire in 2033.
We also have three pending U.S. patent applications directed to methods of treating or preventing congestive heart failure or chronic kidney disease using an anti-GDF15 antibody, and
methods of treating a subject with cancer anorexia-cachexia syndrome with an anti-cancer agent and an anti-GDF15 antibody. These patent applications, if granted, would be expected to expire in
2035.
With respect to our anti-GDF15 platform, we have:
•
U.S.: 3 granted patents, and 4 pending patent applications, if granted, with expirations ranging from 2033 to 2035
•
Europe: 4 granted patents, and 4 pending patent applications, if granted, with expirations ranging from 2033 to 2035; one of the granted patents has been opposed in the European
Patent Office
•
Japan: 3 granted patents, and 2 pending patent applications, if granted, with expirations ranging from 2033 to 2035
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•
Canada: 2 pending patent applications, if granted, with expirations ranging from 2033 to 2035
•
Australia: 2 granted patents, and 1 pending patent application, if granted, with expirations ranging from 2033 to 2035
AV-203 Platform
With respect to our anti-ErbB3 platform, including AV-203, we have five issued U.S. patents and one pending U.S. patent application covering our anti-ErbB3 antibodies, nucleic acids and
expression vectors encoding the antibodies, host cells, methods of making the antibodies and methods of treatment using our anti-ErbB3 antibodies, which are expected to expire from 2031 to 2032.
With respect to our anti-ErbB3 platform we have:
•
U.S.: 5 granted patents, and 1 pending patent application, if granted, with expirations ranging from 2031 to 2032
•
Europe: 2 granted patents, and 1 pending patent application, if granted, with expirations ranging from 2031 to 2032
•
Japan: 3 granted patents with expirations ranging from 2031 to 2032
•
Canada: 1 granted patent expiring in 2031
•
Australia: 3 granted patents with expirations ranging from 2031 to 2032
AV-353 Platform
With respect to our AV-353 platform, we own three issued U.S. patents and two pending U.S. patent applications covering our anti-Notch3 antibodies, nucleic acids and expression vectors
encoding the antibodies, host cells, methods of making the antibodies and methods of treatment using the antibodies. The three issued U.S. patents and the two non-provisional U.S. patent
applications, if granted, would be expected to have expirations ranging from 2033 to 2037.
With respect to our AV-353 platform, we have:
•
U.S.: 3 granted patents with expirations ranging from 2033 to 2037, and 2 pending patent applications, if granted, with expirations ranging from 2033 to 2037
•
Europe: 1 granted patent expiring in 2033, and 1 pending patent application, if granted, expiring in 2037
Many pharmaceutical companies, biotechnology companies and academic institutions are competing with us in the field of oncology and filing patent applications potentially relevant to our
business. With regard to ficlatuzumab, we are aware of one United States patent and its foreign counterparts that contain broad claims related to anti-HGF antibodies having certain binding properties
and their use. In the event that the owner of these patents were to bring an infringement action against us, we may have to argue that our product, its manufacture or use does not infringe a valid claim
of the patent in question. Furthermore, if we were to challenge the validity of any issued United States patent in court, we would need to overcome a statutory presumption of validity that attaches to
every United States patent. This means that in, order to prevail, we would have to present clear and convincing evidence as to the invalidity of the patent’s claims. There is no assurance that a court
would find in our favor on questions of infringement or validity.
Over the years, we have found it necessary or prudent to obtain licenses from third-party intellectual property holders. Where licenses are readily available at reasonable cost, such licenses are
considered a normal cost of doing business. In other instances, however, we may have used the results of freedom-to-operate studies to guide our research away from areas where we believed we
were likely to encounter obstacles in the form of third-party intellectual property. For example, where a third-party holds relevant intellectual property and is a direct competitor, a license might not be
available on commercially reasonable terms or available at all.
In spite of our efforts to avoid obstacles and disruptions arising from third-party intellectual property, it is impossible to establish with certainty that our technology platform or our product
programs will be free of claims by third-party intellectual property holders. Even with modern databases and on-line search engines, literature searches are imperfect and may fail to identify relevant
patents and published applications. Even when a third-party patent is identified, we may conclude upon a thorough analysis, that we do not infringe the patent or that the patent is invalid. If the third-
party patent owner disagrees with our conclusion and we continue with the business activity in question, patent litigation may be initiated against us. Alternatively, we might decide to initiate
litigation in an attempt to have a court declare the third-party patent invalid or non-infringed by our activity. In either scenario, patent litigation typically is costly and time-consuming, and the
outcome is uncertain. The outcome of patent litigation is subject to uncertainties that cannot be quantified in advance, for example, the credibility of expert witnesses who may disagree on technical
interpretation of scientific data. Ultimately, in the case of an adverse outcome in litigation, we could be prevented from commercializing a product or using certain aspects of our technology platform
as a result of patent infringement claims asserted against us. This could have a material adverse effect on our business.
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To protect our competitive position, it may be necessary to enforce our patent rights through litigation against infringing third parties. Litigation to enforce our own patent rights is subject to
the same uncertainties discussed above. In addition, however, litigation involving our patents carries the risk that one or more of our patents will be held invalid (in whole or in part, on a claim-by-
claim basis) or held unenforceable. Such an adverse court ruling could allow third parties to commercialize our products or our platform technology, and then compete directly with us, without
making any payments to us.
Trademarks
We seek trademark protection in the United States and other jurisdictions where available and when appropriate. We have filed applications and obtained registrations for several trademarks
intended for use in the marketing of tivozanib, including the trademark FOTIVDA, which we have registered in the United States and over 35 other jurisdictions, and for which we have filed
applications in additional countries. We own U.S. and EU registrations for a logo containing FOTIVDA in combination with a flame design. We own U.S. registrations for AVEO and AVEO (in
stylized letters) trademarks that we use in connection with our business in general. We have also registered AVEO as a trademark in over 20 other jurisdictions.
Manufacturing
We or our partners currently contract with and rely on third parties for the manufacture of our commercial product and product candidates and intend to do so in the future for both commercial
and clinical needs. We do not own or operate manufacturing facilities for the production of commercial or clinical quantities of our commercial product or product candidates. We currently have no
plans to build our own commercial scale or clinical manufacturing capabilities. Although we rely on third-party contract manufacturers, we have personnel with extensive manufacturing experience
to oversee the relationships with our contract manufacturers. All manufacturing occurs at facilities that are required to comply with FDA requirements and the requirements of regulatory agencies
from the other jurisdictions where we have obtained approval.
FOTIVDA (tivozanib). One of our contract manufacturers has manufactured what we believe to be sufficient quantities of tivozanib drug product (capsules) to support our ongoing and planned
commercialization and clinical trials. A separate contract manufacturer, using our proprietary manufacturing process, has manufactured what we believe to be sufficient lots of drug substance. This
drug substance may be used to manufacture tivozanib drug product (capsules) for any future commercial and clinical needs.
We engage a separate contract manufacturer to bottle, package, label and serialize commercial supply of FOTIVDA on an as-needed basis and we rely on a separate third-party to distribute
commercial supply of FOTIVDA in the United States.
Ficlatuzumab. Through a separate third-party contract manufacturer, we have initiated the clinical manufacture of ficlatuzumab to supply a potential registrational clinical trial in HNSCC and
to enable additional potential development in pancreatic cancer and AML. However, a shortage of required key raw materials and manufacturing supplies also used in COVID-19 vaccine
manufacturing process has delayed the delivery of the clinical supply of ficlatuzumab. We have secured the key required raw materials and manufacturing supplies and now plan to manufacture
ficlatuzumab Phase 3 clinical supply in the second quarter of 2022.
AV-380. We currently have sufficient clinical trial drug supply for AV-380 to support our planned clinical trials. The same contract manufacturer we engaged to initiate clinical manufacturing
of ficlatuzumab will be manufacturing any future clinical supply needs for AV-380. Our CMO for AV-380 has experienced employee shortages, supply chain issues and disruptions related to the
COVID-19 pandemic which has delayed and may continue to delay manufacturing of AV-380.
Despite the delays to ficlatuzumab and AV-380 manufacturing based on COVID-19 related issues, the COVID-19 pandemic has not had a material impact on our commercial and clinical
supply of FOTIVDA (tivozanib) or our clinical supply of AV-203 to date. We currently have a sufficient supply of FOTIVDA (tivozanib) and AV-203 that we believe will meet our ongoing
commercial and clinical needs for more than twelve months from the date of filing this Annual Report on Form 10-K. While we believe there are alternate manufacturers with the capability to supply
for current clinical or potential future commercial needs, contracting with additional contract manufacturers would require significant lead-times and result in additional costs and is not the solution
we expect to follow.
Government Regulation and Product Approval
Government authorities in the United States, at the federal, state and local level, and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the
research, development, testing, manufacture, quality control, approval, packaging, storage, recordkeeping, labeling, advertising, promotion, distribution, marketing, sales, pricing, reimbursement,
post-approval monitoring and reporting, and import and export of pharmaceutical products.
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The processes for obtaining regulatory approvals in the United States and in foreign countries and jurisdictions, along with subsequent compliance with applicable statutes and regulations and other
regulatory authorities, require the expenditure of substantial time and financial resources.
Review and Approval of Drugs and Biologics in the United States
In the United States, the FDA approves and regulates drugs under the Federal Food, Drug, and Cosmetic Act, or FDCA, and related regulations. Biological products are licensed for marketing
under the Public Health Service Act, or PHSA, and subject to regulation under the FDCA and related regulations.
A company, institution, or organization which takes responsibility for the initiation and management of a clinical development program for such products, and their regulatory approval, is
typically referred to as a sponsor. A sponsor seeking approval to market and distribute a new drug or biological product in the United States must typically complete each of the following steps:
•
completion of preclinical laboratory tests in compliance with the FDA’s good laboratory practice, or GLP, regulations and standards;
•
design of a clinical protocol and submission to the FDA of an IND, which must take effect before human clinical trials may begin;
•
approval by an independent institutional review board, or IRB, representing each clinical site before each clinical trial may be initiated;
•
performance of adequate and well-controlled human clinical trials in accordance with good clinical practices, or GCPs, to establish the safety and efficacy of the proposed drug
product for each proposed indication;
•
submission to the FDA of an NDA for a drug candidate product and a biological licensing application, or BLA, for a biological product requesting marketing for one or more
proposed indications;
•
review of the request for approval by an FDA advisory committee, where appropriate or if applicable;
•
completion of one or more FDA inspections of the manufacturing facility or facilities at which the product, or components thereof, are produced to assess compliance with current
Good Manufacturing Practices, or similar foreign standards, which we refer to as cGMPs,to assure the product’s identity, strength, quality and purity;
•
completion of FDA audits of clinical trial sites to assure compliance with GCPs and the integrity of the clinical data;
•
payment of user fees and securing FDA approval of the NDA or BLA; and
•
compliance with any post-approval requirements, including the potential requirement to implement a Risk Evaluation and Mitigation Strategy, or REMS, and the potential
requirement to conduct post-approval studies.
Preclinical Studies
Before a sponsor begins testing a compound with potential therapeutic value in humans, the product candidate enters the preclinical testing stage. Preclinical studies include laboratory
evaluation of the purity and stability of the manufactured substance or active pharmaceutical ingredient and the formulated product, as well as in vitro and animal studies to assess the safety and
activity of the product candidate for initial testing in humans and to establish a rationale for therapeutic use. The conduct of preclinical studies is subject to federal regulations and requirements,
including GLP regulations and the U.S. Department of Agriculture’s Animal Welfare Act, if applicable. Some long-term preclinical testing, such as animal tests of reproductive adverse events and
carcinogenicity, and long-term toxicity studies, may continue after the IND is submitted.
The IND and IRB Processes
An IND is a request for FDA authorization to administer an investigational product candidate to humans. Such authorization must be secured prior to interstate shipment and administration
of any new drug or biologic that is not the subject of an approved NDA or BLA. In support of a request for an IND, a sponsor must submit a protocol for each clinical trial and any subsequent
protocol amendments must be submitted to the FDA as part of the IND. In addition, the results of the preclinical tests, together with manufacturing information, analytical data, any available clinical
data or literature and plans for clinical trials, among other things, are submitted to the FDA as part of an IND. The FDA requires a 30-day
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waiting period after the filing of each IND before clinical trials may begin. This waiting period is designed to allow the FDA to review the IND to determine whether human research subjects will be
exposed to unreasonable health risks. At any time during this 30-day period, or thereafter, the FDA may raise concerns or questions about the conduct of the trials as outlined in the IND and impose a
clinical hold or partial clinical hold. In this case, the IND sponsor and the FDA must resolve any outstanding concerns before clinical trials can begin.
Following commencement of a clinical trial under an IND, the FDA may also place a clinical hold or partial clinical hold on that trial. Clinical holds are imposed by the FDA whenever there is
concern for patient safety and may be a result of new data, findings, or developments in clinical, nonclinical, and/or chemistry, manufacturing, and controls, or CMC. A clinical hold is an order issued
by the FDA to the sponsor to delay a proposed clinical investigation or to suspend an ongoing investigation. A partial clinical hold is a delay or suspension of only part of the clinical work requested
under the IND. For example, a specific protocol or part of a protocol is not allowed to proceed, while other protocols may do so. No more than 30 days after imposition of a clinical hold or partial
clinical hold, the FDA will provide the sponsor a written explanation of the basis for the hold. Following issuance of a clinical hold or partial clinical hold, an investigation may only resume after the
FDA has notified the sponsor that the investigation may proceed. The FDA will base that determination on information provided by the sponsor correcting the deficiencies previously cited or
otherwise satisfying the FDA that the investigation can proceed.
A sponsor may choose, but is not required, to conduct a foreign clinical study under an IND. When a foreign clinical study is conducted under an IND, all FDA IND requirements must be met
unless waived. When a foreign clinical study is not conducted under an IND, the sponsor must ensure that the study complies with certain regulatory requirements of the FDA in order to use the study
as support for an IND or application for marketing approval. The FDA’s regulations are intended to help ensure the protection of human subjects enrolled in non-IND foreign clinical studies, as well
as the quality and integrity of the resulting data. They further help ensure that non-IND foreign studies are conducted in a manner comparable to that required for IND studies.
In addition to the foregoing IND requirements, an IRB representing each institution participating in the clinical trial must review and approve the plan for any clinical trial before it commences
at that institution, and the IRB must conduct continuing review and reapprove the trial at least annually. The IRB must review and approve, among other things, the trial protocol and informed
consent information to be provided to trial subjects. An IRB must operate in compliance with FDA regulations. An IRB can suspend or terminate approval of a clinical trial at its institution, or an
institution it represents, if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the product candidate has been associated with unexpected serious harm to patients.
Additionally, some trials are overseen by an independent group of qualified experts organized by the trial sponsor, known as a data safety monitoring board, or DSMB, or committee. This
group provides authorization for whether or not a trial may move forward at designated check points based on access that only the group maintains to available data from the trial. Suspension or
termination of development during any phase of clinical trials can occur if it is determined that the participants or patients are being exposed to an unacceptable health risk. Other reasons for
suspension or termination may be made by us based on evolving business objectives and/or competitive climate.
Expanded Access to an Investigational Drug for Treatment Use
Expanded access, sometimes called “compassionate use,” is the use of investigational new drug products outside of clinical trials to treat patients with serious or immediately life-threatening
diseases or conditions when there are no comparable or satisfactory alternative treatment options. FDA regulations allow access to investigational drugs under an IND by the company or the treating
physician for treatment purposes on a case-by-case basis for: individual patients (single-patient IND applications for treatment in emergency settings and non-emergency settings); intermediate-size
patient populations; and larger populations for use of the drug under a treatment protocol or Treatment IND Application.
When considering an IND application for expanded access to an investigational product with the purpose of treating a patient or a group of patients, the sponsor and treating physicians or
investigators will determine suitability when all of the following criteria apply: patient(s) have a serious or immediately life-threatening disease or condition, and there is no comparable or satisfactory
alternative therapy to diagnose, monitor, or treat the disease or condition; the potential patient benefit justifies the potential risks of the treatment and the potential risks are not unreasonable in the
context or condition to be treated; and the expanded use of the investigational drug for the requested treatment will not interfere initiation, conduct, or completion of clinical investigations that could
support marketing approval of the product or otherwise compromise the potential development of the product.
There is no obligation for a sponsor to make its investigational products available for expanded access. However, if a sponsor has a policy regarding how it responds to expanded access
requests with respect to product candidates in development to treat serious diseases or conditions, it must make that policy publicly available. Sponsors are required to
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make such policies publicly available upon the earlier of initiation of a Phase 2 or Phase 3 study for a covered investigational product; or 15 days after the investigational product receives designation
from the FDA as a breakthrough therapy, fast track product, or regenerative medicine advanced therapy.
In addition, on May 30, 2018, the Right to Try Act was signed into law. The law, among other things, provides a federal framework for certain patients to access certain investigational new
drug products that have completed a Phase 1 clinical trial and that are undergoing investigation for FDA approval. Under certain circumstances, eligible patients can seek treatment without enrolling
in clinical trials and without obtaining FDA permission under the FDA expanded access program. There is no obligation for a drug manufacturer to make its drug products available to eligible
patients as a result of the Right to Try Act, but the manufacturer must develop an internal policy and respond to patient requests according to that policy.
Human Clinical Studies in Support of an NDA or BLA
Clinical trials involve the administration of the investigational product to human subjects under the supervision of qualified investigators in accordance with GCP requirements, which
include, among other things, the requirement that all research subjects provide their informed consent in writing before their participation in any clinical trial. Clinical trials are conducted under
written trial protocols detailing, among other things, the inclusion and exclusion criteria, the objectives of the trial, the parameters to be used in monitoring safety and the effectiveness criteria to be
evaluated. The FDA has issued regulations authorizing a sponsor to transfer certain responsibilities for the conduct of a clinical study to a CRO.
The clinical investigation of an investigational drug or biological product is generally divided into four phases. Although the phases are usually conducted sequentially, they may overlap or be
combined. The four phases of an investigation are as follows:
•
Phase 1. Phase 1 studies include the initial introduction of an investigational new drug or biological product into humans. These studies are designed to evaluate the safety, dosage
tolerance, metabolism and pharmacologic actions of the investigational drug or biological product in humans, the side effects associated with increasing doses, and if possible, to
gain early evidence on effectiveness.
•
Phase 2. Phase 2 includes the controlled clinical trials conducted to preliminarily or further evaluate the effectiveness of the investigational drug or biological product for a particular
indication(s) in patients with the disease or condition under trial, to determine dosage tolerance and optimal dosage, and to identify possible adverse side effects and safety risks
associated with the drug or biological product. Phase 2 clinical trials are typically well-controlled, closely monitored and conducted in a limited patient population.
•
Phase 3. Phase 3 clinical trials are generally controlled clinical trials conducted in an expanded patient population generally at geographically dispersed clinical trial sites. They are
performed after preliminary evidence suggesting effectiveness of the drug or biological product has been obtained, and are intended to further evaluate dosage, clinical effectiveness
and safety, to establish the overall benefit-risk relationship of the investigational drug or biological product, and to provide an adequate basis for product approval.
•
Phase 4. Post-approval studies may be conducted after initial marketing approval. These studies are used to gain additional experience from the treatment of patients in the intended
therapeutic indication.
A clinical trial may combine the elements of more than one phase and the FDA often requires more than one Phase 3 trial to support marketing approval of a product candidate. A company’s
designation of a clinical trial as being of a particular phase is not necessarily indicative that the study will be sufficient to satisfy the FDA requirements of that phase because this determination cannot
be made until the protocol and data have been submitted to and reviewed by the FDA. Moreover, as noted above, a pivotal trial is a clinical trial that is believed to satisfy FDA requirements for the
evaluation of a product candidate’s safety and efficacy such that it can be used, alone or with other pivotal or non-pivotal trials, to support regulatory approval. Generally, pivotal trials are Phase 3
trials, but they may be Phase 2 trials if the design provides a well-controlled and reliable assessment of clinical benefit, particularly in an area of unmet medical need.
Further, in August 2018, the FDA released a draft guidance entitled “Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics,”
which outlines how developers can utilize an adaptive trial design commonly referred to as a seamless trial design in early stages of oncology biological product development (i.e., the first-in-human
clinical trial) to compress the traditional three phases of trials into one continuous trial called an expansion cohort trial. Information to support the design of individual expansion cohorts are included
in IND applications and assessed by FDA. Expansion cohort trials can potentially bring efficiency to product development and reduce developmental costs and time.
Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur. In addition, IND safety reports
must be submitted to the FDA for any of the
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following: serious and unexpected suspected adverse reactions; findings from other studies or animal or in vitro testing that suggest a significant risk in humans exposed to the drug; and any clinically
important increase in the case of a serious suspected adverse reaction over that listed in the protocol or investigator brochure. The FDA will typically inspect one or more clinical sites to assure
compliance with GCP and the integrity of the clinical data submitted.
Finally, sponsors of clinical trials are required to register and disclose certain clinical trial information on a public registry (clinicaltrials.gov) maintained by the U.S. National Institutes of
Health, or NIH. In particular, information related to the product, patient population, phase of investigation, study sites and investigators and other aspects of the clinical trial is made public as part of
the registration of the clinical trial. The NIH’s Final Rule on registration and reporting requirements for clinical trials became effective in 2017, and both NIH and the FDA have recently signaled the
government’s willingness to begin enforcing those requirements against non-compliant clinical trial sponsors. The failure to submit clinical trial information to clinicaltrials.gov, as required, is a
prohibited act under the FDCA with violations subject to potential civil monetary penalties of up to $10,000 for each day the violation continues.
Manufacturing and Other Regulatory Requirements
Concurrent with clinical trials, sponsors usually complete additional animal safety studies, develop additional information about the chemistry and physical characteristics of the product
candidate and finalize a process for manufacturing commercial quantities of the product candidate in accordance with cGMP requirements. The manufacturing process must be capable of consistently
producing quality batches of the product candidate and, among other criteria, the sponsor must develop methods for testing the identity, strength, quality, and purity of the finished product.
Additionally, appropriate packaging must be selected and tested, and stability studies must be conducted to demonstrate that the product candidate does not undergo unacceptable deterioration over its
shelf life.
In addition, the FDA’s regulations require that pharmaceutical products be manufactured in specific approved facilities and in accordance with cGMPs. The cGMP regulations include
requirements relating to organization of personnel, buildings and facilities, equipment, control of components and product containers and closures, production and process controls, packaging and
labeling controls, holding and distribution, laboratory controls, records and reports and returned or salvaged products. Manufacturers and other entities involved in the manufacture and distribution of
approved pharmaceuticals are required to register their establishments with the FDA and some state agencies, and they are subject to periodic unannounced inspections by the FDA for compliance
with cGMPs and other requirements. Inspections must follow a “risk-based schedule” that may result in certain establishments being inspected more frequently. Manufacturers may also have to
provide, on request, electronic or physical records regarding their establishments. Delaying, denying, limiting, or refusing inspection by the FDA may lead to a product being deemed to be
adulterated. Changes to the manufacturing process, specifications or container closure system for an approved product are strictly regulated and often require prior FDA approval before being
implemented. The FDA’s regulations also require, among other things, the investigation and correction of any deviations from cGMP and the imposition of reporting and documentation requirements
upon the sponsor and any third-party manufacturers involved in producing the approved product.
Pediatric Studies
Under the Pediatric Research Equity Act, or PREA, applications and certain types of supplements to applications must contain data that are adequate to assess the safety and effectiveness of
the product for the claimed indications in all relevant pediatric subpopulations, and to support dosing and administration for each pediatric subpopulation for which the product is safe and effective.
The sponsor must submit an initial Pediatric Study Plan, or PSP, within 60 days of an end-of-Phase 2 meeting or as may be agreed between the sponsor and the FDA. Those plans must contain an
outline of the proposed pediatric study or studies the sponsor plans to conduct, including study objectives and design, age groups, relevant endpoints and statistical approach, or a justification for not
including such detailed information, and any request for a deferral of pediatric assessments or a full or partial waiver of the requirement to provide data from pediatric studies along with supporting
information. The sponsor and the FDA must reach agreement on a final plan. A sponsor can submit amendments to an agreed-upon initial PSP at any time if changes to the pediatric plan need to be
considered based on data collected from nonclinical studies, early phase clinical trials, and/or other clinical development programs.
For investigational products intended to treat a serious or life-threatening disease or condition, the FDA must, upon the request of a sponsor, meet to discuss preparation of the initial
pediatric study plan or to discuss deferral or waiver of pediatric assessments. In addition, the FDA will meet early in the development process to discuss pediatric study plans with sponsors, and the
FDA must meet with sponsors by no later than the end-of-Phase 1 meeting for serious or life-threatening diseases and by no later than ninety days after the FDA’s receipt of the study plan.
The FDA may, on its own initiative or at the request of the sponsor, grant deferrals for submission of some or all pediatric data until after approval of the product for use in adults, or full or
partial waivers from the pediatric data requirements. A deferral may be granted for several reasons, including a finding that the product or therapeutic candidate is ready for approval for use in adults
before pediatric trials are complete or that additional safety or effectiveness data needs
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to be collected before the pediatric trials begin. The law now requires the FDA to send a PREA Non-Compliance letter to sponsors who have failed to submit their pediatric assessments required
under PREA, have failed to seek or obtain a deferral or deferral extension or have failed to request approval for a required pediatric formulation. It further requires the FDA to publicly post the PREA
Non-Compliance letter and sponsor’s response. Unless otherwise required by regulation, the pediatric data requirements do not apply to products with orphan designation, although FDA has recently
taken steps to limit what it considers abuse of this statutory exemption in PREA by announcing that it does not intend to grant any additional orphan drug designations for rare pediatric
subpopulations of what is otherwise a common disease. The FDA also maintains a list of diseases that are exempt from PREA requirements due to low prevalence of disease in the pediatric
population.
Submission and Filing of an NDA or BLA with the FDA
In order to obtain approval to market a drug or biological product in the United States, a marketing application must be submitted to the FDA that provides data establishing the safety and
effectiveness of the proposed drug product for the proposed indication, and the safety, purity and potency of the biological product for its intended indication. The application includes all relevant data
available from pertinent preclinical and clinical trials, including negative or ambiguous results as well as positive findings, together with detailed information relating to the product’s chemistry,
manufacturing, controls and proposed labeling, among other things. Data can come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a
number of alternative sources, including studies initiated by investigators. To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and
effectiveness of the investigational drug product and the safety, purity and potency of the biological product to the satisfaction of the FDA.
The application is the vehicle through which sponsors formally propose that the FDA approve a new product for marketing and sale in the United States for one or more indications. Every
new product candidate must be the subject of an approved NDA or BLA before it may be commercialized in the United States. Under federal law, the submission of most applications is subject to an
application user fee, which for federal fiscal year 2022 is $3,117,218 for an application requiring clinical data. The sponsor of an approved application is also subject to an annual program fee, which
for federal fiscal year 2022 is $369,413. Certain exceptions and waivers are available for some of these fees, such as an exception from the application fee for products with orphan designation and a
waiver for certain small businesses. If an application is withdrawn prior to the FDA acceptance for filing, 75% of these fees may be refunded to the sponsor. If an application is withdrawn after filing,
a lower portion of these fees may be refunded in certain circumstances.
Following submission of an NDA or BLA, the FDA conducts a preliminary review of the application within 60 days of receipt and must inform the sponsor at that time or before whether an
application is sufficiently complete to permit substantive review. In the event that FDA determines that an application does not satisfy this standard, it will issue a Refuse to File, or RTF,
determination to the sponsor. The FDA may request additional information rather than accept the application for filing and the application must be resubmitted with the additional information.
Once the submission is accepted for filing, the FDA begins an in-depth substantive review. The FDA has agreed to specified performance goals in the review process of NDAs and BLAs.
Under that agreement, 90% of applications seeking approval of New Molecular Entities, or NMEs, are meant to be reviewed within ten months from the date on which FDA accepts the NDA for
filing, and 90% of applications for NMEs that have been designated for “priority review” are meant to be reviewed within six months of the filing date. The review process and the Prescription Drug
User Fee Act goal date may be extended by the FDA for three additional months to consider new information or clarification provided by the sponsor to address an outstanding deficiency identified
by the FDA following the original submission.
In connection with its review of an application, the FDA typically will inspect the facility or facilities where the product is or will be manufactured. These pre-approval inspections may
cover all facilities associated with an NDA or BLA submission, including drug component manufacturing (e.g., active pharmaceutical ingredients), finished drug product manufacturing and control
testing laboratories. The scheduling and execution of such pre-approval inspections may be impacted or delayed due to the COVID-19 pandemic. The FDA will not approve an application unless it
determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.
Additionally, before approving an NDA or BLA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP and the integrity of the clinical data submitted to the FDA.
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In addition, as a condition of approval, the FDA may require a sponsor to develop a REMS. REMS use risk minimization strategies beyond the professional labeling to ensure that the benefits
of the product outweigh the potential risks. To determine whether a REMS is needed, the FDA will consider the size of the population likely to use the product, seriousness of the disease, expected
benefit of the product, expected duration of treatment, seriousness of known or potential adverse events, and whether the product is a new molecular entity. Under the FDA Reauthorization Act of
2017, the FDA must implement a protocol to expedite review of responses to inspection reports pertaining to certain applications, including applications for products in shortage or those for which
approval is dependent on remediation of conditions identified in the inspection report.
The FDA may refer an application for a novel product to an advisory committee or explain why such referral was not made. Typically, an advisory committee is a panel of independent experts,
including clinicians and other scientific experts, that reviews, evaluates and provides a recommendation as to whether the application should be approved and under what conditions. The FDA is not
bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions.
The FDA’s Decision on an NDA or BLA
The FDA reviews an application to determine, among other things, whether the product is safe and whether it is effective for its intended use(s), with the latter determination being made on
the basis of substantial evidence. The FDA has interpreted this evidentiary standard to require at least two adequate and well-controlled clinical investigations to establish effectiveness of a new
product. Under certain circumstances, however, FDA has indicated that a single trial with certain characteristics and additional confirmatory information may satisfy this standard. The FDA will
ultimately seek to determine whether the expected benefits of the product outweigh its potential risks to patients. This “benefit-risk” assessment is informed by the extensive body of evidence about
the product’s safety and efficacy in the NDA or BLA.
After evaluating the application and all related information, including the advisory committee recommendations, if any, and inspection reports of manufacturing facilities and clinical trial
sites, the FDA will issue either a Complete Response Letter, or CRL, or an approval letter. A CRL indicates that the review cycle of the application is complete, and the application will not be
approved in its present form. A CRL generally outlines the deficiencies in the submission and may require substantial additional testing or information in order for the FDA to reconsider the
application. The CRL may require additional clinical or other data, additional pivotal Phase 3 clinical trial(s) and/or other significant and time-consuming requirements related to clinical trials,
preclinical studies or manufacturing. If a CRL is issued, the sponsor will have one year to respond to the deficiencies identified by the FDA, at which time the FDA can deem the application
withdrawn or, in its discretion, grant the sponsor an additional six month extension to respond.
An approval letter authorizes commercial marketing of the product with specific prescribing information for specific indications.
If the FDA approves a product, it may limit the approved indications for use for the product, require that contraindications, warnings or precautions be included in the product labeling,
require that post-approval studies, including Phase 4 clinical trials, be conducted to further assess the drug’s safety after approval, require testing and surveillance programs to monitor the product
after commercialization, or impose other conditions, including distribution restrictions or other risk management mechanisms, including REMS, which can materially affect the potential market and
profitability of the product. The FDA may prevent or limit further marketing of a product based on the results of post-market studies or surveillance programs. After approval, many types of changes
to the approved product, such as adding new indications, manufacturing changes and additional labeling claims, are subject to further testing requirements and FDA review and approval.
Fast Track, Breakthrough Therapy, Priority Review and Regenerative Advanced Therapy Designations
The FDA is authorized to designate certain products for expedited review if they are intended to address an unmet medical need in the treatment of a serious or life‑threatening disease or
condition. These programs are referred to as Fast Track designation, breakthrough therapy designation, priority review designation and regenerative advanced therapy designation. None of these
programs changes the standards for approval but each may help expedite the development or approval process governing product candidates.
Specifically, the FDA may designate a product for Fast Track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or
life‑threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. For Fast Track products, sponsors may have greater interactions
with the FDA and the FDA may initiate review of sections of a Fast Track product’s application before the application is complete. This rolling review may be available if the FDA determines, after
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preliminary evaluation of clinical data submitted by the sponsor, that a Fast Track product may be effective. The sponsor must also provide, and the FDA must approve, a schedule for the submission
of the remaining information and the sponsor must pay applicable user fees. However, the FDA’s time period goal for reviewing a Fast Track application does not begin until the last section of the
application is submitted. In addition, the Fast Track designation may be withdrawn by the FDA if the FDA believes that the designation is no longer supported by data emerging in the clinical trial
process.
Second, a product may be designated as a Breakthrough Therapy if it is intended, either alone or in combination with one or more other products, to treat a serious or life‑threatening disease
or condition and preliminary clinical evidence indicates that the product may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as
substantial treatment effects observed early in clinical development. The FDA may take certain actions with respect to Breakthrough Therapies, including holding meetings with the sponsor
throughout the development process; providing timely advice to the product sponsor regarding development and approval; involving more senior staff in the review process; assigning a
cross‑disciplinary project lead for the review team; and taking other steps to design the clinical trials in an efficient manner.
Third, the FDA may designate a product for priority review if it is a product that treats a serious condition and, if approved, would provide a significant improvement in safety or
effectiveness. The FDA determines, on a case‑by-case basis, whether the proposed product represents a significant improvement when compared with other available therapies. Significant
improvement may be illustrated by evidence of increased effectiveness in the treatment of a condition, elimination or substantial reduction of a treatment‑limiting product reaction, documented
enhancement of patient compliance that may lead to improvement in serious outcomes, and evidence of safety and effectiveness in a new subpopulation. A priority designation is intended to direct
overall attention and resources to the evaluation of such applications, and to shorten the FDA’s goal for taking action on a marketing application from ten months to six months.
Finally, with passage of the Cures Act in December 2016, Congress authorized the FDA to accelerate review and approval of products designated as regenerative advanced therapies. A
product is eligible for this designation if it is a regenerative medicine therapy that is intended to treat, modify, reverse or cure a serious or life-threatening disease or condition and preliminary clinical
evidence indicates that the drug has the potential to address unmet medical needs for such disease or condition. The benefits of a regenerative advanced therapy designation include early interactions
with FDA to expedite development and review, benefits available to breakthrough therapies, potential eligibility for priority review and accelerated approval based on surrogate or intermediate
endpoints.
Accelerated Approval Pathway
The FDA may grant accelerated approval to a product for a serious or life‑threatening condition that provides meaningful therapeutic advantage to patients over existing treatments based
upon a determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit. The FDA may also grant accelerated approval for such a condition when
the product has an effect on an intermediate clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, or IMM, and that is reasonably likely to predict an
effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity or prevalence of the condition and the availability or lack of alternative treatments.
Products granted accelerated approval must meet the same statutory standards for safety and effectiveness as those granted traditional approval.
For the purposes of accelerated approval, a surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict
clinical benefit, but is not itself a measure of clinical benefit. Surrogate endpoints can often be measured more easily or more rapidly than clinical endpoints. An intermediate clinical endpoint is a
measurement of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on IMM. The FDA has limited experience with accelerated approvals
based on intermediate clinical endpoints, but has indicated that such endpoints generally may support accelerated approval where the therapeutic effect measured by the endpoint is not itself a clinical
benefit and basis for traditional approval, if there is a basis for concluding that the therapeutic effect is reasonably likely to predict the ultimate clinical benefit of a product.
The accelerated approval pathway is most often used in settings in which the course of a disease is long and an extended period of time is required to measure the intended clinical benefit of
a product, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Thus, accelerated approval has been used extensively in the development and approval of products for
treatment of a variety of cancers in which the goal of therapy is generally to improve survival or decrease morbidity and the duration of the typical disease course requires lengthy and sometimes
large trials to demonstrate a clinical or survival benefit. Thus, the benefit of accelerated approval derives from the potential to receive approval based on surrogate endpoints sooner than possible for
trials with clinical or survival endpoints, rather than deriving from any explicit shortening of the FDA approval timeline, as is the case with priority review.
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The accelerated approval pathway is usually contingent on a sponsor’s agreement to conduct, in a diligent manner, additional post‑approval confirmatory studies to verify and describe the
product’s clinical benefit. As a result, a product candidate approved on this basis is subject to rigorous post‑marketing compliance requirements, including the completion of Phase 4 or post‑approval
clinical trials to confirm the effect on the clinical endpoint. Failure to conduct required post‑approval studies, or confirm a clinical benefit during post‑marketing studies, would allow the FDA to
initiate expedited proceedings to withdraw approval of the product. All promotional materials for product candidates approved under accelerated regulations are subject to prior review by the FDA.
Post-Approval Regulation
Drugs and biologics manufactured or distributed pursuant to FDA approvals are subject to pervasive and continuing regulation by the FDA, including, among other things, requirements
relating to recordkeeping, periodic reporting, product sampling and distribution, advertising and promotion and reporting of adverse experiences with the product. After approval, most changes to the
approved product, such as adding new indications or other labeling claims, are subject to prior FDA review and approval. There also are continuing, annual user fee requirements for any marketed
products and the establishments at which such products are manufactured, as well as new application fees for supplemental applications with clinical data.
In addition, manufacturers and other entities involved in the manufacture and distribution of approved products are required to register their establishments with the FDA and state agencies,
and are subject to periodic unannounced inspections by the FDA and these state agencies for compliance with cGMP requirements. Changes to the manufacturing process are strictly regulated and
often require prior FDA approval before being implemented. The FDA's regulations also require investigation and correction of any deviations from cGMP and impose reporting and documentation
requirements upon the sponsor and any third-party manufacturers that the sponsor may decide to use. Accordingly, manufacturers must continue to expend time, money, and effort in the area of
production and quality control to maintain cGMP compliance.
Once an approval is granted, the FDA may withdraw the approval if compliance with regulatory requirements and standards is not maintained or if problems occur after the product reaches
the market. Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply
with regulatory requirements, may result in revisions to the approved labeling to add new safety information; imposition of post-market studies or clinical trials to assess new safety risks; or
imposition of distribution or other restrictions under a REMS program. Other potential consequences include, among other things:
•
restrictions on the marketing or manufacturing of the product, suspension of the approval, or complete withdrawal of the product from the market or product recalls;
•
fines, warning letters or holds on post-approval clinical trials;
•
refusal of the FDA to approve pending NDAs or supplements to approved NDAs, or suspension or revocation of product license approvals;
•
product seizure or detention, or refusal to permit the import or export of products; or
•
injunctions or the imposition of civil or criminal penalties.
The FDA strictly regulates marketing, labeling, advertising and promotion of products that are placed on the market. Products may be promoted only for the approved indications and in
accordance with the provisions of the approved label. In September 2021, the FDA published final regulations which describe the types of evidence that the agency will consider in determining the
intended use of a drug or biologic. The FDA and other agencies actively enforce the laws and regulations prohibiting the promotion of off-label uses, and a company that is found to have improperly
promoted off-label uses may be subject to significant liability. If a company is found to have promoted off-label uses, it may become subject to adverse public relations and administrative and judicial
enforcement by the FDA, the Department of Justice, or the Office of the Inspector General of the Department of Health and Human Services, as well as state authorities. This could subject a company
to a range of penalties that could have a significant commercial impact, including civil and criminal fines and agreements that materially restrict the manner in which a company promotes or
distributes drug products.
Section 505(b)(2) NDAs
NDAs for most new drug products are based on two full clinical studies which must contain substantial evidence of the safety and efficacy of the proposed new product for the proposed use.
These applications are submitted under Section 505(b)(1) of the FDCA. The FDA is, however, authorized to approve an alternative type of NDA under Section 505(b)(2) of the FDCA. This type of
application allows the sponsor to rely, in part, on the FDA’s previous findings of safety and efficacy for a similar product, or published literature. Specifically, Section 505(b)(2) applies to NDAs for a
drug for which the investigations made to show whether or not the drug is safe for use and effective in use and relied upon by the sponsor for approval of the application “were not conducted by or for
the applicant and for which the applicant has not obtained a right of reference or use from the person by or for whom the investigations were conducted.”
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Section 505(b)(2) thus authorizes the FDA to approve an NDA based on safety and effectiveness data that were not developed by the applicant. NDAs filed under Section 505(b)(2) may
provide an alternate and potentially more expeditious pathway to FDA approval for new or improved formulations or new uses of previously approved products. If the 505(b)(2) applicant can
establish that reliance on the FDA’s previous approval is scientifically appropriate, the applicant may eliminate the need to conduct certain preclinical or clinical studies of the new product. The FDA
may also require companies to perform additional studies or measurements to support the change from the approved product. The FDA may then approve the new drug candidate for all or some of the
label indications for which the referenced product has been approved, as well as for any new indication sought by the Section 505(b)(2) applicant.
Generic Drugs
In 1984, with the passage of the Hatch-Waxman Amendments to the FDCA, Congress established an abbreviated regulatory scheme authorizing the FDA to approve generic drugs that are
shown to contain the same active ingredients as, and to be bioequivalent to, drugs previously approved by the FDA pursuant to NDAs. To obtain approval of a generic drug, a sponsor must submit an
abbreviated new drug application, or ANDA, to the agency. An ANDA is a comprehensive submission that contains, among other things, data and information pertaining to the active pharmaceutical
ingredient, bioequivalence, drug product formulation, specifications and stability of the generic drug, as well as analytical methods, manufacturing process validation data and quality control
procedures. ANDAs are “abbreviated” because they generally do not include preclinical and clinical data to demonstrate safety and effectiveness. Instead, in support of such applications, a generic
manufacturer may rely on the preclinical and clinical testing previously conducted for a drug product previously approved under an NDA, known as the reference-listed drug, or RLD.
Under the Hatch-Waxman Act, the FDA may not approve an ANDA until any applicable period of non-patent exclusivity for the RLD has expired. The FDCA provides a period of five years
of non-patent data exclusivity for a new drug containing a new chemical entity. For the purposes of this provision, a new chemical entity, or NCE, is a drug that contains no active moiety that has
previously been approved by the FDA in any other NDA. This interpretation of the FDCA by the FDA was confirmed with enactment of the Ensuring Innovation Act in April 2021. An active moiety
is the molecule or ion responsible for the physiological or pharmacological action of the drug substance. In cases where such NCE exclusivity has been granted, an ANDA may not be filed with the
FDA until the expiration of five years unless the submission is accompanied by a Paragraph IV certification, in which case the sponsor may submit its application four years following the original
product approval. The FDCA also provides for a period of three years of exclusivity if the NDA includes reports of one or more new clinical investigations, other than bioavailability or
bioequivalence studies, that were conducted by or for the sponsor and are essential to the approval of the application.
As part of the submission of an NDA or certain supplemental applications, NDA sponsors are required to list with the FDA each patent with claims that cover the sponsor’s product or an
approved method of using the product. Upon approval of a new drug, each of the patents listed in the application for the drug is then published in the Orange Book. The FDA’s regulations governing
patent listings were largely codified into law with enactment of the Orange Book Modernization Act in January 2021. When an ANDA applicant files its application with the FDA, the applicant is
required to make a certification to the FDA in connection with any patents listed for the reference product in the Orange Book. Specifically, the ANDA applicant must certify that: (i) the required
patent information has not been filed; (ii) the listed patent has expired; (iii) the listed patent has not expired, but will expire on a particular date and approval is sought after patent expiration; or (iv)
the listed patent is invalid or will not be infringed by the new product. Moreover, to the extent that a Section 505(b)(2) NDA applicant is relying on studies conducted for an already approved product,
the applicant also is required to certify to the FDA concerning any patents listed for the NDA-approved product in the Orange Book to the same extent that an ANDA applicant would.
If the generic drug or follow-on drug applicant does not challenge the innovator’s listed patents, FDA will not approve the ANDA or 505(b)(2) application until all the listed patents claiming
the referenced product have expired. A certification that the new generic product will not infringe the already approved product’s listed patents or that such patents are invalid or unenforceable is
called a Paragraph IV certification. If the ANDA applicant has provided a Paragraph IV certification to the FDA, the applicant must also send notice of the Paragraph IV certification to the NDA
owner and patent holders once the ANDA has been accepted for filing by the FDA. The NDA owner and patent holders may then initiate a patent infringement lawsuit in response to the notice of the
Paragraph IV certification. The filing of a patent infringement lawsuit within 45 days after the receipt of a Paragraph IV certification automatically prevents the FDA from approving the ANDA or
505(b)(2) NDA until the earliest of seven and a half years from the date of approval of the NDA, expiration of the patent and a decision in the infringement case that is favorable to the ANDA or
505(b)(2) NDA applicant.
Biosimilars
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The 2010 Patient Protection and Affordable Care Act, or ACA, which was signed into law on March 23, 2010, included a subtitle called the Biologics Price Competition and Innovation Act
of 2009 or BPCIA. The BPCIA established a regulatory scheme authorizing the FDA to approve biosimilars and interchangeable biosimilars. Since enactment of the BPCIA, the FDA has approved
numerous biosimilar products for use in the United States. In addition, the FDA approved the first interchangeable biosimilar product on July 30, 2021 and a second product previously approved as a
biosimilar was designated as interchangeable in October 2021. The FDA has also issued numerous guidance documents outlining an approach to review and approval of biosimilars and
interchangeable biosimilar products.
Under the BPCIA, a manufacturer may submit an application for licensure of a biologic product that is “biosimilar to” or “interchangeable with” a previously approved biological product or
“reference product.” In order for the FDA to approve a biosimilar product, it must find that there are no clinically meaningful differences between the reference product and proposed biosimilar
product in terms of safety, purity and potency. For the FDA to approve a biosimilar product as interchangeable with a reference product, the agency must find that the biosimilar product can be
expected to produce the same clinical results as the reference product, and (for products administered multiple times) that the biologic and the reference biologic may be switched after one has been
previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of the reference biologic.
An application for a biosimilar product may not be submitted to the FDA until four years following the date of approval of the reference product. The FDA may not approve a biosimilar
product until 12 years from the date on which the reference product was approved. Even if a product is considered to be a reference product eligible for exclusivity, another company could market a
competing version of that product if the FDA approves a full BLA for such product containing the sponsor’s own preclinical data and data from adequate and well-controlled clinical trials to
demonstrate the safety, purity and potency of their product. The BPCIA also created certain exclusivity periods for biosimilars approved as interchangeable products. There have been recent
government proposals to reduce the 12-year reference product exclusivity period, but none has been enacted to date. At the same time, since passage of the BPCIA, many states have passed laws or
amendments to laws, which address pharmacy practices involving biosimilar products.
Orphan Drug Designation and Exclusivity
Under the Orphan Drug Act, the FDA may designate a drug product as an “orphan drug” if it is intended to treat a rare disease or condition, generally meaning that it affects fewer than
200,000 individuals in the United States, or more in cases in which there is no reasonable expectation that the cost of developing and making a drug product available in the United States for
treatment of the disease or condition will be recovered from sales of the product. A company must request orphan drug designation before submitting an NDA or BLA for the candidate product. If the
request is granted, the FDA will disclose the identity of the therapeutic agent and its potential use. Orphan drug designation does not shorten the PDUFA goal dates for the regulatory review and
approval process, although it does convey certain advantages such as tax benefits and exemption from the PDUFA application fee.
If a product with orphan designation receives the first FDA approval for the disease or condition for which it has such designation or for a select indication or use within the rare disease or
condition for which it was designated, the product generally will receive orphan drug exclusivity. Orphan drug exclusivity means that the FDA may not approve another sponsor’s marketing
application for the same drug for the same indication for seven years, except in certain limited circumstances. Orphan exclusivity does not block the approval of a different product for the same rare
disease or condition, nor does it block the approval of the same product for different indications. If a drug or biologic designated as an orphan drug ultimately receives marketing approval for an
indication broader than what was designated in its orphan drug application, it may not be entitled to exclusivity.
Orphan exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same drug or biologic for the same indication is shown to
be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to
meet market demand. Under Omnibus legislation signed by President Trump on December 27, 2020, the requirement for a product to show clinical superiority applies to drug products that received
orphan drug designation before enactment of amendments to the FDCA in 2017 but have not yet been approved by FDA.
Pediatric Exclusivity
Pediatric exclusivity is another type of non-patent marketing exclusivity in the United States and, if granted, provides for the attachment of an additional six months of regulatory exclusivity.
For drug products, the six month exclusivity period may be attached to the term of any existing patent term or regulatory exclusivity. For biologic products, the six month period may only be attached
to any existing regulatory exclusivities but not to any patent terms. This six-month exclusivity may be granted if an NDA or BLA sponsor submits pediatric data that fairly respond to a written
request from the FDA for such data. The data do not need to show the product to be effective in the pediatric population studied;
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rather, if the clinical trial is deemed to fairly respond to the FDA’s request, the additional protection is granted. If reports of requested pediatric studies are submitted to and accepted by the FDA
within the statutory time limits, whatever statutory or regulatory periods of exclusivity or patent protection cover the product are extended by six months. This is not a patent term extension, but it
effectively extends the regulatory period during which the FDA cannot approve another application.
Patent Term Restoration and Extension
A patent claiming a new product may be eligible for a limited patent term extension under the Hatch-Waxman Act, which permits a patent restoration of up to five years for patent term lost
during product development and the FDA regulatory review. The restoration period granted on a patent covering a product is typically one-half the time between the effective date of the IND and the
submission date of a NDA or BLA, plus the time between the submission date of the application and the ultimate approval date. Patent term restoration cannot be used to extend the remaining term of
a patent past a total of 14 years from the product’s approval date. Only one patent applicable to an approved product is eligible for the extension, and the application for the extension must be
submitted prior to the expiration of the patent in question. A patent that covers multiple products for which approval is sought can only be extended in connection with one of the approvals. The
United States Patent and Trademark Office reviews and approves the application for any patent term extension or restoration in consultation with the FDA.
FDA Approval and Regulation of Companion Diagnostics
If safe and effective use of a therapeutic depends on an in vitro diagnostic, then the FDA generally will require approval or clearance of that diagnostic, known as a companion diagnostic, at
the same time that the FDA approves the therapeutic product. In August 2014, the FDA issued final guidance clarifying the requirements that will apply to approval of therapeutic products and in
vitro companion diagnostics. According to the guidance, if the FDA determines that a companion diagnostic device is essential to the safe and effective use of a novel therapeutic product or
indication, the FDA generally will not approve the therapeutic product or new therapeutic product indication if the companion diagnostic device is not approved or cleared for that indication.
In April 2020, the FDA issued additional guidance which describes considerations for the development and labeling of companion diagnostic devices to support the indicated uses of multiple
drug or biological oncology products, when appropriate. The 2020 guidance expands on the policy statement in the 2014 guidance by recommending that companion diagnostic developers consider a
number of factors when determining whether their test could be developed, or the labeling for approved companion diagnostics could be revised through a supplement, to support a broader labeling
claim such as use with a specific group of oncology therapeutic products (rather than listing an individual therapeutic product(s)).
Under the FDCA, in vitro diagnostics, including companion diagnostics, are regulated as medical devices. In the United States, the FDCA and its implementing regulations, and other federal
and state statutes and regulations govern, among other things, medical device design and development, preclinical and clinical testing, premarket clearance or approval, registration and listing,
manufacturing, labeling, storage, advertising and promotion, sales and distribution, export and import, and post‑market surveillance. Unless an exemption applies, diagnostic tests require marketing
clearance or approval from the FDA prior to commercial distribution.
The FDA previously has required in vitro companion diagnostics intended to select the patients who will respond to the product candidate to obtain pre-market approval, or PMA,
simultaneously with approval of the therapeutic product candidate. The PMA process, including the gathering of clinical and preclinical data and the submission to and review by the FDA, can take
several years or longer. It involves a rigorous premarket review during which the sponsor must prepare and provide the FDA with reasonable assurance of the device’s safety and effectiveness and
information about the device and its components regarding, among other things, device design, manufacturing and labeling. PMA applications are subject to an application fee. For federal fiscal year
2022, the standard fee is $374,858 and the small business fee is $93,714.
Review and Approval of Drug Products in the EU
In order to market any product outside of the United States, a company must also comply with numerous and varying regulatory requirements of other countries and jurisdictions regarding
quality, safety and efficacy and governing, among other things, clinical trials, marketing authorization, commercial sales and distribution of drug products. Whether or not it obtains FDA approval for
a product, the company would need to obtain the necessary approvals by the comparable foreign regulatory authorities before it can commence clinical trials or marketing of the product in those
countries or jurisdictions. The approval process ultimately varies between countries and jurisdictions and can involve additional product testing and additional administrative review periods.
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Clinical Trial Approval in the EU
On January 31, 2022, the new Clinical Trials Regulation (EU) No 536/2014 became effective in the EU and replaced the prior Clinical Trials Directive 2001/20/EC. The new regulation aims
at simplifying and streamlining the authorization, conduct and transparency of clinical trials in the EU. Under the new coordinated procedure for the approval of clinical trials, the sponsor of a clinical
trial to be conducted in more than one Member State of the EU, or EU Member State, will only be required to submit a single application for approval. The submission will be made through the
Clinical Trials Information System, a new clinical trials portal overseen by the EMA and available to clinical trial sponsors, competent authorities of the EU Member States and the public.
The new regulation did not change the preexisting requirement that a sponsor must obtain prior approval from the competent national authority of the EU Member State in which the clinical
trial is to be conducted. If the clinical trial is conducted in different EU Member States, the competent authorities in each of these EU Member States must provide their approval for the conduct of
the clinical trial. Furthermore, the sponsor may only start a clinical trial at a specific study site after the applicable ethics committee has issued a favorable opinion.
Parties conducting certain clinical trials must, as in the United States, post clinical trial information in the EU at the EudraCT website: https://eudract.ema.europa.eu.
PRIME Designation in the EU
In March 2016, the EMA launched an initiative to facilitate development of product candidates in indications, often rare, for which few or no therapies currently exist. The PRIority
MEdicines, or PRIME, scheme is intended to encourage drug development in areas of unmet medical need and provides accelerated assessment of products representing substantial innovation
reviewed under the centralized procedure. Products from small- and medium-sized enterprises, or SMEs, may qualify for earlier entry into the PRIME scheme than larger companies. Many benefits
accrue to sponsors of product candidates with PRIME designation, including but not limited to, early and proactive regulatory dialogue with the EMA, frequent discussions on clinical trial designs
and other development program elements, and accelerated marketing authorization application assessment once a dossier has been submitted. Importantly, a dedicated Agency contact and rapporteur
from the CHMP or Committee for Advanced Therapies, or CAT, are appointed early in PRIME scheme facilitating increased understanding of the product at EMA’s Committee level.
Marketing Authorization in the EU
In the EU, marketing authorizations for medicinal products may be obtained through several different procedures founded on the same basic regulatory process.
The centralized procedure provides for the grant of a single marketing authorization that is valid for all EU Member States. The centralized procedure is compulsory for medicinal products
produced by certain biotechnological processes, products designated as orphan medicinal products, and products with a new active substance indicated for the treatment of certain diseases. It is
optional for those products that are highly innovative or for which a centralized process is in the interest of patients. Under the centralized procedure in the EU, the maximum timeframe for the
evaluation of a MAA is 210 days, excluding clock stops, when additional written or oral information is to be provided by the sponsor in response to questions asked by the CHMP. Accelerated
evaluation may be granted by the CHMP in exceptional cases. These are defined as circumstances in which a medicinal product is expected to be of a “major public health interest.” Three cumulative
criteria must be fulfilled in such circumstances: the seriousness of the disease, such as severely disabling or life-threatening diseases, to be treated; the absence or insufficiency of an appropriate
alternative therapeutic approach; and anticipation of high therapeutic benefit. In these circumstances, the EMA ensures that the opinion of the CHMP is given within 150 days.
The decentralized procedure provides for approval by one or more other concerned EU Member States of an assessment of an application for marketing authorization conducted by one EU
Member State, known as the reference EU Member State. In accordance with this procedure, a sponsor submits an application for marketing authorization to the reference EU Member State and the
concerned EU Member States. This application is identical to the application that would be submitted to the EMA for authorization through the centralized procedure. The reference EU Member State
prepares a draft assessment and drafts of the related materials within 120 days after receipt of a valid application. The resulting assessment report is submitted to the concerned EU Member States
which, within 90 days of receipt, must decide whether to approve the assessment report and related materials. If a concerned EU Member State cannot approve the assessment report and related
materials due to concerns relating to a potential serious risk to public health, disputed elements may be referred to the European Commission, whose decision is binding on all EU Member States.
A marketing authorization may be granted only to a sponsor established in the EU. Regulation No. 1901/2006 provides that, prior to obtaining a marketing authorization in the EU, a sponsor
must demonstrate compliance with all
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measures included in a Pediatric Investigation Plan, or PIP, approved by the Pediatric Committee of the EMA, covering all subsets of the pediatric population, unless the EMA has granted a product-
specific waiver, class waiver, or a deferral for one or more of the measures included in the PIP.
Regulatory Data Protection in the EU
In the EU, new chemical entities approved on the basis of a complete independent data package qualify for eight years of data exclusivity upon marketing authorization and an additional two
years of market exclusivity pursuant to Regulation (EC) No 726/2004, as amended, and Directive 2001/83/EC, as amended. Data exclusivity prevents regulatory authorities in the EU from
referencing the innovator’s data to assess a generic (abbreviated) application for a period of eight years. During the additional two‑year period of market exclusivity, a generic marketing authorization
application can be submitted, and the innovator’s data may be referenced, but no generic medicinal product can be marketed until the expiration of the market exclusivity. The overall ten‑year period
will be extended to a maximum of eleven years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic
indications which, during the scientific evaluation prior to authorization, is held to bring a significant clinical benefit in comparison with existing therapies.
Orphan Drug Designation and Exclusivity in the EU
Regulation (EC) No 141/2000 and Regulation (EC) No. 847/2000 provide that a product can be designated as an orphan medicinal product by the European Commission if its sponsor can
establish that the product is intended for the diagnosis, prevention or treatment of: (1) a life-threatening or chronically debilitating condition affecting not more than five in ten thousand persons in the
EU when the application is made, or (2) a life-threatening, seriously debilitating or serious and chronic condition in the EU and that without incentives the medicinal product is unlikely to be
developed. For either of these conditions, the sponsor must demonstrate that there exists no satisfactory method of diagnosis, prevention or treatment of the condition in question that has been
authorized in the EU or, if such method exists, the medicinal product will be of significant benefit to those affected by that condition.
Once authorized, orphan medicinal products are entitled to ten years of market exclusivity in all EU Member States and, in addition, a range of other benefits during the development and
regulatory review process, including scientific assistance for trial protocols, authorization through the centralized marketing authorization procedure covering all member countries and a reduction or
elimination of registration and marketing authorization fees. However, marketing authorization may be granted to a similar medicinal product with the same orphan indication during the ten-year
period with the consent of the marketing authorization holder for the original orphan medicinal product or if the manufacturer of the original orphan medicinal product is unable to supply sufficient
quantities. Marketing authorization may also be granted to a similar medicinal product with the same orphan indication if the product is safer, more effective or otherwise clinically superior to the
original orphan medicinal product. The period of market exclusivity may, in addition, be reduced to six years if it can be demonstrated on the basis of available evidence that the original orphan
medicinal product is sufficiently profitable not to justify maintenance of market exclusivity.
Orphan drug exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same drug or biologic for the same indication is
shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is
not able to meet market demand. This is the case despite an earlier court opinion holding that the Orphan Drug Act unambiguously required the FDA to recognize orphan exclusivity regardless of a
showing of clinical superiority.
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Regulatory Requirements After Marketing Authorization in the EU
Following marketing authorization of a medicinal product in the EU, the holder of the authorization is required to comply with a range of requirements applicable to the manufacturing,
marketing, promotion and sale of medicinal products. These include compliance with the EU’s stringent pharmacovigilance or safety reporting, as well as rules potentially requiring post-authorization
studies and additional monitoring obligations. In addition, the manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory, must also be conducted in
strict compliance with the applicable EU laws, regulations and guidance, including Directive 2001/83/EC, Directive 2003/94/EC, Regulation (EC) No 726/2004 and the European Commission
Guidelines for Good Manufacturing Practice. These requirements include compliance with EU cGMP standards when manufacturing medicinal products and active pharmaceutical ingredients,
including the manufacture of active pharmaceutical ingredients outside of the EU with the intention to import the active pharmaceutical ingredients into the EU. Finally, the marketing and promotion
of authorized drugs, including industry-sponsored continuing medical education and advertising directed toward the prescribers of drugs and/or the general public, are strictly regulated in the EU
notably under Directive 2001/83EC, as amended, and EU Member State laws. Direct-to-consumer advertising of prescription medicines is prohibited across the EU.
Brexit and the Regulatory Framework in the United Kingdom
The United Kingdom’s withdrawal from the EU took place on January 31, 2020. The EU and the U.K. reached an agreement on their new partnership in the Trade and Cooperation
Agreement, or the Agreement, which was applied provisionally beginning on January 1, 2021 and which entered into force on May 1, 2021. The Agreement focuses primarily on free trade by
ensuring no tariffs or quotas on trade in goods, including healthcare products such as medicinal products. Thereafter, the EU and the U.K. will form two separate markets governed by two distinct
regulatory and legal regimes. As such, the Agreement seeks to minimize barriers to trade in goods while accepting that border checks will become inevitable as a consequence that the U.K. is no
longer part of the single market. As of January 1, 2021, the Medicines and Healthcare products Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices
in Great Britain, comprising England, Scotland and Wales under domestic law whereas Northern Ireland continues to be subject to EU rules under the Northern Ireland Protocol. The MHRA will rely
on the Human Medicines Regulations 2012 (SI 2012/1916) (as amended), or the HMR, as the basis for regulating medicines. The HMR has incorporated into the domestic law the body of EU law
instruments governing medicinal products that pre-existed prior to the U.K.’s withdrawal from the EU.
Furthermore, while the Data Protection Act of 2018 in the United Kingdom that “implements” and complements the EU’s General Data Protection Regulation, or GDPR, has achieved Royal
Assent on May 23, 2018 and is now effective in the United Kingdom, it is still unclear whether transfer of data from the European Economic Area, or EEA, to the United Kingdom will remain lawful
under GDPR. The Trade and Cooperation Agreement provides for a transitional period during which the United Kingdom will be treated like an EU member state in relation to processing and
transfers of personal data for four months from January 1, 2021. This may be extended by two further months. After such period, the United Kingdom will be a “third country” under the GDPR
unless the European Commission adopts an adequacy decision in respect of transfers of personal data to the United Kingdom. The United Kingdom has already determined that it considers all of the
EU 27 and EEA member states to be adequate for the purposes of data protection, ensuring that data flows from the United Kingdom to the EU/EEA remain unaffected.
General Data Protection Regulation
The collection, use, disclosure, transfer, or other processing of personal data, including personal health data, regarding individuals who are located in the European Economic Area (EEA),
and the processing of personal data that takes place in the EEA, is subject to the EU General Data Protection Regulation, or GDPR, which became effective on May 25, 2018. The GDPR is wide-
ranging in scope and imposes numerous requirements on companies that process personal data, including requirements relating to processing health and other sensitive data, obtaining consent of the
individuals to whom the personal data relates, providing information to individuals regarding data processing activities, implementing safeguards to protect the security and confidentiality of personal
data, providing notification of data breaches, and taking certain measures when engaging third-party processors. The GDPR imposes strict rules on the transfer of personal data to countries outside
the EU, including the United States, and permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million or 4% of annual global
revenues, whichever is greater. The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies,
and obtain compensation for damages resulting from violations of the GDPR. Compliance with the GDPR will be a rigorous and time-intensive process that may increase the cost of doing business or
require companies to change their business practices to ensure full compliance.
Pharmaceutical Coverage, Pricing and Reimbursement
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In the United States and markets in other countries, patients who are prescribed treatments for their conditions and providers performing the prescribed services generally rely on third-party
payors to reimburse all or part of the associated healthcare costs. Significant uncertainty exists as to the coverage and reimbursement status of products approved by the FDA and other government
authorities. Thus, even if a product candidate is approved, sales of the product will depend, in part, on the extent to which third-party payors, including government health programs in the United
States such as Medicare and Medicaid, commercial health insurers and managed care organizations, provide coverage, and establish adequate reimbursement levels for, the product. The process for
determining whether a payor will provide coverage for a product may be separate from the process for setting the price or reimbursement rate that the payor will pay for the product once coverage is
approved. Third-party payors are increasingly challenging the prices charged, examining the medical necessity, and reviewing the cost-effectiveness of medical products and services and imposing
controls to manage costs. Third-party payors may limit coverage to specific products on an approved list, also known as a formulary, which might not include all of the approved products for a
particular indication.
In order to secure coverage and reimbursement for any product that might be approved for sale, a company may need to conduct expensive pharmacoeconomic studies in order to
demonstrate the medical necessity and cost-effectiveness of the product, in addition to the costs required to obtain FDA or other comparable marketing approvals. Nonetheless, product candidates
may not be considered medically necessary or cost effective. A decision by a third-party payor not to cover a product candidate could reduce physician utilization once the product is approved and
have a material adverse effect on sales, results of operations and financial condition. Additionally, a payor’s decision to provide coverage for a product does not imply that an adequate reimbursement
rate will be approved. Further, one payor’s determination to provide coverage for a drug product does not assure that other payors will also provide coverage and reimbursement for the product, and
the level of coverage and reimbursement can differ significantly from payor to payor.
In the EU, pricing and reimbursement schemes vary widely from country to country. Some countries provide that products may be marketed only after a reimbursement price has been
agreed. Some countries may require the completion of additional studies that compare the cost-effectiveness of a particular drug candidate to currently available therapies or so-called health
technology assessments, in order to obtain reimbursement or pricing approval. For example, the EU provides options for its member states to restrict the range of products for which their national
health insurance systems provide reimbursement and to control the prices of medicinal products for human use. EU member states may approve a specific price for a product or it may instead adopt a
system of direct or indirect controls on the profitability of the company placing the product on the market. Other member states allow companies to fix their own prices for products, but monitor and
control prescription volumes and issue guidance to physicians to limit prescriptions. Recently, many countries in the EU have increased the amount of discounts required on pharmaceuticals and these
efforts could continue as countries attempt to manage healthcare expenditures, especially in light of the severe fiscal and debt crises experienced by many countries in the EU. The downward pressure
on health care costs in general, particularly prescription drugs, has become intense. As a result, increasingly high barriers are being erected to the entry of new products. Political, economic and
regulatory developments may further complicate pricing negotiations, and pricing negotiations may continue after reimbursement has been obtained. Reference pricing used by various EU member
states, and parallel trade, i.e., arbitrage between low-priced and high-priced member states, can further reduce prices. There can be no assurance that any country that has price controls or
reimbursement limitations for pharmaceutical products will allow favorable reimbursement and pricing arrangements for any products, if approved in those countries.
Healthcare Law and Regulation
Healthcare providers and third-party payors play a primary role in the recommendation and prescription of drug products that are granted marketing approval. Arrangements with providers,
consultants, third-party payors and customers are subject to broadly applicable fraud and abuse, anti-kickback, false claims laws, reporting of payments to physicians and teaching physicians and
patient privacy laws and regulations and other healthcare laws and regulations that may constrain business and/or financial arrangements. Restrictions under applicable federal and state healthcare
laws and regulations, include:
•
the federal Anti-Kickback Statute, which prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, paying, receiving or providing remuneration,
directly or indirectly, in cash or in kind, to induce or reward either the referral of an individual for, or the purchase, order or recommendation of, any good or service, for which payment may
be made, in whole or in part, under a federal healthcare program such as Medicare and Medicaid;
•
the federal civil and criminal false claims laws, including the civil False Claims Act, or the FCA, and civil monetary penalties laws, which prohibit individuals or entities from, among other
things, knowingly presenting, or causing to be presented, to the federal government, claims for payment that are false, fictitious or fraudulent or knowingly making, using or causing to be
made or used a false record or statement to avoid, decrease or conceal an obligation to pay money to the federal government;
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•
Foreign Corrupt Practices Act, or FCPA, which prohibits companies and their intermediaries from making, or offering or promising to make improper payments to non-U.S. officials for the
purpose of obtaining or retaining business or otherwise seeking favorable treatment;
•
the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal laws that prohibit, among other things, knowingly and willfully
executing, or attempting to execute, a scheme to defraud any healthcare benefit program or making false statements relating to healthcare matters;
•
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act, and their respective implementing regulations, including the Final Omnibus Rule
published in January 2013, which impose obligations, including mandatory contractual terms, with respect to safeguarding the privacy, security and transmission of individually identifiable
health information;
•
the federal false statements statute, which prohibits knowingly and willfully falsifying, concealing or covering up a material fact or making any materially false statement in connection with
the delivery of or payment for healthcare benefits, items or services;
•
the federal transparency requirements known as the federal Physician Payments Sunshine Act, under the ACA, as amended by the Health Care Education Reconciliation Act, which requires
certain manufacturers of drugs, devices, biologics and medical supplies to report annually to the Centers for Medicare & Medicaid Services, or CMS, within the United States Department of
Health and Human Services, information related to payments and other transfers of value made by that entity to physicians, other healthcare providers and teaching hospitals, as well as
ownership and investment interests held by physicians, other healthcare providers and their immediate family members; and
•
analogous state and foreign laws and regulations, such as state anti-kickback and false claims laws, which may apply to healthcare items or services that are reimbursed by third-party payors,
including private insurers.
Further, some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant compliance guidance promulgated
by the federal government in addition to requiring drug manufacturers to report information related to payments and transfers of value to other health care providers and health care entities, or
marketing expenditures. State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant ways and often
are not preempted by HIPAA, thus complicating compliance efforts.
Healthcare Reform
A primary trend in the U.S. healthcare industry and elsewhere is cost containment. There have been a number of federal and state proposals during the last few years regarding the pricing of
pharmaceutical and biopharmaceutical products, limiting coverage and reimbursement for drugs and other medical products, government control and other changes to the healthcare system in the
United States. By way of example, the United States and state governments continue to propose and pass legislation designed to reduce the cost of healthcare. In March 2010, the United States
Congress enacted the ACA, which, among other things, includes changes to the coverage and payment for products under government health care programs.
Other legislative changes have been proposed and adopted in the United States since the ACA was enacted. These new laws may result in additional reductions in Medicare and other
healthcare funding and otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product
candidate is prescribed or used. Further, there have been several recent U.S. congressional inquiries and proposed state and federal legislation designed to, among other things, bring more
transparency to drug pricing, review the relationship between pricing and manufacturer patient programs, reduce the costs of drugs under Medicare and reform government program reimbursement
methodologies for drug products.
Since enactment of the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law. For example, with
enactment of the Tax Cuts and Jobs Act of 2017, or the Tax Act, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of this
provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019. On December 14, 2018, a U.S. District Court judge in the Northern District of Texas
ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the Tax Act, the remaining
provisions of the ACA are invalid as well. The U.S. Supreme Court heard this case on November 10, 2020 and, on June 17, 2021, dismissed this action after finding that the plaintiffs do not have
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standing to challenge the constitutionality of the ACA. Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.
The Trump Administration also took executive actions to undermine or delay implementation of the PPACA, including directing federal agencies with authorities and responsibilities under
the ACA to waive, defer, grant exemptions from, or delay the implementation of any provision of the ACA that would impose a fiscal or regulatory burden on states, individuals, healthcare providers,
health insurers, or manufacturers of pharmaceuticals or medical devices. On January 28, 2021, however, President Biden rescinded those orders and issued a new executive order that directs federal
agencies to reconsider rules and other policies that limit access to healthcare, and consider actions that will protect and strengthen that access. Under this order, federal agencies are directed to re-
examine: policies that undermine protections for people with pre-existing conditions, including complications related to COVID‑19; demonstrations and waivers under Medicaid and the ACA that
may reduce coverage or undermine the programs, including work requirements; policies that undermine the Health Insurance Marketplace or other markets for health insurance; policies that make it
more difficult to enroll in Medicaid and under the ACA; and policies that reduce affordability of coverage or financial assistance, including for dependents.
The prices of prescription pharmaceuticals have also been the subject of considerable discussion in the United States. There have been several recent U.S. congressional inquiries, as well as
proposed and enacted state and federal legislation designed to, among other things, bring more transparency to pharmaceutical pricing, review the relationship between pricing and manufacturer
patient programs, and reduce the costs of pharmaceuticals under Medicare and Medicaid. In 2020, President Trump issued several executive orders intended to lower the costs of prescription products
and certain provisions in these orders have been incorporated into regulations. These regulations include an interim final rule implementing a most favored nation model for prices that would tie
Medicare Part B payments for certain physician-administered pharmaceuticals to the lowest price paid in other economically advanced countries, effective January 1, 2021. That rule, however, has
been subject to a nationwide preliminary injunction and, on December 29, 2021, CMS issued a final rule to rescind it. With issuance of this rule, CMS stated that it will explore all options to
incorporate value into payments for Medicare Part B pharmaceuticals and improve beneficiaries' access to evidence-based care.
In addition, in October 2020, HHS and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program, or SIP, to import certain prescription
drugs from Canada into the United States. The final rule is currently the subject of ongoing litigation, but at least six states (Vermont, Colorado, Florida, Maine, New Mexico, and New Hampshire)
have passed laws allowing for the importation of drugs from Canada with the intent of developing SIPs for review and approval by the FDA. Further, on November 20, 2020, HHS finalized a
regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the
price reduction is required by law. The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation. The rule
also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and
manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023.
At the state level, individual states are increasingly aggressive in passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing,
including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to
encourage importation from other countries and bulk purchasing. A number of states, for example, require drug manufacturers and other entities in the drug supply chain, including health carriers,
pharmacy benefit managers, wholesale distributors, to disclose information about pricing of pharmaceuticals. In addition, regional health care authorities and individual hospitals are increasingly
using bidding procedures to determine what pharmaceutical products and which suppliers will be included in their prescription drug and other health care programs. These measures could reduce the
ultimate demand for our products, once approved, or put pressure on our product pricing. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of
which could limit the amounts that federal and state governments will pay for healthcare products and services, which could result in reduced demand for our product candidates or additional pricing
pressures.
There have been, and likely will continue to be, additional legislative and regulatory proposals at the foreign, federal, and state levels directed at broadening the availability of healthcare and
containing or lowering the cost of healthcare. Such reforms could have an adverse effect on anticipated revenues from product candidates that we may successfully develop and for which we may
obtain marketing approval and may affect our overall financial condition and ability to develop product candidates.
Employees and Human Capital Resources
As of December 31, 2021, we had 114 full-time employees, which increased to 115 full-time employees as of the date of the filing of this Annual Report on Form 10-K. Of these employees,
approximately half are members of our sales team. Our next largest functions after sales are our technical operations, medical affairs and commercial operations
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functions. None of our employees are represented by a labor union or are covered by a collective bargaining agreement, and we consider our relationship with our employees to be good.
Our human capital is essential to fulfilling our commitment to deliver medicines that provide a better life for cancer patients. We are committed to creating a culture where our employees are
valued. Our core corporate work values, which are integral to our culture and our recruitment and retention initiatives, include:
•
Respect: Trusting, Honest Communication, Collaborative, Considerate, Humility
•
Sense of Thoughtful Urgency: Realistic, Disciplined, Quality Driven, Diligent, Dynamic
•
Integrity: Ethical, Objective, Data Driven, Patient Focused
•
Goal Oriented: Strong Work Ethic, Individual Accountability, Courageous, Perseverance
•
Engaging Working Environment: Fun, Diverse, Sense of Community, Flexibility, Developmental
Our board of directors approves corporate goals on an annual basis, which aids in the development of annual individual employee goals. We have a compensation philosophy of
benchmarking compensation at the 50th percentile for all of our employees, which is based on a survey provided to us by our independent compensation consultant along with input from our
executive leadership team, the compensation committee of the board of directors and our board of directors in an effort to ensure that employee compensation is competitive compared to similar
biotechnology and biopharmaceutical companies with which we compete for talent. For certain of our employees, we recently replaced our Key Employee Change in Control Benefits Plan and other
employment agreements with certain of our employees to our new Executive Severance and Change in Control Benefits Plan, or the Plan. The Plan was updated to meet current market and industry
standards for those employees subject to the Plan including, providing payments to an employee's beneficiary or legal representative in the event of such employee's death or permanent disability and
enhancing severance benefits in a change of control scenario.
Beyond competitive compensation and benefits packages, we provide career development opportunities and encourage ongoing conversations between employees and managers to discuss
individual career development plans. We offer reimbursement for professional memberships as well as professional development courses ranging from technical training, competency-based
workshops and leadership development programs facilitated by external partners who are experts in their respective fields.
We are committed to creating an environment of diversity and inclusion. We believe that diverse backgrounds and perspectives provide us with better ideas and collaboration across our
organization. It is our policy to maintain a work environment free from discrimination based on race, color, religion, national origin, gender, gender identity, transgender status, sexual orientation, age,
physical or mental disability, genetic information, veteran status or marital status.
Corporate Information
We were incorporated under the laws of the State of Delaware on October 19, 2001 as GenPath Pharmaceuticals, Inc. and changed our name to AVEO Pharmaceuticals, Inc. on March 1,
2005.
Available Information
Our Internet website is located at www.aveooncology.com, and our investor relations website is located at https://investor.aveooncology.com. We will make available on our website, free of
charge, our Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, Current Reports on Form 8-K and any amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d)
of the Exchange Act, as soon as reasonably practicable after we electronically file such material with, or furnish it to, the U.S. Securities and Exchange Commission, or SEC, as required by the
Securities Exchange Act of 1934, as amended, which we refer to as the Exchange Act. You can review our electronically filed reports and other information that we file with the SEC on the SEC’s
web site at www.sec.gov.
Investors and others should note that we announce material information to our investors using one or more of the following: SEC filings, press releases and our corporate website, including
without limitation the “Investors” section of our website. We use these channels, as well as social media channels such as Twitter and LinkedIn, in order to achieve broad, non-exclusionary
distribution of information to the public and for complying with our disclosure obligations under Regulation FD. It is possible that the information we post on our corporate website or other social
media could be deemed to be material information. Therefore, we encourage investors, the media, and others interested in our company to review the information we post on the “Investor” section of
our corporate website and on our social media channels.
We have posted copies of our Code of Business Conduct and Ethics and Corporate Governance Guidelines, as well as each of our committee charters, on the “Corporate Governance” sub-
section of the “Investors” section of our website, which you can access free of charge. In addition, we regularly use our website to post information regarding our business, product development
programs and governance, and we encourage investors to use our website, particularly the information in each of the sections entitled “Investors” and “Media,” as a source of information about us.
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References to our website and information found on our website should not be deemed incorporated by reference into this Annual Report on Form 10-K.
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Item 1A.    Risk Factors
You should carefully consider the risks described below in addition to the other information set forth in this Annual Report on Form 10-K, including the Management’s Discussion and
Analysis of Financial Condition and Results of Operations section and the consolidated financial statements and related notes. These risks, some of which have occurred and any of which may occur
in the future, can have a material adverse effect on our business, financial condition, results of operations or the price of our publicly traded securities. The risks described below are not the only
risks we face. Additional risks and uncertainties not currently known to us, or that we currently deem to be immaterial, may occur or become material in the future and adversely affect our business,
reputation, financial condition, results of operations or the price of our publicly traded securities. Therefore, historical operating results, financial and business performance, events and trends are
often not a reliable indicator of future operating results, financial and business performance, events or trends. If any of the following risks occurs, our business, financial condition, and results of
operations and future growth prospects could be materially and adversely affected.
Risks Related to Our Financial Position and Need for Additional Capital
We have incurred significant operating losses since inception and anticipate that we will continue to incur significant operating expenses for the foreseeable future. It is uncertain if we will ever
achieve or sustain profitability.
We have a history of incurring operating losses and as of December 31, 2021, we had an accumulated deficit of $674.5 million. To date, we have not generated significant revenues from the
sale of products. Our operating losses have resulted principally from costs incurred in our discovery and development activities. On March 10, 2021, the FDA approved FOTIVDA in the United
States for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic therapies. We anticipate that we will continue to incur significant operating
expenses for the foreseeable future as we commercialize FOTIVDA in the United States and continue our planned development activities for our clinical stage assets. Our future product revenues will
depend upon the size of markets in which FOTIVDA, and any future products, have received approval, and our ability to achieve sufficient market acceptance, reimbursement from third-party payers
and adequate market share for FOTIVDA and any future products in those markets. The likelihood of our long-term success must be considered in light of the expenses, difficulties and potential
delays to be encountered in the development and commercialization of new pharmaceutical products, competitive factors in the marketplace and the complex regulatory environment in which we
operate.
If we do not effectively manufacture, market and sell FOTIVDA in the United States and if we do not successfully develop, obtain and maintain regulatory approval for our existing and
future pipeline of product candidates we may never generate sufficient revenues from product sales to support our cost structure in order to attain or sustain profitability on a quarterly or annual basis.
Our failure to become and remain profitable would depress the market price of our common stock and could impair our ability to raise capital, expand our business, diversify our product offerings or
continue our operations.
We may require substantial additional funding to advance our pipeline of clinical stage assets, and a failure to obtain this necessary capital when needed would force us to delay, limit, reduce or
terminate our research, product development or commercialization efforts.
We believe that our $87.3 million in cash, cash equivalents and marketable securities as of December 31, 2021, along with net product revenues from product sales of FOTIVDA in the
United States, would enable us to maintain our current operations for more than 12 months following the filing of this Annual Report on Form 10-K.
However, there are numerous risks and uncertainties associated with the research, development and commercialization of pharmaceutical products including, without limitation, risks related
to our ability to generate product revenue from sales of FOTIVDA in the United States, which became commercially available in the United States in March 2021. Accordingly, our future capital
requirements may vary from our current expectations and depend on many factors, including but not limited to:
•
the cost of commercialization activities of FOTIVDA in the United States and any of our product candidates that may be approved for sale, including marketing, sales and
distribution costs;
•
the cost of manufacturing FOTIVDA in the United States, our product candidates and any additional products we may successfully commercialize;
•
the impact of COVID-19 on our operations, business and prospects;
 
43

•
our ability to establish and maintain strategic partnerships, licensing, collaboration or other arrangements and the financial terms of such agreements;
•
the number of product candidates we pursue as well as the development needs and opportunities for each product candidate;
•
the scope, progress, results and costs of researching and developing our product candidates and of conducting preclinical and clinical trials;
•
the timing of, and the costs involved in, completing our clinical trials and obtaining regulatory approvals for our product candidates;
•
the costs involved in preparing, filing, prosecuting, maintaining, defending and enforcing patent claims, including litigation costs and the outcome of such litigation;
•
the absence of any breach, acceleration event or event of default under our 2020 Loan Facility (as defined below), or under any other agreements with third parties;
•
the cost and outcome of any legal actions against us;
•
the timing, receipt and amount of sales of, or royalties on, FOTIVDA and our future products, if any;
•
and general economic, industry and market conditions, including, without limitation, the current adverse impact of the COVID-19 pandemic and political and economic instability
caused by the current armed conflict between Russia and Ukraine and economic sanctions adopted in response to the conflict.
We may require substantial additional funding to advance our pipeline of clinical stage assets. We may seek to sell additional equity or debt securities or obtain additional credit facilities.
The sale of additional equity or convertible debt securities may result in additional dilution to our stockholders. If we raise additional funds through the issuance of debt securities or preferred stock or
through additional credit facilities, these securities and/or the loans under credit facilities could provide for rights senior to those of our common stock and could contain covenants that would restrict
our operations. Additional funds may not be available when we need them, on terms that are acceptable to us, or at all. For example, we may never achieve the milestone specified in the 2020 Loan
Facility that would allow us to access the remaining $5.0 million in available credit. We also expect to seek additional funds through arrangements with partners, licensees, collaborators or other third
parties. These arrangements would generally require us to relinquish or encumber rights to some of our technologies or product candidates, and we may not be able to enter into such arrangements on
acceptable terms, if at all.
If we are unable to raise substantial additional funding to advance our pipeline of clinical stage assets, whether on terms that are acceptable to us, or at all, or if we were to default under the
2020 Loan Facility and Hercules accelerates the then remaining principal payments and fees due under the 2020 Loan Facility, then we may be required to:
•
delay, limit, reduce or terminate our clinical trials or other development activities for one or more of our product candidates; and/or
•
delay, limit, reduce or terminate our establishment of sales and marketing capabilities or other activities that may be necessary to commercialize our product candidates, if approved.
Failure to comply with the covenants or payment obligations under the 2020 Loan Facility could result in an event of default, which could materially and adversely affect our business and our
financial condition.
The 2020 Loan Facility includes certain financial and operational covenants and provides for certain occurrences that constitute events of default. Certain of those covenants may be out of
our control, such as failure to achieve net product revenue at a certain percentage of projected net product revenue. Potential events of default also include circumstances occurring that would have a
material adverse effect on our business, our insolvency or bankruptcy or default on our other obligations or agreements. If we fail to make payments when due, breach any operational covenant or
have any event of default, Hercules could require us to immediately repay all outstanding principal and accrued interest on the loan, plus a prepayment charge, which could have a material adverse
effect on our business and financial condition.
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We have only recently transitioned from a development stage biopharmaceutical company to a commercial stage biopharmaceutical company, which may make it difficult for you to evaluate the
success of our business to date and to assess our future viability.
Other than the marketing approvals for FOTIVDA received by our partner EUSA and the FDA marketing approval for FOTIVDA received in the United States in March 2021, all of our
product candidates are in the development stage. We have only recently demonstrated our ability, or our ability to arrange for a third party, to manufacture a commercial scale medicine and conduct
the sales and marketing activities necessary to commercialize a product. Consequently, any predictions you make about our future success or viability may not be as accurate as they could be if we
had more experience commercializing FOTIVDA. In addition, as a relatively new commercial stage business, we may encounter unforeseen expenses, difficulties, complications, delays and other
known and unknown factors. To be profitable, we will need to continue to successfully transition from a company with a research and development focus to a company capable of supporting
commercial activities. Ultimately, we may not be successful in such a transition.
Risks Related to Development and Commercialization of Our Product Candidates
In the near term, we are substantially dependent on the success of FOTIVDA (tivozanib). If we are unable to successfully commercialize FOTIVDA or maintain marketing approval for
FOTIVDA in its approved indication, or if we are unable to complete planned or ongoing clinical development of tivozanib to obtain marketing approval for tivozanib in other indications, either
alone or with our collaborators, or if we experience significant delays in doing so, our business could be substantially harmed.
Our prospects are substantially dependent on our ability to successfully commercialize FOTIVDA in the United States and maintain marketing approval for FOTIVDA in the United States,
or through EUSA, in those countries outside the United States where FOTIVDA is currently approved. While we recorded a growing number of commercial prescriptions, factors beyond our control
may result in decreases in commercial prescriptions each month or each quarter. If commercial prescription demand becomes stagnant or decreases it would substantially impact our revenues from
product sales, adversely affect our profitability on a quarterly or annual basis and depress the market price of our common stock.
We are also dependent on the success of tivozanib in clinical development and our ability to obtain additional marketing approvals for tivozanib in one or more other indications.
The success of FOTIVDA will depend on a number of factors, including the following:
•
our ability to successfully commercialize FOTIVDA in the United States;
•
our ability to enhance commercial awareness of FOTIVDA;
•
commercial acceptance by physicians, patients, third-party payors and others in the medical community;
•
our ability to gain access to customers during the COVID-19 pandemic;
•
our ability to successfully enroll and complete clinical trials of tivozanib, including the DEDUCTIVE trial and the TiNivo-2 Trial;
•
a continued acceptable safety, tolerability and efficacy profile that is satisfactory to applicable regulatory authorities following any marketing approval;
•
timely receipt of marketing approvals from applicable regulatory authorities such as the FDA;
•
the performance of the contract research organizations, or CROs, we have hired to manage our clinical trials, as well as that of our collaborators, investigator sponsors and other
third-party contractors;
•
the extent of any future post-marketing approval commitments to applicable regulatory authorities;
•
maintenance of existing or establishment of new supply arrangements with third-party raw materials suppliers and manufacturers including with respect to the supply of active
pharmaceutical ingredient for tivozanib and finished drug product that is appropriately packaged for sale;
•
adequate ongoing availability of raw materials and drug product for clinical development and any commercial sales;
•
obtaining and maintaining patent, trade secret protection and regulatory exclusivity, both in the United States and internationally, including our ability to maintain our license
agreement with KKC;
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•
protection of our rights in our intellectual property portfolio, including our ability to maintain our license agreement with KKC; and
•
our ability to compete with other therapies.
Many of these factors are beyond our control. If we are unable to continue to successfully commercialize FOTIVDA in the United States or to develop or receive marketing approval for
tivozanib in other indications, on our own or with our collaborators, or experience delays as a result of any of these factors or otherwise, our business could be substantially harmed.
FOTIVDA, or any one of our product candidates that may receive marketing approval in the future, may fail to achieve the degree of market acceptance by physicians, patients, third-party
payors and others in the medical community necessary for commercial success and the market opportunity for FOTIVDA or any one of our product candidates may be smaller than our
estimates.
FOTIVDA, or any one of our product candidates that may be approved in the future by the appropriate regulatory authorities for marketing and sale, may fail to gain sufficient market
acceptance by physicians, patients, third-party payors and others in the medical community. Physicians are often reluctant to switch their patients from existing therapies even when new and
potentially more effective or convenient treatments enter the market. There are already a number of therapies on the market competitive to FOTIVDA, as well as our other product candidates, in
indications we intend to target.
Efforts to educate the medical community and third-party payors on the benefits of our product candidates have required significant resources and may not ultimately be successful.
Restrictions related to the ongoing COVID-19 pandemic have impeded our ability to gain in-person access to customers, prescribers, other healthcare professionals and to certain institutions that
remain closed to industry representatives. We believe these access challenges caused by the COVID-19 pandemic and the emergence of SARs-CoV-2 variants have potentially slowed the commercial
launch trajectory of FOTIVDA which we believe is causing a protracted launch curve as compared to the pre-COVID open access environment. While we have designed our strategic commercial
approach to be optimized for remote as well as in-person customer engagement capabilities and expanded our digital marketing strategies in light of the restrictions necessitated by the COVID-19
pandemic, changes to standard sales and marketing practices, including the shift from in-person to video and virtual interactions with healthcare professionals, have caused, and may continue to
cause, challenges for the successful commercialization of FOTIVDA.
If FOTIVDA, or any of our product candidates that may be approved for marketing and sale in the future, does not achieve an adequate level of market acceptance, we may not generate
significant revenues and we may not become profitable. The degree of market acceptance of FOTIVDA, or any of our product candidates that may be approved for marketing and sale in the future,
will depend on a number of factors, including:
•
the advantages of the product compared to competitive therapies;
•
the number of competitors approved for similar uses;
•
our ability to gain access to customers during the COVID-19 pandemic;
•
the relative promotional effort and marketing success of us as compared with our competitors;
•
how the product is positioned in physician treatment guidelines and pathways;
•
the prevalence and severity of any side effects;
•
the efficacy and safety of the product;
•
our ability to offer the product for sale at competitive prices;
•
the product’s tolerability, convenience and ease of administration compared to alternative treatments;
•
the willingness of the target patient population to try, and of physicians to prescribe, the product;
•
limitations or warnings, including use restrictions, contained in the product’s approved labeling;
•
the strength of sales, marketing and distribution support;
•
the timing of market introduction of our approved products as well as competitive products;
•
adverse publicity about the product or favorable publicity about competitive products;
•
potential product liability claims;
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•
changes in the standard of care for the targeted indications of the product; and
•
availability and amount of coverage and reimbursement from government payors, managed care plans and other third-party payors.
In addition, the potential market opportunities for FOTIVDA and our product candidates are difficult to estimate precisely. Our estimates of the potential market opportunities are predicated
on many assumptions, including industry knowledge and publications, third-party research reports and other surveys. While we believe that our internal assumptions are reasonable, these assumptions
involve the exercise of significant judgment on the part of our management, are inherently uncertain and the reasonableness of these assumptions has not been assessed by an independent source. If
any of the assumptions prove to be inaccurate, the actual markets for our product candidate could be smaller than our estimates of the potential market opportunities.
If the FDA, EMA or other comparable foreign regulatory authorities approve generic versions of FOTIVDA®, the sales of FOTIVDA® could be adversely affected.
Once an NDA is approved, the product covered thereby becomes a “reference listed drug” in the FDA’s publication, “Approved Drug Products with Therapeutic Equivalence Evaluations,”
commonly known as the Orange Book. Manufacturers may seek approval of generic versions of reference listed drugs through submission of abbreviated new drug applications, or ANDAs, in the
United States. In support of an ANDA, a generic manufacturer need not conduct clinical trials to assess safety and efficacy. Rather, the applicant generally must show that its product has the same
active ingredient(s), dosage form, strength, route of administration and conditions of use or labelling as the reference listed drug and that the generic version is bioequivalent to the reference listed
drug, meaning it is absorbed in the body at the same rate and to the same extent. Generic products may be significantly less costly to bring to market than the reference listed drug and companies that
produce generic products are generally able to offer them at lower prices. Thus, following the introduction of a generic drug, a significant percentage of the sales of any branded product or reference
listed drug is typically lost to the generic product.
The FDA may not approve an ANDA for a generic product until any applicable period of non-patent exclusivity for the reference listed drug has expired. The FDA provides a period of five
years of non-patent exclusivity for a new drug containing a new chemical entity. Specifically, in cases where such exclusivity has been granted, as is the case with FOTIVDA , an ANDA may not be
submitted to the FDA until the expiration of five years, e.g., March 10, 2026, for FOTIVDA®, unless the submission is accompanied by a Paragraph IV certification that a patent covering the
reference listed drug is either invalid or will not be infringed by the generic product, in which case the applicant may submit its application four years following approval of the reference listed drug,
e.g., March 10, 2025, for FOTIVDA .
Generic drug manufacturers may seek to launch generic products following the expiration of the applicable exclusivity period for FOTIVDA , even if we still have patent protection for such
products. Competition that FOTIVDA  could face from generic versions could materially and adversely affect our future revenue, profitability, and cash flows and substantially limit our ability to
obtain a return on the investments we have made in developing FOTIVDA .
In addition to our dependence on the success of FOTIVDA, we depend on the success of our clinical stage assets, including tivozanib (in other indications), ficlatuzumab, AV-380 and AV-203.
Preclinical studies and clinical trials of our product candidates may not be successful. If we are unable to complete the clinical development of, obtain marketing approval for or successfully
commercialize our product candidates, either alone or with a collaborator, or if we experience significant delays in doing so, our business will be materially harmed.
We and any collaborators, including our partners and sublicensees, are not permitted to commercialize, market, promote or sell any product candidate in the United States without obtaining
marketing approval from the FDA. Foreign regulatory authorities, such as the European Medicines Agency, or the EMA, impose similar requirements. We and our collaborators must complete
extensive preclinical development and clinical trials that demonstrate the safety and efficacy of our product candidates in humans before we can obtain these approvals. Despite our efforts to design
satisfactory clinical trial protocols, we cannot guarantee that the clinical trial protocols of any of our ongoing clinical trials will satisfy the rigorous standards of the FDA and/or the EMA to support a
marketing approval. If we seek to amend the clinical trial protocols for any of our clinical trials this may delay site enrollment and completion, as in the case of the TiNivo-2 Trial where we made a
clinical trial protocol amendment. The TiNivo-2 trial protocol was amended based on (i) emerging evidence that the lower 0.89 mg dose was effective in combination with an ICI, (ii) that the lower
dose may optimize the risk/benefit profile and result in better tolerability for the combination and (iii) the FDA’s recommendation to investigate an optimal dose of tivozanib in the combination
setting under its Project Optimus initiative. We cannot be certain that this
®
®
®
®
®
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amendment to the TiNivo-2 protocol will satisfy the FDA's Project Optimus initiative to investigate the optimal dose of tivozanib in the combination setting and, if it does not, we may be required to
conduct additional clinical trials which would delay and adversely impact the timing of marketing approval of tivozanib in combination with nivolumab or other therapies.
We depend heavily on the success of our clinical stage assets and our clinical trials may not be successful. If delays in manufacturing, trial site initiation or patient enrollment occur, whether
due to the impacts of the ongoing COVID-19 pandemic or otherwise, our clinical stage assets will develop at a slower pace than we had planned. For example, the delivery of the clinical supply of
ficlatuzumab for a potential registrational clinical trial of ficlatuzumab in R/M HNSCC was significantly delayed due to the shortage of key raw materials and manufacturing supplies also used in
COVID-19 vaccine manufacturing which required us to delay the start date of this potential registrational clinical trial until 2023.
Preclinical and clinical testing is expensive, is difficult to design and implement, can take many years to complete and is inherently uncertain as to outcome. We cannot guarantee that any
clinical trials will be conducted as planned or completed on schedule, if at all, particularly given that many of our clinical trial sites are research hospitals that have imposed restrictions on entry and
other activity as a result of the COVID-19 pandemic. The preclinical and clinical development of our product candidates is susceptible to the risk of failure inherent at any stage of product
development. For example, in December 2020, the FDA approved our investigational new drug, or IND, application for AV-380 for the potential treatment of cancer cachexia. In October 2021, we
completed enrollment for a Phase 1 clinical trial in healthy subjects. Initial data observed satisfactory a reduction of GDF15 in subjects and no drug related adverse events were identified. However,
operational errors at the trial site have caused data integrity concerns and we have notified the FDA. We plan to discuss with the FDA the suitability of the data for regulatory purposes and our ability
to publish the data from this trial. We do not expect the data quality issues in the Phase 1 clinical trial to impact our plans to initiate a Phase 1b clinical trial in cancer patients in the second half of
2022. We cannot be certain that the data integrity concerns related to the Phase 1 clinical trial will not ultimately delay the development of our AV-380 program.
Moreover, we, or any collaborators, may experience any of a number of possible unforeseen adverse events in connection with clinical trials, many of which are beyond our control,
including:
•
we, or our collaborators, may fail to demonstrate efficacy in a clinical trial or across a broad population of patients;
•
the supply or quality of raw materials, manufactured product candidates or other materials necessary to conduct clinical trials of our product candidates may be significantly
delayed, insufficient, inadequate or not available at an acceptable cost, or we may experience interruptions in supply, due to challenges related to the COVID-19 pandemic or
otherwise;
•
it is possible that even if one or more of our product candidates has a beneficial effect, that effect (a) will not be detected during preclinical or clinical evaluation or (b) may indicate
an apparent positive effect of a product candidate that is greater than the actual positive effect as a result of one or more of a variety of factors, including the size, duration, design,
measurements, conduct or analysis of our clinical trials;
•
we may fail to detect toxicity or intolerability of our product candidates, or mistakenly believe that our product candidates are toxic or not well tolerated when that is not in fact the
case;
•
adverse events or undesirable side effects caused by, or other unexpected properties of, any product candidates that we may develop could cause us, any collaborators, an
institutional review board or regulatory authorities to interrupt, delay or halt clinical trials of one or more of our product candidates and could result in a more restrictive label or the
delay or denial of marketing approval by the FDA or comparable foreign regulatory authorities;
•
if any of our product candidates is associated with adverse events or undesirable side effects or has properties that are unexpected, we, or any collaborators, may need to abandon
development or limit development of that product candidate to certain uses or subpopulations in which the undesirable side effects or other characteristics are less prevalent, less
severe or more acceptable from a risk-benefit perspective;
•
regulators or institutional review boards may not authorize us, any collaborators or our or their investigators to commence a clinical trial or conduct a clinical trial at a prospective
trial site;
•
we, or any collaborators, may have delays in reaching or fail to reach agreement on acceptable clinical trial contracts or clinical trial protocols with prospective trial sites;
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•
clinical trials of our product candidates may produce unfavorable or inconclusive results, including with respect to the safety, tolerability, efficacy or pharmacodynamic and
pharmacokinetic profile of the product candidate;
•
we, or any collaborators, may decide, or regulators may require us or them, to conduct additional clinical trials or abandon product development programs;
•
the number of patients required for clinical trials of our product candidates may be larger than we, or any collaborators, anticipate, patient enrollment in these clinical trials may be
slower than we, or any collaborators, anticipate or participants may drop out of these clinical trials at a higher rate than we, or any collaborators, anticipate;
•
our estimates of the patient populations available for study may be higher than actual patient numbers and result in our inability to sufficiently enroll our trials;
•
the cost of planned clinical trials of our product candidates may be greater than we anticipate;
•
our third-party contractors or those of any collaborators, including those manufacturing our product candidates or components or ingredients thereof or conducting clinical trials on
our behalf or on behalf of any collaborators, may fail to comply with regulatory requirements, including GMPs, GCPs or GLPs, or meet their contractual obligations to us or any
collaborators in a timely manner or at all;
•
patients that enroll in a clinical trial may misrepresent their eligibility to do so or may otherwise not comply with the clinical trial protocol, resulting in the need to increase the
needed enrollment size for the clinical trial, extend the clinical trial’s duration, or drop the patients from the final efficacy analysis for the clinical trial, which can negatively affect
the statistical power of the results;
•
our decision, or a decision by regulators or institutional review boards, that may require us to suspend or terminate clinical research for various reasons, including noncompliance
with regulatory requirements or their standards of conduct, a finding that the participants are being exposed to unacceptable health risks, undesirable side effects or other unexpected
characteristics of the product candidate or findings of undesirable effects caused by a chemically or mechanistically similar product or product candidate;
•
the FDA or comparable foreign regulatory authorities may disagree with our, or any collaborators’, clinical trial designs or our or their interpretation of data from preclinical studies
and clinical trials;
•
the FDA or comparable foreign regulatory authorities may fail to approve or subsequently find fault with the manufacturing processes or facilities of third-party manufacturers with
which we, or any collaborators, enter into agreements for clinical and commercial supplies;
•
the approval policies or regulations of the FDA or comparable foreign regulatory authorities may significantly change in a manner rendering our clinical data insufficient to obtain
marketing approval; and
•
constraints on our, or any collaborators’, ability to conduct or complete clinical trials for our product candidates due to the COVID-19 pandemic, including slowdowns in patient
enrollment, or necessary supplies, restrictions on patient monitoring at hospital clinical trial sites, closures of third-party facilities, and other disruptions to clinical trial activities.
Product development costs for us and our collaborators will increase if we experience delays in testing or pursuing marketing approvals, and we may be required to obtain additional funds to
complete clinical trials and prepare for possible commercialization. We do not know whether any clinical trials will begin as planned, will need to be restructured or will be completed on schedule or
at all. Significant clinical trial delays also could shorten any periods during which we may have the exclusive right to commercialize our product candidates or allow our competitors to bring products
to market before we do, which could impair our ability to successfully commercialize our product candidates and may harm our business and results of operations. In addition, many of the factors that
lead to clinical trial delays may ultimately lead to the denial of marketing approval of any of our product candidates.
If the commercial launch of FOTIVDA for which we recruited a sales force and established marketing, market access and medical affairs teams and distribution capabilities is not successful for
any reason, we could incur substantial costs
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and our investment would be lost if we cannot retain or reassign our sales, marketing, market access and medical affairs personnel.
To achieve commercial success for FOTIVDA, we have expended and anticipate that we will continue to expend significant resources to support our sales force, marketing, market access
and medical affairs teams and distribution capabilities. There are risks involved with establishing our own sales, marketing, distribution, training and support capabilities. For example, recruiting and
training sales and marketing personnel is expensive and time consuming and could delay our ability to focus on other priorities. If the commercial launch of FOTIVDA is not successful for any
reason, this would be costly, and our investment would be lost if we cannot retain or reassign our sales, marketing, market access and medical affairs personnel or terminate on favorable terms any
agreements entered into with third parties to support our commercialization efforts.
Factors that may inhibit or limit our efforts to commercialize FOTIVDA on our own include:
•
our inability to train and retain adequate numbers of effective sales, marketing, training and support personnel;
•
the inability of sales personnel to obtain access to physicians, including key opinion leaders, or to educate an adequate number of physicians of the benefits of FOTIVDA over
alternative treatment options;
•
limited access to our customers due to the COVID-19 pandemic; and
•
unforeseen costs and expenses associated with establishing and maintaining an independent sales, marketing, training and support organization.
If our salesforce, marketing, market access and medical affairs teams and distribution capabilities fail, or are otherwise unsuccessful, it would materially adversely impact the
commercialization of FOTIVDA, impact our ability to generate revenue and harm our business.
If we fail to develop and commercialize other product candidates, we may be unable to grow our business.
Although the commercialization of FOTIVDA and the continued development of tivozanib is our primary focus, as part of our growth strategy, we are developing a pipeline of product
candidates. These other product candidates will require additional, time-consuming and costly development efforts, by us or by our collaborators, prior to commercial sale, including preclinical
studies, clinical trials and approval by the FDA and/or applicable foreign regulatory authorities. All product candidates are prone to the risks of failure that are inherent in pharmaceutical product
development, including the possibility that the product candidate will not be shown to be sufficiently safe and/or effective for approval by regulatory authorities. In addition, we cannot assure you that
any such products that are approved will be manufactured or produced economically, successfully commercialized or widely accepted in the marketplace, or will be more effective than other
commercially available alternatives.
We may not obtain additional marketing approvals for tivozanib in other indications or initial approval for our other product candidates.
We may not obtain additional marketing approvals for our product candidates. It is possible that the FDA or comparable foreign regulatory agencies may refuse to accept for substantive
review any future application that we or a collaborator may submit to market and sell our product candidates, or that any such agency may conclude after review of our or our collaborator’s data that
such application is insufficient to obtain marketing approval of our product candidate.
If the FDA or other comparable foreign regulatory agency does not accept or approve any future application to market and sell any of our product candidates, such regulators may require
that we conduct additional clinical trials, preclinical studies or manufacturing validation studies and submit that data before they will reconsider our application. Depending on the extent of these or
any other required trials or studies, approval of any application that we submit may be delayed by several years, or may require us or our collaborator to expend more resources than we or they have
available. It is also possible that additional trials or studies, if performed and completed, may not be considered sufficient by the FDA or other foreign regulatory agency to approve our applications
for marketing and commercialization.
Any delay in obtaining, or an inability to obtain, marketing approvals would prevent us or our collaborators from commercializing tivozanib in other indications or our product candidates
and generating revenues. If any of these outcomes occur, we would not be eligible for certain milestone and royalty revenue under our partnership agreements, our
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collaborators could terminate our partnership agreements and we may be forced to abandon our development efforts for our product candidates, any of which could significantly harm our business.
Results of early clinical trials may not be predictive of results of later clinical trials, and interim results of clinical trials may not be predictive of the final results or the success of clinical trials.
The outcome of early clinical trials, such as our DEDUCTIVE trial and our ficlatuzumab trials in HNSCC, pancreatic cancer and AML, may not be predictive of the success of later clinical
trials. Many companies in the pharmaceutical and biotechnology industries have suffered significant setbacks in late-stage clinical trials after achieving positive results in earlier development, and we
have, and could in the future, face similar setbacks. In addition, interim results and analyses of clinical trials do not necessarily predict the final results or the success of a trial once it is complete.
While the design of a clinical trial may help to establish whether its results will support approval of a product, flaws in the design of a clinical trial may not become apparent until the clinical
trial is well advanced. We have limited experience in designing clinical trials and may be unable to design and execute a clinical trial to support marketing approval. In addition, preclinical and
clinical data are often susceptible to varying interpretations and analyses. Many companies that believed their product candidates performed satisfactorily in preclinical studies and clinical trials have
nonetheless failed to obtain marketing approval for the product candidates. Even if we, or any collaborators, believe that the results of clinical trials for our product candidates warrant marketing
approval, the FDA or comparable foreign regulatory authorities may disagree and may not grant marketing approval of our product candidates. For example, in June 2013, we suffered such a setback
when the FDA issued a complete response letter, or the 2013 CRL, informing us that it would not approve tivozanib for the first-line treatment of RCC based solely on the data from the TIVO-1 trial,
and recommended that we perform an additional clinical trial adequately sized to assure the FDA that tivozanib did not adversely affect overall survival, or OS. We then designed and initiated our
TIVO-3 trial to address the FDA’s concerns about the negative OS trend expressed in the 2013 CRL, which took time and resources and delayed our efforts to obtain marketing approval for tivozanib
in the United States.
If we fail to receive positive results in clinical trials of our product candidates, the development timeline and regulatory approval and commercialization prospects for our most advanced
product candidates, and, correspondingly, our business and financial prospects would be negatively impacted.
If we or our collaborators experience delays or difficulties in the enrollment of patients in clinical trials, receipt of necessary regulatory approvals could be delayed or prevented.
We or our collaborators may not be able to initiate or continue clinical trials for our product candidates if we are unable to locate and enroll a sufficient number of eligible patients to
participate in clinical trials. Patient enrollment is a significant factor in the timing of clinical trials, and is affected by many factors, including:
•
the impact of the COVID-19 pandemic;
•
the size and nature of the patient population;
•
the severity of the disease under investigation;
•
the availability of approved therapeutics for the relevant disease;
•
the evolving standard of care landscape;
•
the proximity of patients to clinical sites;
•
the design of and eligibility criteria for the trial;
•
efforts to facilitate timely enrollment; and
•
competing clinical trials.
In addition, participation in our clinical trials will be affected by clinicians’ and patients’ perceptions as to the potential advantages and risks of the drug being studied and the drug being
provided as a control in relation to other available therapies, including any new drugs that may be approved or any changes to the standard of care for the indications we are investigating. For
example, changes in the standard of care in HCC have extended treatment time with first line therapies and reduced the presence of a sufficient patient pool suitable for the DEDUCTIVE trial, which
has delayed patient enrollment for the trial.
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If approved, our product candidates, such as ficlatuzumab, AV-380, or AV-203, that are licensed and regulated as biologics may face competition from biosimilars approved through an
abbreviated regulatory pathway.
The Biologics Price Competition and Innovation Act of 2009, or BPCIA, was enacted as part of the Patient Protection and Affordable Care Act, or the ACA, to establish an abbreviated
pathway for the approval of biosimilar and interchangeable biological products. The regulatory pathway establishes legal authority for the FDA to review and approve biosimilar biologics, including
the possible designation of a biosimilar as “interchangeable” based on its similarity to an approved biologic. Under the BPCIA, our antibody product candidates, for example, ficlatuzumab, AV-380 or
AV-203, if approved by the FDA, would benefit from 12 years of data exclusivity from the time of first licensure. While the FDA could not accept an application for a biosimilar or interchangeable
product based on our biologic product candidates, such as ficlatuzumab, AV-380 or AV-203, as the reference biological product until four years after the date of first licensure of our product
candidate, during this 12-year period of exclusivity, another party may still independently develop and receive approval of a competing biologic, so long as its BLA does not rely on our product
candidate’s data or submit the application as a biosimilar application. The law is complex and is still being interpreted and implemented by the FDA. As a result, its ultimate impact, implementation,
and meaning are subject to uncertainty, and any new policies or processes adopted by the FDA could have a material adverse effect on the future commercial prospects for our biological products.
We believe that any of the biological product candidates we develop under a BLA, such as ficlatuzumab, AV-380 or AV-203, should qualify for the 12-year period of exclusivity. However,
there is a risk that this exclusivity could be shortened due to congressional action or otherwise, or that the FDA will not consider the subject product candidates to be reference products for competing
products, potentially creating the opportunity for biosimilar competition sooner than anticipated. Moreover, the extent to which a biosimilar, once approved, will be substituted for any one of the
reference products in a way that is similar to traditional generic substitution for non-biological products will depend on a number of marketplace and regulatory factors that are still developing.
Nonetheless, the approval of a biosimilar to our biologic product candidates, such as ficlatuzumab, AV-380 or AV-203, would have a material adverse impact on our business due to increased
competition and pricing pressure.
Even if a product candidate receives marketing approval, we or others may later discover that the product is less effective than previously believed or causes undesirable side effects that were not
previously identified, which could compromise our ability or that of any collaborators to market the product, and could cause regulatory authorities to take certain regulatory actions.
It is possible that our clinical trials may indicate an apparent positive effect of a product candidate that is greater than the actual positive effect, if any, or alternatively fail to identify
undesirable side effects. For example, despite the recent FDA marketing approval of FOTIVDA in the United States, we, or others, may discover that FOTIVDA is less effective or tolerable than
previously believed. If, we, or others, discover that a product is less effective than previously believed or causes undesirable side effects that were not previously identified, any of the following
adverse events could occur:
•
regulatory authorities may withdraw their approval of the product or seize the product;
•
we, or any of our collaborators, may be required to recall the product, change the way the product is administered or conduct additional clinical trials;
•
additional restrictions may be imposed on the marketing of, or the manufacturing processes for, the particular product;
•
we, or any of our collaborators, may be subject to fines, injunctions or the imposition of civil or criminal penalties;
•
regulatory authorities may require the addition of labeling statements, such as a “black box” warning or a contraindication;
•
we, or any of our collaborators, may be required to create a Medication Guide outlining the risks of the previously unidentified side effects for distribution to patients;
•
we could be sued and held liable for harm caused to patients;
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•
physicians and patients may stop using our product; and
•
our reputation may suffer.
Any of these events could harm our business and operations and could negatively impact our stock price.
We may expend our limited resources to pursue a particular product candidate or indication and fail to capitalize on product candidates or indications that may be more profitable or for which
there is a greater likelihood of success.
Because we have limited financial and managerial resources, we intend to focus on developing product candidates for specific indications that we identify as most likely to succeed, in terms
of their potential for marketing approval and commercialization, as well as those that are most aligned with our strategic goals. As a result, we may forego or delay pursuit of opportunities with other
product candidates or for other indications that may prove to have greater commercial potential.
Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or profitable market opportunities. Our spending on current and future research and
development programs and product candidates for specific indications may not yield any commercially viable product candidates. If we do not accurately evaluate the commercial potential or target
market for a particular product candidate, we may relinquish valuable rights to that product candidate through collaboration, licensing or other royalty arrangements in cases in which it would have
been more advantageous for us to retain sole development and commercialization rights to the product candidate.
We face substantial competition from existing approved products. Our competitors may also discover, develop or commercialize new competing products before, or more successfully, than we do.
The biotechnology and pharmaceutical industries are highly competitive, and our future success depends on our ability to demonstrate and maintain a competitive advantage with respect to
the design, development and commercialization of product candidates. Our core competitors include pharmaceutical and biotech organizations, as well as academic research institutions, clinical
research laboratories and government agencies that are focusing on the research and development of small molecules and antibodies for cancer treatment. Many of our competitors have greater
financial, technical and human resources than we do. Established competitors may invest heavily to discover and develop novel compounds that could make our product candidates obsolete.
For instance, there are several therapies in clinical development for RCC, HCC and HNSCC that may alter the competitive landscape for the treatment of these cancers. As such, it is difficult
to predict how these changes will inform our perspective on the key competitors for our products in RCC, HCC and HNSCC in the future. In addition, any new product that competes with an
approved product must demonstrate compelling advantages in efficacy, convenience, tolerability and safety in order to obtain approval, to overcome price competition and to be commercially
successful.
Mergers and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated in favor of our competitors. Additionally, many
competitors have greater experience in product discovery and development, obtaining FDA and other regulatory approvals and commercialization capabilities, which may provide them with a
competitive advantage. If we are not able to compete effectively, our business will not grow and our financial condition and operations will suffer.
We believe that our ability to compete will depend on our ability to execute on the following objectives:
•
design studies, execute on development plans and commercialize products that are competitive to other products in the market in terms of, among other things, safety, efficacy,
convenience or price;
•
obtain and maintain patent and/or other proprietary protection for our processes and product candidates;
•
obtain required regulatory approvals;
•
obtain favorable reimbursement, formulary and guideline status;
•
collaborate with others in the design, development and commercialization of our products; and
•
evaluate and pursue strategic business development and partnership opportunities for our programs.
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FOTIVDA, or any other product candidate that we or our collaborators are able to commercialize, may become subject to unfavorable pricing regulations, third-party payor reimbursement
practices or healthcare reform initiatives, any of which could harm our business.
The commercial success of our product candidates will depend substantially, both domestically and abroad, on the extent to which the costs of our product candidates will be paid by third-
party payors, including government health care programs and private health insurers. For example, our European licensee for FOTIVDA, EUSA, is working to secure reimbursement approval for and
commercially launch FOTIVDA in many of the countries in which FOTIVDA has been approved. However, there is significant competition in the first-line RCC setting in the EU due to the approval
of several immunotherapy combinations which have become a standard of care and impacted the market opportunity for monotherapy treatments. If EUSA is unable to secure reimbursement
approval, or reimbursement is limited, and if EUSA is unable to commercially launch FOTIVDA in additional countries and does not seek to expand the label for FOTIVDA to the relapsed or
refractory RCC setting, it may materially impact our ability to generate revenue from sales of FOTIVDA outside of the United States. Even if coverage is provided, the approved reimbursement
amount may not be high enough to allow us or our collaborators to establish or maintain pricing sufficient to realize a sufficient return on our investments. In the United States, no uniform policy of
coverage and reimbursement for products exists among third-party payors, and coverage and reimbursement levels for products can differ significantly from payor to payor. As a result, the coverage
determination process is often time consuming and costly and may require us to provide scientific and clinical support for the use of our products to each payor separately, with no assurance that
coverage and adequate reimbursement will be obtained or applied consistently.
There is significant uncertainty related to third-party payor coverage and reimbursement of newly approved drugs. Marketing approvals, pricing and reimbursement for new drug products
vary widely from country to country. Some countries require approval of the sale price of a drug before it can be marketed. In many countries, the pricing review period begins after marketing or
product licensing approval is granted. In some foreign markets, prescription pharmaceutical pricing remains subject to continuing governmental control even after initial approval is granted. As a
result, we or our collaborators might obtain marketing approval for a product in a particular country, but then be subject to price regulations that delay commercial launch of the product, possibly for
lengthy time periods, which may negatively impact the revenues we are able to generate from the sale of the product in that country. Adverse pricing limitations may hinder our ability to recoup our
or their investment in one or more product candidates, even if our product candidates obtain marketing approval.
Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or part of the costs associated with their treatment. Therefore, our
ability, and the ability of any collaborators, to successfully commercialize any of our product candidates will depend in part on the extent to which coverage and adequate reimbursement for these
products and related treatments will be available from third-party payors. Third-party payors decide which medications they will cover and establish reimbursement levels. The healthcare industry is
acutely focused on cost containment, both in the United States and elsewhere. Government authorities and other third-party payors have attempted to control costs by limiting coverage and the
amount of reimbursement for particular medications, which could affect our ability to sell our product candidates profitably. These payors may not view our products, even if approved, as cost-
effective, and coverage and reimbursement may not be available to our customers or may not be sufficient to allow our products to be marketed on a competitive basis. Cost-control initiatives could
cause us or our collaborators to decrease the price we might establish for products, which could result in lower than anticipated product revenues. If the prices for our products, if any, decrease or if
governmental and other third-party payors do not provide coverage or adequate reimbursement, our prospects for revenue and profitability will suffer.
There may also be delays in obtaining coverage and reimbursement for newly approved drugs, such as FOTIVDA, and coverage may be more limited for FOTIVDA than the indication for
which the drug is approved by the FDA or comparable foreign regulatory authorities. Moreover, eligibility for reimbursement does not imply that any drug will be paid for in all cases or at a rate that
covers our costs, including research, development, manufacture, sale and distribution. Reimbursement rates may vary, for example, according to the use of the product and the clinical setting in which
it is used. Reimbursement rates may also be based on reimbursement levels already set for lower cost drugs or may be incorporated into existing payments for other services.
In addition, increasingly, third-party payors are requiring higher levels of evidence of the benefits and clinical outcomes of new technologies and are challenging the prices charged. We
cannot be sure that coverage will be available for any product candidate that we, or third-parties, commercialize and, if available, that the reimbursement rates will be adequate. Further, the net
reimbursement for drug products may be subject to additional reductions if there are changes to laws that presently restrict imports of drugs from countries where they may be sold at lower prices
than in the United
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States. An inability to promptly obtain coverage and adequate payment rates from both government-funded and private payors for any of our product candidates for which we obtain regulatory
approval could significantly harm our operating results and our overall financial condition.
If product liability lawsuits are brought against us, we may incur substantial liabilities and may be required to limit commercialization of our product candidates.
We face a risk of product liability as a result of the commercialization of FOTIVDA and the clinical testing of our product candidates. If we cannot successfully defend ourselves against
product liability claims, we may incur substantial liabilities or be required to limit the development or commercialization of our product candidates. Even a successful defense could require
significant financial and management resources. Regardless of the merits or eventual outcome, product liability claims may result in:
•
decreased commercial demand for FOTIVDA, resulting in loss of revenue;
•
delay or termination of our clinical trials, or the withdrawal of clinical trial participants;
•
significant costs to defend the related litigation;
•
substantial monetary awards to trial participants or patients;
•
product recalls, withdrawals or labeling, marketing or promotional restrictions;
•
the inability to develop or commercialize our product candidates;
•
injury to our reputation and negative media attention; and
•
a decline in our stock price.
Although we maintain general liability insurance and clinical trial liability insurance, this insurance may not fully cover potential liabilities that we may incur. The cost of any product
liability litigation or other proceeding, even if resolved in our favor, could be substantial. Insurance coverage is becoming increasingly expensive. We increased our insurance coverage for the
commercialization of FOTIVDA and we will need to increase our insurance coverage further if we commercialize any of our other products that receive marketing approval. If we are unable to
maintain sufficient insurance coverage at an acceptable cost or to otherwise protect against potential product liability claims, it could prevent or inhibit the development, commercial production and
sale of our product candidates, which could harm our business, financial condition, results of operations and prospects.
Our internal computer systems or other company technology to collect and store information, or those of any third parties with which we contract, may fail or suffer security breaches, which
could result in a material disruption of our product development programs.
Despite the implementation of security measures, our internal computer systems and those of third parties with which we contract are vulnerable to damage or interruption from computer
viruses, worms and other destructive or disruptive software, unauthorized access, natural disasters, terrorism, war and telecommunication and electrical failures. Such systems are also vulnerable to
service interruptions or to security breaches from inadvertent or intentional actions by our employees, third-party vendors and/or business partners, or from cyber incidents by malicious third parties.
Our sensitive commercial and personal information also may be subject to security breaches in other contexts, related to personal devices or other technology or systems where this information can be
collected, stored and used. Cyber incidents are increasing in their frequency, sophistication and intensity, and have become increasingly difficult to detect. Cyber incidents could include the
deployment of harmful malware, ransomware, denial-of-service attacks, unauthorized access to or deletion of files, social engineering and other means to affect service reliability and threaten the
confidentiality, integrity and availability of information. Cyber incidents also could include phishing attempts or e-mail fraud to cause payments or information to be transmitted to an unintended
recipient. We could be subject to risks caused by cyber incidents, misappropriation, misuse, leakage, falsification or intentional or accidental release or loss of information maintained in the
information systems and networks of our company, including commercial information and personal information of our employees, patients, clinical trial participants and third-party vendors.
System failures, accidents, cyber incidents or security breaches could cause interruptions in our operations, and could result in a material disruption of our commercialization and clinical
activities and business operations, whether due to a loss of our trade secrets or other proprietary information or other similar disruptions, in addition to possibly requiring substantial expenditures of
resources to remedy. For example, the loss of clinical trial data from completed or future trials
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could result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data. To the extent that any disruption or security breach were to result in a loss
of, or damage to, our data or applications, or inappropriate disclosure of confidential or proprietary information, we could incur liability, our competitive position could be harmed and our product
research, development and commercialization efforts could be delayed. We may in certain instances be required to provide notification to individuals or others in connection with the loss of their
personal or commercial information. In addition, we may not have adequate insurance coverage to provide compensation for any losses associated with such events.
If a material breach of our security or that of our vendors occurs, the market perception of the effectiveness of our security measures could be harmed, we could lose business and our
reputation and credibility could be damaged. We could be required to expend significant amounts of money and other resources to repair or replace information systems or networks. Although we
develop and maintain systems and controls designed to prevent these events from occurring, and we have a process to identify and mitigate threats, the development and maintenance of these
systems, controls and processes is costly and requires ongoing monitoring and updating as technologies change and efforts to overcome security measures become more sophisticated. Moreover,
despite our efforts, the possibility of these events occurring cannot be eliminated entirely.
Risks Related to the COVID-19 Pandemic
The COVID-19 pandemic has adversely disrupted, and is expected to continue to adversely disrupt our operations, including our ability to commercialize FOTIVDA by restricting in-person
access to treating oncologists and restricting in-person access to certain institutions, our ability to initiate new trials or complete ongoing clinical trials and our ability to manufacture clinical
product and may have other adverse effects on our business, operations and ability to raise capital.
The COVID-19 pandemic, which began in December 2019 and has spread worldwide, has caused many governments to implement measures to slow the spread of the outbreak through
quarantines, strict travel restrictions, heightened border scrutiny and other measures. The outbreak and government measures taken in response have also had a significant impact, both direct and
indirect, on businesses and commerce, as worker shortages have occurred, supply chains have been disrupted, facilities and production have been suspended, and demand for certain goods and
services, such as manufacturing materials, medical services and supplies, has spiked, while demand for other goods and services, such as travel, has fallen. The future progression of the pandemic and
its effects on our business and operations are uncertain.
Restrictions related to the ongoing COVID-19 pandemic have impeded our ability to gain in-person access to customers, prescribers, and other healthcare professionals and certain
institutions remain closed to industry representatives. We believe these access challenges caused by the COVID-19 pandemic and the emergence of SARs-CoV-2 variants have potentially slowed the
commercial launch trajectory of FOTIVDA which we believe is causing a protracted launch curve as compared to the pre-COVID open access environment. While we have designed our strategic
commercial approach to be optimized for remote as well as in-person customer engagement capabilities and expanded our digital marketing strategies in light of the restrictions necessitated by the
COVID-19 pandemic, changes to standard sales and marketing practices, including the shift from in-person to video and virtual interactions with healthcare professionals, have caused, and may
continue to cause, challenges for the successful commercialization of FOTIVDA.
The COVID-19 pandemic has also impacted the initiation, enrollment and completion of certain of our ongoing and planned clinical trials both in the United States and in the EU. For
example, the pandemic partially slowed enrollment of the DEDUCTIVE trial in that it hindered patients' ability to attend routine physical medical assessments with their clinicians resulting in delays
in diagnosis and, at times, treatment of cancer in patients. In addition, in-person monitoring visits are currently on hold at certain of the active clinical trial sites for our DEDUCTIVE trial and to the
extent possible, due to the COVID-19 pandemic, monitoring is being conducted remotely. We do not yet know whether remote management of this function will prove to be sufficient.
Similarly, the CRO for our TiNivo-2 trial has been impacted by cancer research staffing shortages related to, among other things, COVID-19 infections and competition for staff at clinical
trial sites resulting in delays to site initiation, contracting and enrollment. Currently, certain academic institutions have frozen enrollment on all trials or refused to take on additional clinical trials due
to these staffing shortages and these staffing shortages have adversely impacted trial site initiation and enrollment of the TiNivo-2 trial.
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The COVID-19 pandemic has delayed and may continue to delay or otherwise adversely affect these clinical development activities, including our ability to recruit and retain patients in our
ongoing clinical trials, as a result of many factors, including:
•
diversion of healthcare resources away from the conduct of our clinical trials in order to focus on pandemic concerns, including the availability of necessary materials,
including manufacturing supplies, the attention of physicians serving as our clinical trial investigators, access to hospitals serving as our clinical trial sites, availability of
hospital staff supporting the conduct of our clinical trials and the reluctance of patients enrolled in our clinical trials to visit clinical trial sites;
•
potential interruptions in global shipping affecting the transport of clinical trial materials, such as investigational drug product, patient samples and other supplies used in
our clinical trials;
•
the impact of further limitations on travel that could interrupt key clinical trial activities, such as clinical trial site initiations and monitoring activities, travel by our
employees, contractors or patients to clinical trial sites or the ability of employees at any of our CMO or CROs to report to work, any of which could delay or adversely
impact the conduct or progress of our clinical trials, and limit the amount of clinical data we will be able to report;
•
any future interruption of, or delays in receiving, supplies of clinical trial material from our contract manufacturing organizations or, in the case of combination trials, our
study collaborators, due to staffing shortages, production slowdowns or stoppages or disruptions in delivery systems; and
•
availability of future capacity at CMOs to produce sufficient drug substance and drug product to meet forecasted clinical trial demand if any of these manufacturers elect or
are required to divert attention or resources to the manufacture of other pharmaceutical products.
The extent of any adverse impact on our clinical trials will depend on numerous evolving factors that cannot be predicted with any level of certainty.
Any negative impact that the COVID-19 pandemic has on the ability of our suppliers to provide materials for our product candidates could cause additional delays with respect to product
development activities, which could materially and adversely affect our ability to initiate or complete clinical trials, obtain regulatory approval for and to commercialize our product candidates,
increase our operating expenses, affect our ability to raise additional capital and have a material adverse effect on our financial results. For example, the COVID-19 pandemic has, and may continue
to, cause delays in the manufacturing of our product candidates ficlatuzumab and AV-380. A shortage of required key raw materials and manufacturing supplies also used in COVID-19 vaccine
manufacturing process delayed the delivery of the clinical supply of ficlatuzumab originally expected in the first half of 2022 and will require the Company to delay the start date of this potential
registrational clinical trial until the first half of 2023, which, if approved, may impact timing of potential commercialization and associated revenue generation. Similarly, a separate CMO has
experienced employee shortages, supply chain issues and disruptions related to the COVID-19 pandemic which has delayed and may continue to delay manufacturing of AV-380. While we believe
there are alternate manufacturers with capability to supply clinical or, if approved, commercial supply of AV-380 necessary to meet our needs, contracting with additional CMOs would require
significant lead-times and result in additional costs and currently is not the solution we expect to follow.
The COVID-19 pandemic continues to evolve and its ultimate scope, duration and effects are unknown. The extent of the impact of the disruptions to our business, the supply chain,
preclinical studies, clinical trials and commercialization efforts as a result of the outbreak will depend on future developments, which are highly uncertain and cannot be predicted with confidence.
The macroeconomic impacts arising from the duration of the COVID-19 pandemic, including supply chain disruptions, may have prolonged and unforeseen adverse impacts to our industry, business
and operations. In addition, this pandemic has adversely impacted economies worldwide and may cause additional disruption in the financial markets, both of which could result in adverse effects on
our business, operations and ability to raise capital.
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Risks Related to Our Dependence on Third Parties
We rely on third parties, such as CROs, to conduct clinical trials for our product candidates, and if they do not properly and successfully perform their obligations to us, we may not be able to
obtain regulatory approvals for our product candidates.
We, in consultation with our collaborators, where applicable, design the clinical trials for our product candidates, but we rely on CROs and other third parties to perform many of the
functions in managing, monitoring and otherwise carrying out many of these trials. We compete with larger companies for the resources of these third parties. In addition, these third parties may be
adversely affected by the COVID-19 pandemic.
Although we plan to continue to rely on these third parties to conduct our ongoing and any future clinical trials, we are responsible for ensuring that each of our clinical trials is conducted in
accordance with its general investigational plan and protocol. Moreover, the FDA and foreign regulatory agencies require us to comply with regulations and standards, including GCPs and GLPs for
designing, conducting, monitoring, recording, analyzing and reporting the results of clinical trials to assure that the data and results are credible and accurate and that the rights, integrity and
confidentiality of trial participants are protected. Our reliance on third parties that we do not control does not relieve us of these responsibilities and requirements. If these third parties do not
successfully carry out their duties under their agreements with us, if the quality or accuracy of the data they obtain, process and analyze is compromised for any reason or if they otherwise fail to
comply with clinical trial protocols or meet expected deadlines, our clinical trials may experience delays or may fail to meet regulatory requirements. For example, the third-party CRO that conducted
our AV-380 Phase 1 clinical trial evaluating the safety of AV-380 in healthy subjects failed to comply with regulatory requirements applicable to the clinical trial, including GCPs and GLPs, which
resulted in data integrity concerns. We have notified the FDA and plan to discuss the errors that occurred at the trial site with the FDA to confirm whether we will be able to publish the data from this
trial and the suitability of the data for regulatory purposes. If the FDA determines that the data from the clinical trial is not suitable for use, our development of AV-380 may be delayed.
The third parties on whom we rely generally may terminate their engagements with us at any time. If we are required to enter into alternative arrangements because of any such termination,
the introduction of our product candidates to market could be delayed. If our clinical trials do not meet regulatory requirements or if these third parties need to be replaced, our preclinical
development activities or clinical trials may be extended, delayed, suspended or terminated. If any of these events occur, we may not be able to obtain regulatory approval of our product candidates
and our reputation could be harmed.
We rely on third-party manufacturers and third-party suppliers to produce, supply, store and transport our preclinical and clinical product candidate supplies, and we rely on third-parties to
produce, store and distribute commercial supplies of FOTIVDA. Any failure by a third-party manufacturer or a third-party supplier to timely produce or provide required manufacturing
supplies for us or to safely store product candidate supplies and commercial supplies of FOTIVDA may delay or impair our ability to manufacture product, initiate or complete our clinical trials
or commercialize our product candidates.
We have relied upon third-party manufacturers for the manufacture of our product candidates for preclinical and clinical testing purposes and intend to continue to do so in the future. If we
are unable to arrange for third-party manufacturing sources, or to do so on commercially reasonable terms, we may not be able to complete development of such product candidates or to market them.
Reliance on third-party manufacturers entails risks to which we would not be subject if we manufactured product candidates ourselves, including reliance on the third-party for regulatory
compliance, quality assurance and safe-keeping of our product candidate supplies, the possibility of breach of the manufacturing agreement by the third-party because of factors beyond our control,
failure of the third-party to accept orders for supply of drug substance or drug product and the possibility of termination or nonrenewal of the agreement by the third-party, based on its own business
priorities, at a time that is costly or damaging to us. In addition, the FDA and other regulatory authorities require that our product candidates be manufactured according to current good manufacturing
practices, or cGMPs. Any failure by our third-party manufacturers to comply with cGMPs or failure to scale-up manufacturing processes as needed, including any failure to safely transport and
deliver sufficient quantities of product candidates in a timely manner, could lead to a delay in, or failure to obtain, regulatory approval of any of our product candidates. In addition, such failure could
be the basis for action by the FDA to withdraw approvals for product candidates previously granted to us and for other regulatory action, including recall or seizure, fines, imposition of operating
restrictions, total or partial suspension of production or injunctions.
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We rely on our manufacturers to purchase from third-party suppliers the materials necessary to produce our product candidates for our clinical studies and commercial manufacturing. There
are a small number of suppliers of raw and starting materials that we use to manufacture our product candidates, many of whom have experienced delays and challenges related to the COVID-19
pandemic. Such suppliers may not be able to provide these materials to our manufacturers at the times we need them or on commercially reasonable terms. For example, the delivery of the clinical
supply of ficlatuzumab for a potential registrational clinical trial of ficlatuzumab in R/M HNSCC was significantly delayed due to the shortage of key raw materials and manufacturing supplies also
used in COVID-19 vaccine manufacturing, which required us to delay the start date of this potential registrational clinical trial until 2023. We do not have any control over the process or timing of the
acquisition of these materials by our manufacturers and delays related to the COVID-19 pandemic to provide raw and starting materials that we use to manufacture our product candidates could delay
or disrupt our ability to initiate or continue clinical trials on our scheduled timelines or at all, which may impact timing of potential commercialization and associated revenue generation.
More recently, one of our CMOs has experienced employee shortages, supply chain issues and disruptions related to the COVID-19 pandemic which have delayed and may continue to delay
manufacturing of AV-380 preclinical supply. Any significant delay in the supply of a product candidate or the raw material components thereof for a scheduled or ongoing clinical trial due to the
COVID-19 pandemic, the need to replace a third-party supplier or other factors could considerably delay completion of our clinical studies, product testing and potential regulatory approval of our
product candidates.
Because of the complex nature of many of our early stage compounds and product candidates, our manufacturers may not be able to manufacture such compounds and product candidates at
a cost or quantity or in the timeframe necessary to develop and commercialize the related products. As our product development pipeline matures, we will have a greater need for commercial
manufacturing capacity and we may be required to establish or access large-scale commercial manufacturing capabilities. In addition, we do not own or operate manufacturing facilities for the
production of clinical or commercial quantities of our product candidates and we currently have no plans to build our own clinical or commercial scale manufacturing capabilities. To meet our
projected needs for commercial manufacturing, third parties with whom we currently work may need to increase their scale of production or we may need to secure alternate suppliers.
We rely on third parties to securely store product candidate supplies and commercial supplies of FOTIVDA. While we have sought to protect our product candidate supplies and commercial
supplies of FOTIVDA through diversification of storage locations, there are times when such supplies may be placed in jeopardy due to unforeseen circumstances such as the disruption to the supply
chain caused by the COVID-19 pandemic. If our product candidate supplies or commercial supplies of FOTIVDA were lost, destroyed, significantly delayed or otherwise compromised, it would
delay or impair our ability to complete clinical trials and commercialize FOTIVDA.
We rely on our licensee EUSA, over whom we have little control, for the sales, marketing and distribution efforts associated with the commercialization of FOTIVDA in certain countries in the
EUSA territory and any failure by EUSA to devote the necessary resources and attention to market and sell FOTIVDA effectively and successfully may materially impact our ability to generate
revenue from the EUSA licensed territory.
In December 2015, we entered into the EUSA Agreement, under which we granted to EUSA the exclusive, sublicensable right to develop, manufacture and commercialize FOTIVDA in the
territories of Europe (excluding Russia, Ukraine and the Commonwealth of Independent States), Latin America (excluding Mexico), Africa and Australasia for all diseases and conditions in humans,
excluding non-oncologic diseases or conditions of the eye. We have limited contractual rights to force EUSA to invest significantly in the commercialization of FOTIVDA in jurisdictions covered by
the EUSA Agreement. For instance, under the EUSA Agreement, EUSA is not required to opt into the data from the TIVO-3 trial to seek to expand the label for FOTIVDA to the relapsed or
refractory RCC setting and, to date, has not chosen to do so. Further, in December 2021, EUSA announced that it had signed an agreement with Recordati, S.p.A. to be acquired and has indicated that
the acquisition is anticipated to close in the first half of 2022. In the event that EUSA, or Recordati, fails to adequately commercialize FOTIVDA because it lacks adequate financial or other
resources, decides to focus on other initiatives or otherwise, our ability to successfully commercialize FOTIVDA in the applicable jurisdictions would be limited, which may adversely affect our
business, financial condition, results of operations and prospects.
In addition, the EUSA Agreement may be terminated by either party upon prior written notice. If EUSA, or Recordati upon the closing of its acquisition of EUSA, terminated the EUSA
Agreement, we may not be able to secure an alternative distributor in the applicable territories on a timely basis or at all, in which case our ability to generate revenue from sales of FOTIVDA outside
the United States would be materially harmed.
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Further, while EUSA is working to secure reimbursement approval in and commercially launch FOTIVDA in additional countries in the EUSA territory, there is significant competition in
the first-line RCC setting in the EU due to the approval of several immunotherapy combinations which have become a standard of care and impacted the market opportunity for monotherapy
treatments. If EUSA, or Recordati upon the closing of its acquisition of EUSA, is unable to secure reimbursement approval in and commercially launch FOTIVDA in additional countries in the
EUSA territory and does not seek to expand the label for FOTIVDA to the relapsed or refractory RCC setting, it may materially impact our ability to generate revenue from sales of FOTIVDA
outside the United States.
We may not be successful in establishing or maintaining strategic partnerships to further the development of our therapeutic programs. Additionally, if any of our current or future strategic
partners fails to perform its obligations or terminates the partnership, the development and commercialization of the product candidates under such agreement could be delayed or terminated.
Such failures could have a material adverse effect on our operations and business.
Our success will depend in significant part on our ability to attract and maintain strategic partners and strategic relationships with other biotechnology or pharmaceutical companies to
support the development and commercialization of our product candidates. In these partnerships, we would expect our strategic partner to provide capabilities in research, development, regulatory
filings, marketing and sales, in addition to funding.
We face significant competition in seeking appropriate strategic partners, and the negotiation process is time-consuming and complex. Moreover, we may not be successful in our efforts to
establish a strategic partnership or other alternative arrangements for any product candidates and programs because our product candidates may be deemed to be at too early of a stage of development
for collaborative effort or third parties may not view our product candidates as having the requisite potential.
If we are not able to establish and maintain strategic partnerships:
•
the development of certain of our product candidates may be delayed or terminated;
•
the internal cash expenditures needed to develop such product candidates would increase significantly, and we may not have the cash resources to develop such product
candidates on our own; and
•
we may have fewer resources with which to continue to operate our business.
Even if we are successful in our efforts to establish new strategic partnerships, the terms that we agree upon may not be favorable to us. If any strategic partner were to breach or terminate its
arrangements with us, the development and commercialization of the affected product candidate could be delayed, curtailed or terminated because we may not have sufficient financial resources or
capabilities to continue development and commercialization of the product candidate on our own. If any current or future strategic partners do not devote sufficient time and resources to their
arrangements with us, we may not realize the potential commercial benefits of the arrangement, and our results of operations may be adversely affected. For example, in March 2020, CANbridge
advised us that it was evaluating alternative development plans for AV-203, which would delay the initiation of clinical trials of AV-203. Then, in March 2021, CANbridge exercised its right to
terminate the CANbridge Agreement for convenience. The transfer of the AV-203 program occurred in September 2021, which has delayed the initiation of clinical trials of AV-203 even further.
Our current partners and licensees can terminate their agreements with us under various conditions, including without cause, at which point they would no longer continue to develop our
products. For example, in September 2020 Biodesix exercised its Opt-Out right under the Biodesix Agreement. As a result, Biodesix is not required to contribute to the future development costs of
ficlatuzumab in exchange for a reduced economic interest in any future ficlatuzumab revenues.
Much of the potential revenue from any of our strategic partnerships will likely consist of contingent payments, such as development milestones and royalties payable on sales of any
successfully developed drugs. Any such contingent revenue will depend upon our, and our strategic partners’, ability to successfully develop, introduce, market and sell new drugs. In some cases, we
are not involved in these processes, and we depend entirely on our strategic partners. Any of our strategic partners may fail to develop or effectively commercialize these drugs because it:
•
decides not to devote the necessary resources due to internal constraints, such as limited personnel with the requisite scientific expertise, limited cash resources or
specialized equipment
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limitations, or the belief that other product candidates may have a higher likelihood of obtaining regulatory approval or may potentially generate a greater return on
investment;
•
does not have sufficient resources necessary to carry the product candidate through clinical development, regulatory approval and commercialization; or
•
cannot obtain the necessary regulatory approvals.
If one or more of our strategic partners fails to develop or effectively commercialize product candidates for any reason, we may not be able to replace the strategic partner with another
partner to develop and commercialize a product candidate under the terms of the strategic partnership. We may also be unable to obtain, on terms acceptable to us, a license from such strategic partner
to any of its intellectual property that may be necessary or useful for us to continue to develop and commercialize a product candidate. Any of these events could have a material adverse effect on our
business, results of operations and our ability to achieve future profitability and could cause our stock price to decline.
Our operations or those of the third parties upon whom we depend might be affected by the occurrence of a natural disaster, pandemic, war or other catastrophic event.
We depend on our employees, consultants, CMOs, CROs, as well as regulatory agencies and other parties, for the continued operation of our business. While we maintain disaster recovery
plans, they might not adequately protect us. Despite any precautions we take for natural disasters or other catastrophic events, these events, including terrorist attacks, pandemics, hurricanes, fires,
floods and ice and snowstorms, could result in significant disruptions to our research and development, preclinical studies, clinical trials, and, ultimately, commercialization of our products. Long-
term disruptions in the infrastructure caused by events, such as natural disasters, the outbreak of war (including expansion of the current armed conflict between Russia and Ukraine), the escalation of
hostilities and acts of terrorism or other “acts of God,” particularly involving cities in which we have offices, manufacturing or clinical trial sites, could adversely affect our businesses. Although we
carry business interruption insurance policies and typically have provisions in our contracts that protect us in certain events, our coverage might not include or be adequate to compensate us for all
losses that may occur. Any natural disaster or catastrophic event affecting us, our CMOs, our CROs, regulatory agencies or other parties with which we are engaged could have a material adverse
effect on our operations and financial performance.
Risks Related to Our Intellectual Property Rights
We could be unsuccessful in obtaining or maintaining adequate patent protection for one or more of our product candidates, or the scope of our patent protection could be insufficiently broad,
which could result in competition and a decrease in the potential market share for our product candidates.
We cannot be certain that patents will be issued or granted with respect to applications that are currently pending, or that issued or granted patents will not later be found to be invalid and/or
unenforceable. The patent position of biotechnology and pharmaceutical companies is generally uncertain because it involves complex legal and factual considerations. The standards applied by the
United States Patent and Trademark Office, or USPTO, and foreign patent offices in granting patents are not always applied uniformly or predictably. For example, there is no uniform worldwide
policy regarding patentable subject matter or the scope of claims allowable in biotechnology and pharmaceutical patents. Consequently, patents may not issue from our pending patent applications.
As such, we do not know the degree of future protection that we will have on our proprietary products and technology. For example, we have filed a patent application directed to our clinical protocol
for using tivozanib to treat refractory cancers, including, following therapy with checkpoint inhibitors. It is possible that we may not successfully obtain a granted patent based upon this patent
application. The scope of patent protection that the USPTO will grant with respect to the antibodies in our antibody product pipeline is also uncertain. It is possible that the USPTO will not allow
broad antibody claims that cover closely related antibodies as well as the specific antibody. Upon receipt of FDA approval, competitors would be free to market antibodies almost identical to ours,
including biosimilar antibodies, thereby decreasing our market share.
If we do not obtain patent term extensions under the Hatch-Waxman Act and similar non-U.S. legislation to extend the term of patents covering each of our product candidates, our business
may be materially harmed.
Patents have a limited duration. The term of a U.S. patent, if granted from an application filed on or after June 8, 1995, is generally 20 years from its earliest U.S. non-provisional filing date.
Even if patents covering our product candidates are obtained, once the patents expire, we may be open to competition from competitive medications. Given the amount of time required for the
development, testing and regulatory review of new product candidates, patents protecting such candidates might expire before or shortly after such candidates are commercialized. As a result, our
owned or in-
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licensed patent rights may not provide us with sufficient rights to exclude others from commercializing products similar or identical to ours.
Depending upon the circumstances, the term of our owned and in-licensed patent rights that cover our product candidates may be extended in the United States under the Hatch-Waxman Act,
by Supplementary Protection Certificates, or SPCs, in certain countries, and by similar legislation in other countries, for delays incurred when seeking marketing approval for a drug candidate. For
example, the Hatch-Waxman Act permits a patent term extension of up to five years for a patent covering an approved product as compensation for effective patent term lost during product
development and the FDA regulatory review process. However, we may not receive an extension if we fail to apply within the applicable deadline, fail to apply prior to expiration of relevant patents
or otherwise fail to satisfy applicable requirements. Moreover, the length of the extension could be less than we request. If we are unable to obtain a patent term extension or the term of any such
extension is less than we request, the period during which we can enforce our patent rights for that product will be shortened and our competitors may obtain approval to market competing products
sooner. As a result, our revenue from applicable products could be materially reduced. For example, we have exclusive license rights to a first U.S. patent covering the tivozanib molecule and its
therapeutic use, which, inclusive of a one year interim extension granted by the USPTO, is scheduled to expire in April 2023, and a second U.S. patent covering the crystalline form of tivozanib,
which is scheduled to expire in November 2023. In view of the length of time tivozanib had been under regulatory review at the FDA, a patent term extension of up to five years may be available.
Although we have applied for patent term extensions on each U.S. patent, only one patent may be extended, and, when appropriate, we will have to elect which patent is to be extended. If a five-year
extension were to be granted, if applied to the first patent, the term could be extended to April of 2027, and if applied to the second patent, the term could be extended to November of 2028. However,
the length of the extension could be less than we request, or no extension may be granted at all.
In addition, SPCs have been granted for the patent covering the tivozanib molecule in Belgium, Finland, France, Germany, Italy, the Netherlands, Norway, Poland, Portugal, Spain, Sweden
and the United Kingdom, extending the term of the patents in each of these countries up to April 2027. An SPC has been granted for the patent covering the crystalline form of tivozanib in Ireland
extending the term of that patent to October 2028. The remaining pending application for an SPC on the patent covering the tivozanib molecule in Denmark may not be similarly granted, or may be
granted for a shorter period than requested. If we are unable to obtain a patent term extension or the term of any such extension is less than we request, the period of time during which the patent
rights covering tivozanib or its use can be enforced will be shortened, and our competitors may obtain approval to market a competing product sooner. As a result, our potential revenue from
tivozanib could be materially reduced, causing material harm to our business.
Issued patents covering one or more of our products could be found invalid or unenforceable if challenged in patent office proceedings, or in court.
If we or one of our strategic partners were to initiate legal proceedings against a third-party to enforce a patent covering one of our products, the defendant could counterclaim that our patent
is invalid and/or unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity and/or unenforceability are commonplace. In addition, with respect to FOTIVDA,
generic manufacturers could challenge the patents covering FOTIVDA as part of the process of obtaining regulatory approval via an abbreviated new drug application, or ANDA. Grounds for a
validity challenge could be an alleged failure to meet one or more statutory requirements for patentability, including, for example, lack of novelty, obviousness, lack of written description or non-
enablement. In addition, patent validity challenges may, under certain circumstances, be based upon non-statutory obviousness-type double patenting, which, if successful, could result in a finding
that the claims are invalid for obviousness-type double patenting or the loss of patent term, including a patent term adjustment granted by the USPTO, if a terminal disclaimer is filed to obviate a
finding of obviousness-type double patenting. Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information
from the USPTO, or made a misleading statement, during prosecution. Additionally, third parties are able to challenge the validity of issued patents through administrative proceedings in the patent
offices of certain countries, including the USPTO and the European Patent Office. Although we have conducted due diligence on patents we have exclusively in-licensed, and we believe that we have
conducted our patent prosecution in accordance with the duty of candor and in good faith, the outcome following legal assertions of invalidity and unenforceability during patent litigation is
unpredictable. With respect to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during prosecution. If
a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the patent protection on one of our products. Such a loss of patent
protection could have a material adverse impact on our business. Further, an intellectual property litigation could lead to unfavorable publicity that could harm our reputation and cause the market
price of our common stock to decline.
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Claims that our platform technologies, our products or the sale or use of our products infringe the patent rights of third parties could result in costly litigation or could require substantial time
and money to resolve, even if litigation is avoided.
We cannot guarantee that our platform technologies, our products or the use of our products, do not infringe third-party patents. Third parties might allege that we are infringing their patent
rights or that we have misappropriated their trade secrets. Such third parties might resort to litigation against us. The basis of such litigation could be existing patents or patents that issue in the future.
It is also possible that we failed to identify relevant third-party patents or applications. For example, applications filed before November 29, 2000, and certain applications filed after that date
that will not be filed outside the United States remain confidential until patents issue. Patent applications in the United States and elsewhere are published approximately 18 months after the earliest
filing, which is referred to as the priority date. Therefore, patent applications covering our products or platform technology could have been filed by others without our knowledge. Additionally,
pending patent applications which have been published can, subject to certain limitations, be later amended in a manner that could cover our platform technologies, our products or the use of our
products.
With regard to ficlatuzumab, we are aware of one United States patent and its foreign counterparts that contain broad claims related to anti-HGF antibodies having certain binding properties
and their use. In the event that the owner of these patents were to bring an infringement action against us, we may have to argue that our product, its manufacture or use does not infringe a valid claim
of the patent in question. Furthermore, if we were to challenge the validity of any issued United States patent in court, we would need to overcome a statutory presumption of validity that attaches to
every United States patent. This means that, in order to prevail, we would have to present clear and convincing evidence as to the invalidity of the patent’s claims. There is no assurance that a court
would find in our favor on questions of infringement or validity.
In order to avoid or settle potential claims with respect to any of the patent rights described above or any other patent rights of third parties, we may choose or be required to seek a license
from a third-party and be required to pay license fees or royalties or both. These licenses may not be available on commercially acceptable terms, or at all. Even if we or our strategic partners were
able to obtain a license, the rights may be non-exclusive, which could result in our competitors gaining access to the same intellectual property. Ultimately, we could be prevented from
commercializing a product, or be forced to cease some aspect of our business operations, if, as a result of actual or threatened patent infringement claims, we are unable to enter into licenses on
acceptable terms. This could harm our business significantly.
Defending against claims of patent infringement or misappropriation of trade secrets could be costly and time-consuming, regardless of the outcome. Thus, even if we were to ultimately
prevail, or to settle at an early stage, such litigation could burden us with substantial unanticipated costs. In addition, litigation or threatened litigation could result in significant demands on the time
and attention of our management team, distracting them from the pursuit of other company business.
Unfavorable outcomes in an intellectual property litigation could limit our research and development activities and/or our ability to commercialize certain products.
If third parties successfully assert intellectual property rights against us, we might be barred from using aspects of our technology platform, or barred from developing and commercializing
related products. Prohibitions against using specified technologies, or prohibitions against commercializing specified products, could be imposed by a court or by a settlement agreement between us
and a plaintiff. In addition, if we are unsuccessful in defending against allegations of patent infringement or misappropriation of trade secrets, we may be forced to pay substantial damage awards to
the plaintiff. There is inevitable uncertainty in any litigation, including intellectual property litigation. There can be no assurance that we would prevail in any intellectual property litigation, even if
the case against us is weak or flawed. If litigation leads to an outcome unfavorable to us, we may be required to obtain a license from the patent owner in order to continue our research and
development programs or our partnerships or to market our products. It is possible that the necessary license will not be available to us on commercially acceptable terms, or at all. This could limit
our research and development activities, our ability to commercialize specified products, or both.
Most of our competitors are larger than we are and have substantially greater resources. They are, therefore, likely to be able to sustain the costs of complex patent litigation longer than we
could. In addition, the uncertainties associated with litigation could have a material adverse effect on our ability to raise the funds necessary to continue our clinical trials, in-license needed
technology or enter into strategic partnerships that would help us bring our product candidates to market.
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In addition, any future patent litigation, interference or other administrative proceedings will result in additional expense and distraction of our personnel. An adverse outcome in such
litigation or proceedings may expose us or our strategic partners to loss of our proprietary position, expose us to significant liabilities or require us to seek licenses that may not be available on
commercially acceptable terms, if at all.
Tivozanib and certain of our product candidates are protected by patents exclusively licensed from other companies or institutions. If the licensors terminate the licenses or fail to maintain or
enforce the underlying patents, our competitive position would be harmed and our partnerships could be terminated.
Certain of our product candidates and out-licensing arrangements depend on patents and/or patent applications owned by other companies or institutions with which we have entered into
intellectual property licenses. In particular, we hold exclusive licenses from KKC for tivozanib and from St. Vincent’s for therapeutic applications that benefit from inhibition or decreased expression
or activity of MIC-1, which we refer to as GDF15 and which we use in our AV-380 program. We may enter into additional license agreements as part of the development of our business in the future.
Our licensors may not successfully prosecute certain patent applications which we have licensed and on which our business depends or may prosecute them in a manner not in the best interests of our
business. Even if patents issue from these applications, our licensors may fail to maintain these patents, may decide not to pursue litigation against third-party infringers, may fail to prove
infringement or may fail to defend against counterclaims of patent invalidity or unenforceability. In addition, in spite of our best efforts, a licensor could claim that we have materially breached a
license agreement and terminate the license, thereby removing our or our licensees’ ability to obtain regulatory approval for and to market any product covered by such license. If these in-licenses are
terminated, or if the underlying patents fail to provide the intended market exclusivity, competitors would have the freedom to seek regulatory approval of, and to market, identical products. In
addition, the partners to which we have sublicensed certain rights under these licenses, such as EUSA, would likely have grounds for terminating our partnerships if these licenses are terminated or
the underlying patents are not maintained or enforced. This could have a material adverse effect on our results of operations, our competitive business position and our business prospects.
Confidentiality agreements with employees, consultants and third parties may not prevent unauthorized disclosure of trade secrets and other proprietary information.
In addition to patents, we rely on trade secrets, technical know-how and proprietary information concerning our business strategy in order to protect our competitive position. In the course of
our research, development and business activities, we often rely on confidentiality agreements to protect our proprietary information. Such confidentiality agreements are used, for example, when we
talk to potential strategic partners. In addition, each of our employees and consultants are required to sign a confidentiality agreement upon joining our company. We take steps to protect our
proprietary information, and we seek to carefully draft our confidentiality agreements to protect our proprietary interests. Nevertheless, there can be no guarantee that an employee, consultant or an
outside party will not make an unauthorized disclosure of our proprietary confidential information. This might happen intentionally or inadvertently. It is possible that a competitor will make use of
such information, and that our competitive position will be compromised, in spite of any legal action we might take against persons making such unauthorized disclosures.
Trade secrets are difficult to protect. Although we use reasonable efforts to protect our trade secrets, our employees, consultants or outside scientific collaborators might intentionally or
inadvertently disclose our trade secret information to competitors. Enforcing a claim that a third-party illegally obtained and is using any of our trade secrets is expensive and time-consuming, and the
outcome is unpredictable. In addition, courts outside the United States sometimes are less willing than U.S. courts to protect trade secrets. Moreover, our competitors may independently develop
equivalent knowledge, methods and know-how.
Our research and development strategic partners may have rights to publish data and other information to which we have rights. In addition, we sometimes engage individuals or entities to
conduct research relevant to our business. The ability of these individuals or entities to publish or otherwise publicly disclose data and other information generated during the course of their research
is subject to certain contractual limitations. These contractual provisions may be insufficient or inadequate to protect our confidential information. If we do not apply for patent protection prior to
such publication, or if we cannot otherwise maintain the confidentiality of our proprietary technology and other confidential information, then our ability to obtain patent protection or to protect our
trade secret information may be jeopardized.
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We rely significantly upon information technology, and any failure, inadequacy, interruption or security lapse of that technology, including any cyber security incidents, could harm our ability to
operate our business effectively and result in a material disruption of our product development programs.
We could be subject to risks caused by misappropriation, misuse, leakage, falsification or intentional or accidental release or loss of information maintained in the information systems and
networks of our company. Outside parties may attempt to penetrate our systems or those of our partners or fraudulently induce our employees or employees of our partners to disclose sensitive
information to gain access to our data. Like other companies, we may experience threats to our data and systems, including malicious codes and computer viruses, cyber-attacks or other system
failures. Any system failure, accident or security breach that causes interruptions in our operations, for us or our partners, could result in a material disruption of our product development programs
and business operations, in addition to possibly requiring substantial expenditures of resources to remedy. For example, the loss of clinical trial data from completed clinical trials could result in
delays in our regulatory approval efforts and we could incur significant increases in costs to recover or reproduce the data. The risk of cyber incidents could also be increased by cyberwarfare in
connection with the ongoing conflict between Russia and Ukraine, including potential proliferation of malware from the conflict into systems unrelated to the conflict. To the extent that any
disruption or security breach results in a loss of, or damage to, our data or applications, or inappropriate public disclosure of confidential or proprietary information, we may incur liabilities and the
further development of our product candidates may be delayed.
The number and complexity of these security threats continue to increase over time. If a breach of our security systems or that of our partners occurs, the market perception of the
effectiveness of our security measures could be harmed, we could lose business and our reputation and credibility could be damaged. We could be required to expend significant amounts of money
and other resources to repair or replace information systems or networks. Although we develop and maintain systems and controls designed to prevent these events from occurring, and we have a
process to identify and mitigate threats, the development and maintenance of these systems, controls and processes is costly and requires ongoing monitoring and updating as technologies change and
efforts to overcome security measures become more sophisticated. Moreover, despite our efforts, the possibility of these events occurring cannot be eliminated entirely.
Intellectual property rights may not address all potential threats to our competitive advantage.
The degree of future protection afforded by our intellectual property rights is uncertain because intellectual property rights have limitations, and may not adequately protect our business, or
permit us to maintain our competitive advantage. The following examples are illustrative:
•
Others may be able to make compounds or antibodies that are similar to our product candidates but that are not covered by the claims of the patents that we own or have
exclusively licensed.
•
The term of patents that we own or have exclusively licensed may be insufficient to prevent competitors from introducing products that are competitive with our product
candidates.
•
If the licenses we have that relate to our product candidates are terminated by the licensors, we may be prevented from commercializing our product candidates.
•
We or our licensors or strategic partners might not have been the first to make the inventions covered by the issued patent or pending patent application that we own or have
exclusively licensed.
•
We or our licensors or strategic partners might not have been the first to file patent applications covering certain of our inventions.
•
Others may independently develop similar or alternative technologies or duplicate any of our technologies without infringing our intellectual property rights.
•
Our pending patent applications might not lead to issued patents.
•
Issued patents that we own or have exclusively licensed may not provide us with a competitive advantage; for example, our issued patents may not be broad enough to
prevent the commercialization of products competitive with one or more of our product candidates, or may be held invalid or unenforceable, as a result of legal challenges
by our competitors.
•
Our competitors might conduct research and development activities in countries where we do not have patent rights and then use the information learned from such
activities to develop
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competitive products for sale in our or our strategic partners’ existing or potential commercial markets.
•
We may not develop additional proprietary technologies that are patentable.
•
The patents of others may have an adverse effect on our business.
Changes in U.S. patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.
As is the case with other biopharmaceutical companies, our success is heavily dependent on intellectual property, particularly patents. Obtaining and enforcing patents in the
biopharmaceutical industry involves both technological complexity and legal complexity. Therefore, obtaining and enforcing biopharmaceutical patents is costly, time-consuming and inherently
uncertain. In addition, several events in the last decade have increased uncertainty with regard to our ability to obtain patents in the future and the value of patents once obtained. Among these, in
September 2011, patent reform legislation passed by Congress was signed into law in the United States. The patent law introduced changes including a first-to-file system for determining which
inventors may be entitled to receive patents, and post-grant challenges, such as inter-partes review and post-grant review proceedings that allow third parties to challenge newly issued patents. The
burden of proof required for challenging a patent in these proceedings is lower than in district court litigation, and patents in the biopharmaceutical industry have been successfully challenged using
these new post-grant challenges. In addition, the U.S. Supreme Court has ruled on several patent cases in recent years, either narrowing the scope of patent protection available in specified
circumstances or weakening the rights of patent owners in specified situations. Depending on decisions by the U.S. Congress, the federal courts and the USPTO, the laws and regulations governing
patents could change in unpredictable ways that could further weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain in the future.
Risks Related to Regulatory Approval and Marketing of Our Product Candidates and Other Legal Compliance Matters
The regulatory approval process is expensive, time-consuming and uncertain and may prevent us from obtaining marketing approvals for the commercialization of some or all of our product
candidates. If we or our collaborators are not able to obtain, or if there are delays in obtaining, required regulatory approvals, we will not be able to market and commercialize our product
candidates, and our ability to generate revenue will be materially impaired.
Our product candidates and the activities associated with their development and commercialization, including their design, testing, manufacture, safety, efficacy, recordkeeping, labeling,
storage, approval, advertising, promotion, sale and distribution, export and import, are subject to comprehensive regulation by the FDA and other regulatory agencies in the United States, and by the
EMA and comparable regulatory authorities in other countries. Failure to obtain marketing approval for a product candidate will prevent us from commercializing the product candidate. We have only
limited experience in filing and supporting the applications necessary to gain marketing approvals and expect to rely on third-party CROs to assist us in this process.
The process of obtaining marketing approvals, both in the United States and abroad, is expensive and may take many years, especially if additional clinical trials are required. Securing
marketing approval requires the submission of extensive preclinical and clinical data and supporting information to the various regulatory authorities for each therapeutic indication to establish the
product candidate’s safety and efficacy. It also requires the submission of information about the product manufacturing process to, and inspection of manufacturing facilities by, the relevant regulatory
authority. Our product candidates may not be effective, may be only moderately effective or may prove to have undesirable or unintended side effects, toxicities or other characteristics that may delay
or preclude our obtaining marketing approval or prevent or limit commercial use.
In addition, the FDA and comparable authorities in other countries have substantial discretion in the approval process and may refuse to accept any application or may decide that our data is
insufficient for approval and require additional preclinical, clinical or other studies. Changes in marketing approval policies during the development period, changes in or the enactment of additional
statutes or regulations or changes in regulatory review for each submitted product application, may cause delays in the approval or rejection of an application. In addition, a regulatory agency’s
varying interpretations of the data obtained from preclinical and clinical testing could delay, limit or prevent marketing approval of a product candidate. For example, in June 2013, the FDA issued
the 2013 CRL informing us that it would not approve tivozanib for the first-line treatment of RCC based solely on the data from the TIVO-1 trial.
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Failure to obtain marketing approval in foreign jurisdictions would prevent our product candidates from being marketed abroad and may limit our ability to generate revenue from
product sales.
In order to market and sell our medicines in the EU and many other jurisdictions, we or our collaborators must obtain marketing approvals and comply with numerous and varying regulatory
requirements. The approval procedure varies among countries and can involve additional testing. The time required to obtain approval may differ substantially from that required to obtain FDA
approval. The regulatory approval process outside the United States generally includes all of the risks associated with obtaining FDA approval. Approval by the FDA does not ensure approval by
regulatory authorities in other countries or jurisdictions, and approval by one regulatory authority outside the United States does not ensure approval by regulatory authorities in other countries or
jurisdictions or by the FDA. We or our collaborators may not obtain marketing approvals from regulatory authorities outside the United States on a timely basis, if at all, and we may not receive
necessary approvals to commercialize our products in any particular market.
In many countries outside the United States, a product candidate must be approved for reimbursement before the product can be approved for sale in that country. In some cases, the price
that we intend to charge for our products, if approved, is also subject to approval. Obtaining non-U.S. regulatory approvals and compliance with non-U.S. regulatory requirements could result in
significant delays, difficulties and costs for us and any future collaborators and could delay or prevent the introduction of our product candidates in certain countries. In addition, if we or any future
collaborators fail to obtain the non-U.S. approvals required to market our product candidates outside the United States or if we or any future collaborators fail to comply with applicable non-U.S.
regulatory requirements, our target market will be reduced and our ability to realize the full market potential of our product candidates will be harmed and our business, financial condition, results of
operations and prospects may be adversely affected.
Additionally, we could face heightened risks with respect to seeking marketing approval in the United Kingdom as a result of the withdrawal of the United Kingdom from the EU, commonly
referred to as Brexit. The United Kingdom is no longer part of the European Single Market and European Union Customs Union. As of January 1, 2021, the Medicines and Healthcare products
Regulatory Agency, or the MHRA, became responsible for supervising medicines and medical devices in Great Britain, comprising England, Scotland and Wales under domestic law, whereas
Northern Ireland will continue to be subject to European Union rules under the Northern Ireland Protocol. The MHRA will rely on the Human Medicines Regulations 2012 (SI 2012/1916) (as
amended), or the HMR, as the basis for regulating medicines. The HMR has incorporated into the domestic law of the body of European Union law instruments governing medicinal products that
pre-existed prior to the United Kingdom’s withdrawal from the EU. Any delay in obtaining, or an inability to obtain, any marketing approvals, as a result of Brexit or otherwise, may force us to
restrict or delay efforts to seek regulatory approval in the United Kingdom for our product candidates, which could significantly and materially harm our business.
We expect that we will be subject to additional risks in commercializing any of our product candidates that receive marketing approval outside the United States, including tariffs, trade
barriers and regulatory requirements; economic weakness, including inflation, or political instability in particular foreign economies and markets; compliance with tax, employment, immigration and
labor laws for employees living or traveling abroad; foreign currency fluctuations, which could result in increased operating expenses and reduced revenue, and other obligations incident to doing
business in another country; and workforce uncertainty in countries where labor unrest is more common than in the United States.
We are conducting, and intend in the future to conduct, clinical trials for certain of our product candidates at sites outside the United States. The FDA may not accept data from trials conducted
in such locations and the conduct of trials outside the United States could subject us to additional delays and expense.
We are conducting, and intend in the future to conduct, one or more of our clinical trials with trial sites that are located outside the United States. Although the FDA may accept data from
clinical trials conducted outside the United States, acceptance of these data is subject to certain conditions imposed by the FDA. For example, the clinical trial must be well designed and conducted
and performed by qualified investigators in accordance with good clinical practice. The FDA must be able to validate the data from the trial through an onsite inspection if necessary. The trial
population must also have a similar profile to the U.S. population, and the data must be applicable to the U.S. population and U.S. medical practice in ways that the FDA deems clinically meaningful,
except to the extent the disease being studied does not typically occur in the United States. In addition, while these clinical trials are subject to the applicable local laws, the FDA acceptance of the
data will be dependent upon its determination that the trials also complied with all applicable U.S. laws and regulations. There can be no assurance that the FDA will accept data from clinical trials
conducted outside of the United States. If the FDA does not accept the data from any trial that we conduct outside the United States, it would likely
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result in the need for additional trials, which would be costly and time-consuming and delay or permanently halt our development of our product candidates.
In addition, the conduct of clinical trials outside the United States could have a significant adverse impact on us or the trial results. Risks inherent in conducting international clinical trials
include:
•
clinical practice patterns and standards of care that vary widely among countries;
•
non-U.S. regulatory authority requirements that could restrict or limit our ability to conduct our clinical trials;
•
administrative burdens of conducting clinical trials under multiple non-U.S. regulatory authority schema;
•
foreign exchange rate fluctuations; and
•
diminished protection of intellectual property in some countries.
We may seek certain designations for our product candidates, including Breakthrough Therapy, Fast Track and Priority Review designations in the US, and PRIME Designation in the EU, but
we might not receive such designations, and even if we do, such designations may not lead to a faster development or regulatory review or approval process, and does not increase the likelihood
that product candidate will receive marketing approval.
We may seek certain designations for one or more of our product candidates that could expedite review and approval by the FDA. A Breakthrough Therapy product is defined as a product
that is intended, alone or in combination with one or more other products, to treat a serious condition, and preliminary clinical evidence indicates that the product may demonstrate substantial
improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. For products that have been
designated as Breakthrough Therapies, interaction and communication between the FDA and the sponsor of the trial can help to identify the most efficient path for clinical development while
minimizing the number of patients placed in ineffective control regimens.
The FDA may also designate a product for Fast Track review if it is intended, whether alone or in combination with one or more other products, for the treatment of a serious or life
threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. For Fast Track products, sponsors may have greater interactions
with the FDA and the FDA may initiate review of sections of a Fast Track product’s application before the application is complete. This rolling review may be available if the FDA determines, after
preliminary evaluation of clinical data submitted by the sponsor, that a Fast Track product may be effective.
For example, we have been granted Fast Track designation for the investigation of ficlatuzumab and cetuximab for the treatment of patients with relapsed or recurrent HNSCC. Marketing
applications filed by sponsors of product candidates in Fast Track development may qualify for priority review under the policies and procedures offered by the FDA, but the Fast Track designation
does not assure any such qualification or ultimate marketing approval by the FDA. Even though we have received Fast Track designation for ficlatuzumab and cetuximab, we may not experience a
faster development process, review or approval compared to conventional FDA procedures, and receiving a Fast Track designation does not provide assurance of ultimate FDA approval. In addition,
the FDA may withdraw Fast Track designation if it believes that the designation is no longer supported by data from our clinical development program. Further, the FDA may withdraw Fast Track
designation at any time. As such, a Fast Track designation by the FDA, even though granted for ficlatuzumab may not lead to a faster development or regulatory review or approval process, and does
not increase the likelihood that ficlatuzumab will receive marketing approval.
We may also seek a priority review designation for one or more of our product candidates. If the FDA determines that a product candidate offers major advances in treatment or provides a
treatment where no adequate therapy exists, the FDA may designate the product candidate for priority review. A priority review designation means that the goal for the FDA to review an application
is six months, rather than the standard review period of ten months.
These designations are within the discretion of the FDA. Accordingly, even if we believe that one of our product candidates meets the criteria for these designations, the FDA may disagree
and instead determine not to make such designation. Further, even if we receive a designation, the receipt of such designation for a product candidate may not result in a faster development or
regulatory review or approval process compared to products considered for approval under conventional FDA procedures and does not assure ultimate approval by the FDA. In addition, even if one
or more of our product candidates qualifies for these designations, the FDA may later decide that the product candidates no longer meet the conditions for qualification or decide that the time period
for FDA review or approval will not be shortened.
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In the EU, we may seek PRIME designation for our product candidates in the future. PRIME is a voluntary program aimed at enhancing the EMA’s role to reinforce scientific and regulatory
support in order to optimize development and enable accelerated assessment of new medicines that are of major public health interest with the potential to address unmet medical needs. The program
focuses on medicines that target conditions for which there exists no satisfactory method of treatment in the EU or even if such a method exists, it may offer a major therapeutic advantage over
existing treatments. PRIME is limited to medicines under development and not authorized in the EU and the applicant intends to apply for an initial marketing authorization application through the
centralized procedure. To be accepted for PRIME, a product candidate must meet the eligibility criteria in respect of its major public health interest and therapeutic innovation based on information
that is capable of substantiating the claims.
The benefits of a PRIME designation include the appointment of a CHMP rapporteur to provide continued support and help to build knowledge ahead of a marketing authorization
application, early dialogue and scientific advice at key development milestones, and the potential to qualify products for accelerated review, meaning reduction in the review time for an opinion on
approvability to be issued earlier in the application process. PRIME enables an applicant to request parallel EMA scientific advice and health technology assessment advice to facilitate timely market
access. Even if we receive PRIME designation for any of our product candidates, the designation may not result in a materially faster development process, review or approval compared to
conventional EMA procedures. Further, obtaining PRIME designation does not assure or increase the likelihood of EMA’s grant of a marketing authorization.
We may not be able to obtain orphan drug designation or orphan drug exclusivity for our product candidates, and, even if we do, that exclusivity may not prevent the FDA or the EMA from
approving other competing products.
Regulatory authorities in some jurisdictions, including in the United States and EU, may designate drugs and biologics for relatively small patient populations as orphan drugs. Under the
Orphan Drug Act, the FDA may designate a product as an orphan drug if it is intended to treat a rare disease or condition, which is generally defined as a patient population of fewer than 200,000
individuals annually in the United States. Generally, a product with orphan drug designation only becomes entitled to orphan drug exclusivity if it receives the first marketing approval for the
indication for which it has such designation, in which case the FDA or the EMA will be precluded from approving another marketing application for the same product for that indication for the
applicable exclusivity period. The applicable exclusivity period is seven years in the United States and ten years in the EU. The European exclusivity period can be reduced to six years if a product no
longer meets the criteria for orphan drug designation or if the product is sufficiently profitable so that market exclusivity is no longer justified.
We or our collaborators may seek orphan drug designations for our product candidates and may be unable to obtain such designations. Moreover, even if we do secure such designations and
orphan drug exclusivity for a product, that exclusivity may not effectively protect the product from competition because different products can be approved for the same condition. Further, even after
an orphan drug is approved, the FDA can subsequently approve the same drug or biologic for the same condition if the FDA concludes that the later product is clinically superior in that it is shown to
be safer, to be more effective or to make a major contribution to patient care. Finally, orphan drug exclusivity may be lost if the FDA or the EMA determines that the request for designation was
materially defective or if the manufacturer is unable to assure sufficient quantity of the product to meet the needs of patients with the rare disease or condition.
The FDA may further reevaluate the Orphan Drug Act and its regulations and policies. This may be particularly true in light of a decision from the Court of Appeals for the 11  Circuit in
September 2021 finding that, for the purpose of determining the scope of exclusivity, the term “same disease or condition” means the designated “rare disease or condition” and could not be
interpreted by the Agency to mean the “indication or use.” We do not know if, when, or how the FDA may change the orphan drug regulations and policies in the future, and it is uncertain how any
changes might affect our business. Depending on what changes the FDA may make to its orphan drug regulations and policies, our business could be adversely impacted.
Inadequate funding for the FDA, the SEC and other government agencies, including from government shut downs, or other disruptions to these agencies’ operations, could hinder their ability
to hire and retain key leadership and other personnel, prevent new products and services from being developed or commercialized in a timely manner or otherwise prevent those agencies from
performing normal business functions on which the operation of our business may rely, which could negatively impact our business.
The ability of the FDA to review and approve new products can be affected by a variety of factors, including government budget and funding levels, ability to hire and retain key personnel
and accept the payment of user fees, and
th
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statutory, regulatory and policy changes. Average review times at the agency have fluctuated in recent years as a result. Disruptions at the FDA and other agencies may also slow the time necessary
for new product candidates to be reviewed and/or approved by necessary government agencies, which would adversely affect our business. In addition, government funding of the SEC and other
government agencies on which our operations may rely, including those that fund research and development activities, is subject to the political process, which is inherently fluid and unpredictable.
Disruptions at the FDA and other agencies may also slow the time necessary for new product candidates to be reviewed and/or approved by necessary government agencies, which would
adversely affect our business. For example, over the last several years the U.S. government has shut down several times and certain regulatory agencies, such as the FDA and the SEC, have had to
furlough critical FDA, SEC and other government employees and stop critical activities. If a prolonged government shutdown occurs, it could significantly impact the ability of the FDA to timely
review and process our regulatory submissions, which could have a material adverse effect on our business. Further, future government shutdowns could impact our ability to access the public
markets and obtain necessary capital in order to properly capitalize and continue our operations.
Separately, in response to the COVID-19 pandemic, a number of companies announced receipt of complete response letters due to the FDA’s inability to complete required inspections for
their applications. As of May 26, 2021, the FDA noted it was continuing to ensure timely reviews of applications for medical products during the ongoing COVID-19 pandemic in line with its user
fee performance goals and conducting mission critical domestic and foreign inspections to ensure compliance of manufacturing facilities with FDA quality standards. However, the FDA may not be
able to continue its current pace and review timelines could be extended, including where a pre-approval inspection or an inspection of clinical sites is required and due to the ongoing COVID-19
pandemic and travel restrictions, the FDA is unable to complete such required inspections during the review period. Regulatory authorities outside the U.S. may adopt similar restrictions or other
policy measures in response to the COVID-19 pandemic and may experience delays in their regulatory activities. If a prolonged government shutdown or other disruption occurs, it could significantly
impact the ability of the FDA to timely review and process our regulatory submissions, which could have a material adverse effect on our business. Future shutdowns or other disruptions could also
affect other government agencies such as the SEC, which may also impact our business by delaying review of our public filings, to the extent such review is necessary, and our ability to access the
public markets.
FOTIVDA and any product candidate for which we or our collaborators obtain marketing approval are subject to ongoing regulation and could be subject to restrictions or withdrawal from the
market, and we may be subject to substantial penalties if we fail to comply with regulatory requirements.
FOTIVDA and any product candidate for which we or our collaborators obtain marketing approval in the future will be subject to continual requirements of and review by the FDA and other
regulatory authorities. These requirements include submissions of safety and other post-marketing information and reports, registration and listing requirements, cGMP requirements relating to
quality control and manufacturing, quality assurance and corresponding maintenance of records and documents, and requirements regarding the distribution of samples to physicians and
recordkeeping. Even if marketing approval of a product candidate is granted, the approval may be subject to limitations on the indicated uses for which the product may be marketed or to the
conditions of approval, or contain requirements for costly post-marketing testing and surveillance to monitor the safety or efficacy of the medicine, including the requirement to implement a risk
evaluation and mitigation strategy. For example, FDA approval of FOTIVDA is subject to limitations on the indicated uses for which FOTIVDA may be marketed, specifically the treatment of adults
with relapsed or refractory advanced RCC who have progressed following two or more systemic therapies. Accordingly, we expect to continue to expend time, money and effort in all areas of
regulatory compliance, including manufacturing, production, product surveillance and quality control. If we fail to comply with these requirements, we could have the marketing approval for
FOTIVDA withdrawn by regulatory authorities and our ability to market any products could be limited, which could adversely affect our ability to achieve or sustain profitability.
We and our collaborators must also comply with requirements concerning advertising and promotion for FOTIVDA or any of our product candidates for which we may obtain regulatory
approval. Promotional communications with respect to prescription products are subject to a variety of legal and regulatory restrictions and must be consistent with the information in the product’s
approved labeling. Thus, we are restricted from promoting any products we develop for indications or uses for which they are not approved. The FDA and other agencies, including the Department of
Justice, or the DOJ, closely regulate and monitor the post-approval marketing and promotion of products to ensure that they are marketed and distributed only for the approved indications and in
accordance with the provisions of the approved labeling. Violations of the Federal Food, Drug, and Cosmetic Act and other statutes, including the False Claims Act, relating to the
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promotion and advertising of prescription products may lead to investigations and enforcement actions alleging violations of federal and state health care fraud and abuse laws, as well as state
consumer protection laws.
Failure to comply with regulatory requirements, may yield various results, including:
•
restrictions on such products, manufacturers or manufacturing processes;
•
restrictions on the labeling or marketing of a product;
•
restrictions on distribution or use of a product;
•
requirements to conduct post-marketing studies or clinical trials;
•
warning letters or untitled letters;
•
withdrawal of the products from the market;
•
refusal to approve pending applications or supplements to approved applications that we submit;
•
recall of products;
•
damage to relationships with collaborators;
•
unfavorable press coverage and damage to our reputation;
•
fines, restitution or disgorgement of profits or revenues;
•
suspension or withdrawal of marketing approvals;
•
refusal to permit the import or export of our products;
•
product seizure;
•
injunctions or the imposition of civil or criminal penalties; and
•
litigation involving patients using our products.
Similar restrictions apply to the approval of our products in the EU. The holder of a marketing authorization is required to comply with a range of requirements applicable to the
manufacturing, marketing, promotion and sale of medicinal products. These include: compliance with the EU’s stringent pharmacovigilance or safety reporting rules, which can impose post-
authorization studies and additional monitoring obligations; the manufacturing of authorized medicinal products, for which a separate manufacturer’s license is mandatory; and the marketing and
promotion of authorized drugs, which are strictly regulated in the EU and are also subject to EU Member State laws. Non-compliance with EU requirements regarding safety monitoring or
pharmacovigilance, and with requirements related to the development of products for the pediatric population, can also result in significant financial penalties.
Our relationships with healthcare providers, physicians and third-party payors are subject to applicable anti-kickback, fraud and abuse and other healthcare laws and regulations, which, in the
event of a violation, could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and diminished profits and future earnings.
Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of FOTIVDA and any product candidate for which we may obtain
marketing approval in the future. Our arrangements with healthcare providers, physicians and third-party payors may expose us to broadly applicable fraud and abuse laws and other healthcare laws
and regulations that may constrain the business or financial arrangements and relationships through which we market, sell and distribute FOTIVDA and any products for which we may obtain
marketing approval in the future. Restrictions under applicable federal and state healthcare laws and regulations include the federal Anti-Kickback Statute, the False Claims Act, Health Insurance
Portability and Accountability Act of 1996, or HIPAA, and the Physician Payments Sunshine Act. There are also analogous state and foreign laws and regulations that may apply to sales or marketing
arrangements and claims involving healthcare items or services reimbursed by third-party payors, including private insurers. Further, some state laws require pharmaceutical companies to comply
with the pharmaceutical industry’s voluntary compliance guidelines and may require manufacturers to report information related to payments and other transfers of value to other healthcare providers
and healthcare entities, or marketing expenditures. Efforts to ensure that our business arrangements with third parties will comply with applicable healthcare laws and regulations involve substantial
costs.
Efforts to ensure that our business arrangements with third parties comply with applicable healthcare laws and regulations involve substantial costs. It is possible that governmental
authorities will conclude that our business practices
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may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse or other healthcare laws and regulations. If our business practices or operations are found
to be in violation of any of the laws described above, other or future healthcare laws or case law or any governmental regulations that may apply to us, we may be subject to significant civil, criminal
and administrative penalties, damages, fines, individual imprisonment, integrity obligations, exclusion from government funded healthcare programs, such as Medicare and Medicaid, and the
curtailment or restructuring of our operations. Any such penalties could adversely affect our financial results.
We have implemented a corporate compliance program designed to ensure that we will market and sell FOTIVDA and any future products that we successfully develop from our product
candidates in compliance with all applicable laws and regulations, but we cannot guarantee that this program will protect us from governmental investigations or other actions or lawsuits stemming
from a failure to be in compliance with such laws or regulations. If any such actions are instituted against us and we are not successful in defending ourselves or asserting our rights, those actions
could have a significant impact on our business, including the imposition of significant fines or other sanctions. Further, if any of the physicians or other healthcare providers or entities with whom
we do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or administrative sanctions, including exclusion from government funded healthcare
programs, which could impact us.
Any relationships we may have with customers, healthcare providers and professionals and third-party payors, among others, will be subject to applicable anti-kickback, fraud and abuse and
other healthcare laws and regulations, which could expose us to penalties, including criminal sanctions, civil penalties, contractual damages, reputational harm, fines, disgorgement, exclusion
from participation in government healthcare programs, curtailment or restricting of our operations and diminished profits and future earnings.
Healthcare providers, physicians and third-party payors will play a primary role in the recommendation and prescription of any products for which we are able to obtain marketing approval.
Any arrangements we have with healthcare providers, third-party payors and customers will subject us to broadly applicable fraud and abuse and other healthcare laws and regulations. The laws and
regulations may constrain the business or financial arrangements and relationships through which we conduct clinical research, market, sell and distribute any products for which we obtain marketing
approval. These include the following:
Anti-Kickback Statute. The federal Anti-Kickback Statute prohibits, among other things, persons and entities from knowingly and willfully soliciting, offering, receiving or providing
remuneration (including any kickback, bribe or rebate), directly or indirectly, in cash or in kind, to induce or reward or in return for, either the referral of an individual for or the purchase, lease or
order of a good, facility, item or service for which payment may be made under a federal healthcare program such as Medicare and Medicaid.
False Claims Laws. The federal false claims and civil monetary penalties laws, including the federal civil False Claims Act, impose criminal and civil penalties, including through civil
whistleblower or qui tam actions against individuals or entities for, among other things, knowingly presenting or causing to be presented false or fraudulent claims for payment by a federal healthcare
program or making a false statement or record material to payment of a false claim or avoiding, decreasing or concealing an obligation to pay money to the federal government, with potential liability
including mandatory treble damages and significant per-claim penalties.
HIPAA. The federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, imposes criminal and civil liability for, among other things, executing a scheme or making
materially false statements in connection with the delivery of or payment for health care benefits, items or services. Additionally, HIPAA, as amended by the Health Information Technology for
Economic and Clinical Health Act and its implementing regulations, also imposes obligations on covered entities and their business associates that perform certain functions or activities that involve
the use or disclosure of protected health information on their behalf, including mandatory contractual terms and technical safeguards, with respect to maintaining the privacy, security and
transmission of individually identifiable health information.
Transparency Requirements. The federal Physician Payments Sunshine Act requires certain manufacturers of drugs, devices, biologics and medical supplies for which payment is available
under Medicare, Medicaid or the Children’s Health Insurance Program, with specific exceptions, to report annually to CMS information related to payments or transfers of value made to physicians,
other healthcare providers and teaching hospitals, as well as information regarding ownership and investment interests held by physicians, other healthcare providers and their immediate family
members.
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Analogous State and Foreign Laws. Analogous state and foreign fraud and abuse laws and regulations, such as state anti-kickback and false claims laws, can apply to sales or marketing
arrangements and claims involving healthcare items or services reimbursed by non-governmental third-party payors and are generally broad and are enforced by many different federal and state
agencies as well as through private actions. Some state laws require pharmaceutical companies to comply with the pharmaceutical industry’s voluntary compliance guidelines and the relevant
compliance guidance promulgated by the federal government and require drug manufacturers to report information related to payments and other transfers of value to physicians and other healthcare
providers or marketing expenditures. State and foreign laws also govern the privacy and security of health information in some circumstances, many of which differ from each other in significant
ways and often are not pre-empted by HIPAA, thus complicating compliance efforts.
Efforts to ensure that any business arrangements we have with third parties and our business generally, will comply with applicable healthcare laws and regulations will involve substantial
costs. It is possible that governmental authorities will conclude that our business practices may not comply with current or future statutes, regulations or case law involving applicable fraud and abuse
or other healthcare laws and regulations. If our operations are found to be in violation of any of these laws or any other governmental regulations that may apply to us, we may be subject to
significant civil, criminal and administrative penalties, damages, fines, individual imprisonment, additional reporting requirements and oversight if we become subject to a corporate integrity
agreement or similar agreement to resolve allegations of non-compliance with these laws, exclusion of products from government funded healthcare programs, such as Medicare and Medicaid,
disgorgement, contractual damages, reputational harm and the curtailment or restructuring of our operations. Defending against any such actions can be costly, time-consuming and may require
significant financial and personnel resources. Therefore, even if we are successful in defending against any such actions that may be brought against us, our business may be impaired. Further, if any
of the physicians or other healthcare providers or entities with whom we expect to do business is found to be not in compliance with applicable laws, they may be subject to criminal, civil or
administrative sanctions, including exclusions from government funded healthcare programs.
The provision of benefits or advantages to physicians to induce or encourage the prescription, recommendation, endorsement, purchase, supply, order or use of medicinal products is also
prohibited in the EU. The provision of benefits or advantages to physicians is governed by the national anti-bribery laws of EU member states. In addition, payments made to physicians in certain EU
member states must be publicly disclosed. Moreover, agreements with physicians often must be the subject of prior notification and approval by the physician’s employer, his or her competent
professional organization and/or the regulatory authorities of the individual EU member states. These requirements are provided in the national laws, industry codes or professional codes of conduct,
applicable in the EU member states. Failure to comply with these requirements could result in reputational risk, public reprimands, administrative penalties, fines or imprisonment.
Reporting and payment obligations under the Medicaid Drug Rebate Program and other governmental drug pricing programs are complex and may involve subjective decisions. Any failure to
comply with those obligations could subject us to penalties and sanctions.
As a condition of reimbursement by various federal and state health insurance programs, biotechnology and pharmaceutical companies are required to calculate and report certain pricing
information to federal and state agencies. The regulations governing the calculations, price reporting and payment obligations are complex and subject to interpretation by various government and
regulatory agencies, as well as the courts. We have made reasonable assumptions where there is lack of regulations or clear guidance and such assumptions involve subjective decisions and estimates.
We are required to report any revisions to our calculations, price reporting and payment obligations previously reported or paid. Such revisions could affect liability to federal and state payers and
also adversely impact our reported financial results of operations in the period of such restatement.
Uncertainty exists as new laws, regulations, judicial decisions or new interpretations of existing laws, or regulations related to our calculations, price reporting or payments obligations
increases the chances of a legal challenge, restatement or investigation. If we become subject to investigations, restatements or other inquiries concerning compliance with price reporting laws and
regulations, we could be required to pay or be subject to additional reimbursements, penalties, sanctions or fines, which could have a material adverse effect on our business, financial condition and
results of operations. In addition, it is possible that future healthcare reform measures could be adopted, which could result in increased pressure on pricing and reimbursement of products and thus
have an adverse impact on our financial position or business operations.
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Further, state Medicaid programs may be slow to invoice pharmaceutical companies for calculated rebates resulting in a lag between the time a sale is recorded and the time the rebate is
paid. This results in a company having to carry a liability on its consolidated balance sheets for the estimate of rebate claims expected for Medicaid patients. If actual claims are higher than our
current estimates, our financial position and results of operations could be adversely affected.
In addition to retroactive rebates and the potential for 340B Program refunds, if we are found to have knowingly submitted any false price information related to the Medicaid Drug Rebate
Program to the Centers for Medicare & Medicaid Services, or CMS, we may be liable for civil monetary penalties. Such failure could also be grounds for CMS to terminate our Medicaid drug rebate
agreement, pursuant to which we participate in the Medicaid program. In the event that CMS terminates our rebate agreements, federal payments may not be available under government programs,
including Medicaid or Medicare Part B, for covered outpatient drugs.
Additionally, if we were found to have overcharged the government in connection with the FSS program or TriCare Retail Pharmacy Program, whether due to a misstated Federal Ceiling
Price or otherwise, we would be required to refund the difference to the government. Failure to make necessary disclosures and/or to identify contract overcharges could result in allegations against us
under the FCA and other laws and regulations. Unexpected refunds to the government, and responding to a government investigation or enforcement action, would be expensive and time-consuming,
and could have a material adverse effect on our business, financial condition, results of operations and growth prospects.
Our collaborators are also subject to similar requirements outside of the U.S. and thus the attendant risks and uncertainties. If our collaborators suffer material and adverse effects from such
risks and uncertainties, our rights and benefits for our licensed products could be negatively impacted, which could have a material and adverse impact on our revenues.
Current and future legislation may increase the difficulty and cost for us and any collaborators to obtain marketing approval of and commercialize our product candidates and affect the prices
we, or they, may obtain.
In the United States and foreign jurisdictions, there have been a number of legislative and regulatory changes and proposed changes regarding the healthcare system that could prevent or
delay marketing approval of our product candidates, restrict or regulate post-approval activities and affect our ability to profitably sell FOTIVDA or any product candidates for which we may obtain
marketing approval. We expect that current laws, as well as other healthcare reform measures that may be adopted in the future, may result in more rigorous coverage criteria and in additional
downward pressure on the price that we or any collaborators may receive for FOTIVDA or any product candidate for which we may obtain marketing approval in the future.
In March 2010, President Obama signed into law the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Affordability Reconciliation Act, or
collectively the ACA. Since enactment of the ACA, there have been, and continue to be, numerous legal challenges and Congressional actions to repeal and replace provisions of the law. For
example, with the enactment of the Tax Cuts and Jobs Act of 2017, or TCJA, which was signed by President Trump on December 22, 2017, Congress repealed the “individual mandate.” The repeal of
this provision, which requires most Americans to carry a minimal level of health insurance, became effective in 2019. Further, on December 14, 2018, a U.S. District Court judge in the Northern
District of Texas ruled that the individual mandate portion of the ACA is an essential and inseverable feature of the ACA, and therefore because the mandate was repealed as part of the TCJA, the
remaining provisions of the ACA are invalid as well. The U.S. Supreme Court heard this case on November 10, 2020 and on June 17, 2021, dismissed this action after finding that the plaintiffs do not
have standing to challenge the constitutionality of the ACA. Litigation and legislation over the ACA are likely to continue, with unpredictable and uncertain results.
The prices of prescription pharmaceuticals have also been the subject of considerable discussion in the United States. There have been several recent U.S. congressional inquiries, as well as
proposed and enacted state and federal legislation designed to, among other things, bring more transparency to pharmaceutical pricing, review the relationship between pricing and manufacturer
patient programs, and reduce the costs of pharmaceuticals under Medicare and Medicaid. In 2020, President Trump issued several executive orders intended to lower the costs of prescription products
and certain provisions in these orders have been incorporated into regulations. These regulations include an interim final rule implementing a most favored nation model for prices that tie Medicare
Part B payments for certain physician-administered pharmaceuticals to lower prices paid in other economically advanced countries, effective January 1, 2021. The rule, however, has been subject to a
nationwide preliminary injunction and, on December 29, 2021, CMS issued a final
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rule to rescind it. With issuance of this rule, CMS stated that it will explore all options to incorporate value into payments for Medicare Part B pharmaceuticals and improve beneficiaries' access to
evidence-based care.
In addition, in October 2020, HHS and the FDA published a final rule allowing states and other entities to develop a Section 804 Importation Program, or SIP, to import certain prescription
drugs from Canada into the United States. The final rule is currently the subject of ongoing litigation, but at least six states (Vermont, Colorado, Florida, Maine, New Mexico, and New Hampshire)
have passed laws allowing for the importation of drugs from Canada with the intent of developing SIPs for review and approval by the FDA. Further, on November 20, 2020, HHS finalized a
regulation removing safe harbor protection for price reductions from pharmaceutical manufacturers to plan sponsors under Part D, either directly or through pharmacy benefit managers, unless the
price reduction is required by law. The implementation of the rule has been delayed by the Biden administration from January 1, 2022 to January 1, 2023 in response to ongoing litigation. The rule
also creates a new safe harbor for price reductions reflected at the point-of-sale, as well as a new safe harbor for certain fixed fee arrangements between pharmacy benefit managers and
manufacturers, the implementation of which have also been delayed by the Biden administration until January 1, 2023.
At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control pharmaceutical and biological product pricing, including price or patient
reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from
other countries and bulk purchasing. In addition, regional health care authorities and individual hospitals are increasingly using bidding procedures to determine what pharmaceutical products and
which suppliers will be included in their prescription drug and other health care programs. These measures could reduce the ultimate demand for our products, once approved, or put pressure on our
product pricing. We expect that additional state and federal healthcare reform measures will be adopted in the future, any of which could limit the amounts that federal and state governments will pay
for healthcare products and services, which could result in reduced demand for FOTIVDA or our product candidates or additional pricing pressures.
Finally, outside the United States, in some nations, including those of the EU, the pricing of prescription pharmaceuticals is subject to governmental control and access. In these countries,
pricing negotiations with governmental authorities can take considerable time after the receipt of marketing approval for a product. To obtain reimbursement or pricing approval in some countries, we
or our collaborators may be required to conduct a clinical trial that compares the cost-effectiveness of our product to other available therapies. If reimbursement of FOTIVDA is unavailable or limited
in scope or amount, or if pricing is set at unsatisfactory levels, our business could be materially harmed.
Compliance with global privacy and data security requirements could result in additional costs and liabilities to us or inhibit our ability to collect and process data globally, and the failure to
comply with such requirements could subject us to significant fines and penalties, which may have a material adverse effect on our business, financial condition or results of operations.
The regulatory framework for the collection, use, safeguarding, sharing, transfer and other processing of information worldwide is rapidly evolving and is likely to remain uncertain for the
foreseeable future. Virtually every jurisdiction in which we operate has established its own data security and privacy frameworks with which we must comply, with additional laws and amendments
being passed on a regular basis. As one example, the collection, use, disclosure, transfer or other processing of personal data regarding individuals in the EU, including personal health data, is subject
to the EU General Data Protection Regulation, or the GDPR, which applies to all member states of the European Economic Area, or EEA. The GDPR is wide-ranging in scope and imposes numerous
requirements on companies that process personal data. In addition, the GDPR also imposes strict rules on the transfer of personal data to countries outside the EU, including the United States and, as a
result, increases the scrutiny that clinical trial sites located in the EEA should apply to transfers of personal data from such sites to countries that are considered to lack an adequate level of data
protection, such as the United States. The GDPR also permits data protection authorities to require destruction of improperly gathered or used personal information and/or impose substantial fines for
violations of the GDPR and it also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies and obtain
compensation for damages resulting from violations of the GDPR. In addition, the GDPR provides that EU member states may make their own further laws and regulations limiting the processing of
personal data, including genetic, biometric or health data. Compliance with the GDPR is a rigorous, expensive and time-consuming process that may increase our cost of doing business or require us
to change our business practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with any EU activities.
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Given the breadth and depth of the GDPR and changes in data protection obligations, preparing for and complying with these requirements is rigorous, expensive and time-consuming and
requires significant resources and a review of our technologies, systems and practices, as well as those of any third-party collaborators, service providers, contractors or consultants that process or
transfer personal data collected in the EU and otherwise across the world. The GDPR and other changes in laws or regulations associated with the enhanced protection of certain types of sensitive
data, such as healthcare data or other personal information from our clinical trials participants, could require us to change our business practices and put in place additional compliance mechanisms,
may interrupt or delay our development, regulatory and commercialization activities and increase our cost of doing business, and could lead to government enforcement actions, private litigation and
significant fines and penalties against us and could have a material adverse effect on our business, financial condition or results of operations.
Similar actions are either in place or under way in the United States. There are a broad variety of data protection laws that are applicable to our activities, and a wide range of enforcement
agencies at both the state and federal levels that can review companies for privacy and data security concerns based on general consumer protection laws. The Federal Trade Commission and state
attorneys general all are aggressive in reviewing privacy and data security protections for consumers. New laws also are being considered at both the state and federal levels. For example, the
California Consumer Privacy Act—which went into effect on January 1, 2020—is creating similar risks and obligations as those created by GDPR, though the California Consumer Privacy Act does
exempt certain information collected as part of a clinical trial subject to the Federal Policy for the Protection of Human Subjects (the Common Rule). Many other states are considering similar
legislation. Accordingly, failure to comply with federal and state laws (both those currently in effect and future legislation) regarding privacy and security of personal information could expose us to
fines and penalties under such laws. Even if we are not determined to have violated these laws, government investigations into these issues typically require the expenditure of significant resources
and generate negative publicity, which could harm our reputation and our business.
Laws and regulations governing any international operations we may have in the future may preclude us from developing, manufacturing and selling certain products outside of the United
States and require us to develop and implement costly compliance programs.
If we expand our operations outside of the United States, we must dedicate additional resources to comply with numerous laws and regulations in each jurisdiction in which we plan to
operate. The Foreign Corrupt Practices Act, or FCPA, prohibits any U.S. individual or business from paying, offering, authorizing payment or offering of anything of value, directly or indirectly, to
any foreign official, political party or candidate for the purpose of influencing any act or decision of the foreign entity in order to assist the individual or business in obtaining or retaining business.
The FCPA also obligates companies whose securities are listed in the United States to comply with certain accounting provisions requiring the company to maintain books and records that accurately
and fairly reflect all transactions of the corporation, including international subsidiaries, and to devise and maintain an adequate system of internal accounting controls for international operations.
Compliance with the FCPA is expensive and difficult, particularly in countries in which corruption is a recognized problem. In addition, the FCPA presents particular challenges in the
pharmaceutical industry, because, in many countries, hospitals are operated by the government, and doctors and other hospital employees are considered foreign officials. Certain payments to
hospitals in connection with clinical trials and other work have been deemed to be improper payments to government officials and have led to FCPA enforcement actions.
Various laws, regulations and Executive Orders also restrict the use and dissemination outside of the United States, or the sharing with certain non-U.S. nationals, of information classified
for national security purposes, as well as certain products and technical data relating to those products. If we expand our presence outside of the United States, it will require us to dedicate additional
resources to comply with these laws, and these laws may preclude us from developing, manufacturing, marketing or selling certain products and product candidates outside of the United States, which
could limit our growth potential and increase our development costs.
The failure to comply with laws governing international business practices may result in substantial civil and criminal penalties and suspension or debarment from government contracting.
The SEC also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the FCPA’s accounting provisions.
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If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could have a material adverse effect on our
business.
We are subject to numerous environmental, health and safety laws and regulations, including those governing laboratory procedures and the handling, use, storage, treatment and disposal of
hazardous materials and wastes. From time to time and in the future, our operations may involve the use of hazardous and flammable materials, including chemicals and biological materials, and may
also produce hazardous waste products. Even if we contract with third parties for the proper disposal of these materials and waste products, we cannot completely eliminate the risk of contamination
or injury resulting from these materials. In the event of contamination or injury resulting from the use or disposal of our hazardous materials, we could be held liable for any resulting damages, and
any liability could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties for failure to comply with such laws and regulations.
We maintain workers’ compensation insurance to cover us for costs and expenses we may incur due to injuries to our employees resulting from the use of hazardous materials, but this
insurance may not provide adequate coverage against potential liabilities. We do not maintain insurance for environmental liability or toxic tort claims that may be asserted against us and we could
incur significant costs associated with environmental liability or toxic tort claims for failure to comply with such laws and regulations.
In addition, we may incur substantial costs in order to comply with current or future environmental, health and safety laws and regulations. Current or future environmental laws and
regulations may impair our research, development or production efforts, which could adversely affect our business, financial condition, results of operations or prospects. In addition, failure to
comply with these laws and regulations may result in substantial fines, penalties or other sanctions.
Risks Related to Employee Matters and Managing Potential Growth
If we fail to attract and keep senior management, we may be unable to successfully develop our product candidates, conduct our clinical trials and commercialize our product candidates.
Our success depends in part on our continued ability to attract, retain and motivate highly qualified management personnel. We are highly dependent upon our senior management, as well as
others on our management team. The loss of services of employees and, in particular, of a member of management could delay or prevent our ability to successfully commercialize FOTIVDA in the
United States, our ability to successfully maintain or enter into new licensing arrangements or collaborations, the successful development of our product candidates, the completion of our planned
clinical trials or the attainment of regulatory approvals and successful commercialization of our product candidates. We do not carry “key person” insurance covering any members of our senior
management. Our employment arrangements with all of these individuals are “at will,” meaning they or we can terminate their service at any time.
We face intense competition for qualified individuals from numerous pharmaceutical and biotechnology companies, universities, governmental entities and other research institutions, many
of which have substantially greater resources with which to reward qualified individuals than we do. We may face challenges in retaining our existing senior management and key employees and
recruiting new employees to join our company as our business needs change. In addition, the COVID-19 pandemic may negatively impact our ability to recruit and build out our organization as
planned. We may be unable to attract and retain suitably qualified individuals, and our failure to do so could have an adverse effect on our ability to implement our future business plans.
Our employees or consultants may engage in misconduct or other improper activities, including noncompliance with regulatory standards and requirements and/or insider trading.
We are exposed to the risk of employee or consultant fraud or other misconduct. Misconduct by employees or consultants could include intentional failures to comply with FDA regulations,
to provide accurate information to the FDA, to comply with manufacturing standards we have established, to comply with federal and state health-care fraud and abuse laws and regulations, to report
financial information or data accurately or to disclose unauthorized activities to us. In particular, marketing, sales and business arrangements in the healthcare industry are subject to extensive laws
and regulations intended to prevent fraud, kickbacks, self-dealing and other abusive practices. These laws and regulations may restrict or prohibit a wide range of pricing, discounting, marketing and
promotion, sales commission, customer incentive programs and other business arrangements. Employee or consultant misconduct could also involve the improper use of information obtained in the
course of clinical trials, which could result in regulatory sanctions and serious harm to our reputation.
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We have adopted a Code of Business Conduct and Ethics, but it is not always possible to identify and deter employee or consultant misconduct, and the precautions we take to detect and
prevent this activity may not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming from a
failure to be in compliance with such laws or regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have
a significant impact on our business, including the imposition of significant fines or other sanctions.
In addition, during the course of our operations, our directors, executives, employees and consultants may have access to material nonpublic information regarding our business, our results
of operations or potential transactions we are considering. Despite the adoption of an Insider Trading Policy, we may not be able to prevent a director, executive, employee or consultant from trading
in our common stock on the basis of, or while having access to, material nonpublic information. If a director, executive, employee or consultant was to be investigated, or an action was to be brought
against a director, executive, employee or consultant for insider trading, it could have a negative impact on our reputation and our stock price. Such a claim, with or without merit, could also result in
substantial expenditures of time and money and divert attention of our management team from other tasks important to the success of our business.
Risks Related to Ownership of Our Common Stock
The market price of our common stock has been, and is likely to be, highly volatile, and could fall below the price you paid. A significant decline in the value of our stock price could also result
in securities class-action litigation against us.
The market price of our common stock has been, and is likely to continue to be, highly volatile and subject to wide fluctuations in price in response to various factors, many of which are
beyond our control, including:
•
announcements relating to our product, FOTIVDA, including as it relates to commercial performance, sales and any future regulatory matters;
•
new products, product candidates or new uses for existing products introduced or announced by our strategic partners, or our competitors, and the timing of these introductions or
announcements;
•
actual or anticipated results from and any delays in our manufacturing or clinical trials;
•
sales of common stock by us or our stockholders in the future, as well as the overall trading volume of our common stock;
•
the effect of the COVID-19 outbreak on the healthcare system and the economy generally and on our supply chain, manufacturing timelines, preclinical studies, clinical trials,
commercial activities and other operations specifically;
•
the results of regulatory reviews and other regulatory correspondence relating to our product, product candidates or our clinical trials;
•
the results of our efforts to develop, acquire or in-license additional product candidates or products;
•
disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection for our technologies;
•
announcements by us of material developments in our business, financial condition, partnerships and/or operations;
•
announcements by us or our competitors of significant acquisitions, strategic partnerships, joint ventures and capital commitments;
•
additions or departures of key scientific or management personnel;
•
conditions or trends in the biotechnology and biopharmaceutical industries, including the recent sell off in the stock market for many companies in the biotechnology and
biopharmaceutical industries;
•
actual or anticipated changes in revenue, expense or earnings estimates, development timelines or recommendations by securities analysts; and
•
general economic and market conditions on our industry and market conditions, and other factors that may be unrelated to our operating performance or the operating performance
of our competitors, including changes in market valuations of similar companies.
 
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In addition, the stock market in general and the market for biotechnology and biopharmaceutical companies in particular have experienced extreme price and volume fluctuations that have
often been unrelated or disproportionate to the operating performance of those companies. These broad market and industry factors may seriously harm the market price of our common stock,
regardless of our operating performance.
Periods of volatility in the market for a company’s stock are often followed by litigation against the company. For example, following our failure to obtain FDA approval for tivozanib in
2013, we and certain of our former officers and directors were involved in several legal proceedings. Following our January 2019 announcement that the FDA did not recommend we file an NDA for
tivozanib at that time, several lawsuits were filed against us, our directors, and certain of our current and former officers. While the 2019 Class Action was dismissed, any litigation instituted against
us in the future could result in substantial costs and diversion of management’s attention and resources, which could materially and adversely affect our business and financial condition.
We and our collaborators may not achieve development and commercialization goals in the estimated time frames that we publicly announce, which could have an adverse impact on our
business and could cause our stock price to decline.
We set goals and make public statements regarding our expected timing for certain accomplishments, such as statements we have made about the initiation and completion of clinical trials,
filing and approval of regulatory applications and other developments and milestones under our research and development programs and those of our partners and collaborators for tivozanib,
ficlatuzumab, AV-380 and AV-203. The actual timing of these events can vary significantly due to a number of factors, including those discussed elsewhere in this section “Part II, Item 1A. Risk
Factors.” As a result, there can be no assurance that our preclinical studies and clinical trials will advance or be completed in the time frames we expect or announce, that we will make regulatory
submissions or receive regulatory approvals as planned, that we will be successful in our commercial launch or that we will be able to adhere to our currently anticipated schedule for the achievement
of key milestones under any of our programs. If we fail to achieve one or more of the events described above as planned, our business could be materially adversely affected and the price of our
common stock could decline.
Our management has broad discretion over our use of available cash and cash equivalents and might not spend our available cash and cash equivalents in ways that increase the value of your
investment.
Our management has broad discretion on where and how to use our cash and cash equivalents and, as a stockholder, you rely on the judgment of our management regarding the application of
our available cash and cash equivalents to fund our operations. Our management might not apply our cash and cash equivalents in ways that increase the value of your investment. We expect to use a
substantial portion of our cash to fund existing and future research and development of our preclinical and clinical product candidates, with the balance, if any, to be used for working capital and other
general corporate purposes, which may in the future include investments in, or acquisitions of, complementary businesses, joint ventures, partnerships, services or technologies. Our management
might not be able to yield a significant return, if any, on any investment of this cash. You will not have the opportunity to influence our decisions on how to use our cash reserves.
If we fail to meet the requirements for continued listing on the Nasdaq Capital Market, our common stock could be delisted from trading, which would decrease the liquidity of our common
stock and our ability to raise additional capital.
Our common stock is currently listed on the Nasdaq Capital Market, or Nasdaq. We are required to meet specified requirements to maintain our listing on Nasdaq, including a minimum
market value of listed securities of $35.0 million, a minimum bid price of $1.00 per share for our common stock and other continued listing requirements.
In the past we have, from time to time, received deficiency letters from Nasdaq as a consequence of our failure to satisfy such requirements. Although we have been able to regain
compliance with the listing requirements within the manner and time periods prescribed by Nasdaq in the past, there can be no assurance that we will be able to maintain compliance with the Nasdaq
continued listing requirements in the future or regain compliance with respect to any future deficiencies. If we fail to satisfy Nasdaq’s continued listing requirements, we may transfer to the OTC
Bulletin Board, which generally has lower financial requirements for initial listing, to avoid delisting. However, we may not be able to satisfy the initial listing requirements for the OTC Bulletin
Board. Having our common stock trade on the OTC Bulletin Board could adversely affect the liquidity of our common stock. Any such event could make it more difficult to dispose of, or obtain
accurate quotations for the price of, our common stock, and there also would likely be a reduction in our coverage by securities analysts and the news media, which could cause the price of our
common stock to decline further. We may
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also face other material adverse consequences in such event, such as negative publicity, a decreased ability to obtain additional financing, diminished investor and/or employee confidence and the loss
of business development opportunities, some or all of which may contribute to a further decline in our stock price.
Fluctuations in our quarterly operating results could adversely affect the price of our common stock.
Our quarterly operating results may fluctuate significantly. Some of the factors that may cause our operating results to fluctuate on a period-to-period basis include:
•
the level of net product revenues from the sales of FOTIVDA;
•
the level of expenses incurred to commercialize FOTIVDA;
•
the level of expenses incurred in connection with our clinical development programs, including development and manufacturing costs relating to our clinical development
candidates;
•
the implementation of restructuring and cost-savings strategies;
•
the implementation or termination of collaboration, licensing, manufacturing or other material agreements with third parties, and non-recurring revenue or expenses under any such
agreement;
•
costs associated with litigation in which we may become involved;
•
changes in our 2020 Loan Facility, including the existence of any event of default that may accelerate then remaining principal payments and fees due thereunder;
•
non-cash changes in fair value related to re-valuations of our outstanding warrant liability as a result of fluctuations in our stock price; and
•
compliance with regulatory requirements.
Period-to-period comparisons of our historical and future financial results may not be meaningful, and investors should not rely on them as an indication of future performance. Our
fluctuating results may fail to meet the expectations of securities analysts or investors. Our failure to meet these expectations may cause the price of our common stock to decline.
Unstable market and economic conditions may have serious adverse consequences on our business, financial condition and stock price.
Global credit and financial markets have experienced extreme volatility and disruptions since 2020 due to the COVID-19 pandemic and the government measures taken in response to the
pandemic. We expect that rapid or extended periods of deterioration in credit and financial markets and confidence in economic conditions will continue. Our general business strategy may be
adversely affected by external economic conditions and a volatile business environment or unpredictable and unstable market conditions. If the equity and credit markets are not favorable at any time
we seek to raise capital, it may make any necessary debt or equity financing more difficult, more costly and more dilutive. Failure to secure any necessary financing in a timely manner and on
favorable terms could have a material adverse effect on our growth strategy, financial performance and stock price and could require us to delay or abandon clinical development plans. In addition,
there is a risk that one or more of our current service providers, manufacturers or other partners may not survive economically turbulent times, which could directly affect our ability to attain our
operating goals on schedule and on budget.
As of December 31, 2021, we had approximately $87.3 million of cash, cash equivalents and marketable securities consisting of cash on deposit with banks and in a U.S. government money
market fund, and high-grade debt securities, including commercial paper. As of the date of this report, we are not aware of any downgrades, material losses or other significant deterioration in the fair
value of our cash equivalents or marketable securities. However, no assurance can be given that deterioration in conditions of the global credit and financial markets would not negatively impact our
current portfolio of cash equivalents and marketable securities or our ability to meet our financing objectives. Dislocations in the credit market may adversely impact the value and/or liquidity of cash
equivalents and marketable securities owned by us.
Future sales of shares of our common stock, including shares issued upon the exercise of currently outstanding options, could negatively affect our stock price.
A substantial portion of our outstanding common stock can be traded without restriction at any time. Some of these shares are currently restricted as a result of securities laws, but will be
able to be sold, subject to any applicable
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volume limitations under federal securities laws with respect to affiliate sales, in the near future. As such, sales of a substantial number of shares of our common stock in the public market could
occur at any time. These sales, or the perception in the market that the holders of a large number of shares intend to sell such shares, could reduce the market price of our common stock. In addition,
we have a significant number of shares that are subject to outstanding options. The exercise of these options and the subsequent sale of the underlying common stock could cause a further decline in
our stock price. These sales also might make it difficult for us to sell equity securities in the future at a time and at a price that we deem appropriate.
If securities or industry analysts do not publish research or publish inaccurate or unfavorable research about our business, our share price and trading volume could decline.
The trading market for our common stock may depend in part on the research and reports that securities or industry analysts publish about us or our business. We do not have any control
over these analysts. There can be no assurance that analysts will cover us, or provide favorable coverage. A lack of research coverage may negatively impact the market price of our common stock.
To the extent we do have analyst coverage, if one or more analysts downgrade our stock or change their opinion of our stock, our share price would likely decline. In addition, if one or more analysts
cease coverage of our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which could cause our share price or trading volume to decline.
Provisions in our certificate of incorporation, our by-laws or Delaware law might discourage, delay or prevent a change in control of our company or changes in our management and,
therefore, depress the market price of our common stock.
Provisions of our certificate of incorporation, our by-laws or Delaware law may have the effect of deterring unsolicited takeovers or delaying or preventing a change in control of our
company or changes in our management, including transactions in which our stockholders might otherwise receive a premium for their shares over then current market prices. In addition, these
provisions may limit the ability of stockholders to approve transactions that they may deem to be in their best interest. These provisions include:
•
advance notice requirements for stockholder proposals and nominations;
•
the inability of stockholders to act by written consent or to call special meetings;
•
the ability of our board of directors to make, alter or repeal our by-laws; and
•
the ability of our board of directors to designate the terms of and issue new series of preferred stock without stockholder approval, which could be used to institute a rights plan, or a
poison pill, that would work to dilute the stock ownership of a potential hostile acquirer, likely preventing acquisitions that have not been approved by our board of directors.
In addition, Section 203 of the Delaware General Corporation Law prohibits a publicly-held Delaware corporation from engaging in a business combination with an interested stockholder,
generally a person which together with its affiliates owns, or within the last three years has owned, 15% of our voting stock, for a period of three years after the date of the transaction in which the
person became an interested stockholder, unless the business combination is approved in a prescribed manner.
The existence of the foregoing provisions and anti-takeover measures could limit the price that investors might be willing to pay in the future for shares of our common stock. They could
also deter potential acquirers of our company, thereby reducing the likelihood that a stockholder could receive a premium for shares of our common stock held by a stockholder in an acquisition.
Our business could be negatively affected as a result of the actions of activist stockholders.
Proxy contests have been waged against companies in the biopharmaceutical industry over the last few years. If faced with a proxy contest, we may not be able to successfully respond to the
contest, which would be disruptive to our business. Even if we are successful, our business could be adversely affected by a proxy contest because:
•
responding to proxy contests and other actions by activist stockholders may be costly and time-consuming, and may disrupt our operations and divert the attention of management
and our employees;
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•
perceived uncertainties as to the potential outcome of any proxy contest may result in our inability to consummate potential acquisitions, collaborations or in-licensing opportunities
and may make it more difficult to attract and retain qualified personnel and business partners; and
•
if individuals that have a specific agenda different from that of our management or other members of our board of directors are elected to our board of directors as a result of any
proxy contest, such an election may adversely affect our ability to effectively and timely implement our strategic plan and create additional value for our stockholders.
Failure to maintain effective internal controls in accordance with Section 404 of the Sarbanes-Oxley Act could have a material adverse effect on our ability to produce accurate financial
statements and on our stock price.
Section 404 of the Sarbanes-Oxley Act of 2002 requires us, on an annual basis, to review and evaluate our internal controls. In addition, our independent registered public accounting firm
has attested to the effectiveness of our internal controls. Despite our efforts, we can provide no assurance as to our, or our independent registered public accounting firm’s, conclusions with respect to
the effectiveness of our internal control over financial reporting under Section 404. There is a risk that neither we nor our independent registered public accounting firm will be able to conclude
within the prescribed timeframe that our internal control over financial reporting is effective as required by Section 404. This could result in an adverse reaction in the financial markets due to a loss
of confidence in the reliability of our financial statements.
If we are unable to successfully remediate any material weaknesses in our internal control, the accuracy and timing of our financial reporting may be adversely affected, we may be unable to
maintain compliance with securities law requirements regarding timely filing of periodic reports in addition to applicable stock exchange listing requirements, investors may lose confidence in our
financial reporting and our stock price may decline as a result. We also could become subject to investigations by Nasdaq, the SEC or other regulatory authorities.
We do not expect to pay any cash dividends for the foreseeable future.
Our stockholders should not rely on an investment in our common stock to provide dividend income. We do not anticipate that we will pay any cash dividends to holders of our common
stock in the foreseeable future. Instead, we plan to retain any earnings to maintain and expand our existing operations. In addition, our ability to pay cash dividends is currently prohibited by the terms
of our debt financing arrangements and any future debt financing arrangement may contain terms prohibiting or limiting the amount of dividends that may be declared or paid on our common stock.
In addition, the terms of the 2020 Loan Facility preclude, and any future debt agreements may preclude us from, paying dividends. Accordingly, investors must rely on sales of their common stock
after price appreciation, which may never occur, as the only way to realize any return on their investment. As a result, investors seeking cash dividends should not purchase our common stock.
Changes in tax laws or in their implementation or interpretation may adversely affect our business and financial condition.
The rules dealing with U.S. federal, state and local income taxation are constantly under review by persons involved in the legislative process and by the Internal Revenue Service and the
U.S. Treasury Department. Changes to tax laws (which changes may have retroactive application) could adversely affect us or holders of our common stock. In recent years, many such changes have
been made and changes are likely to continue to occur in the future. For example, the TCJA was enacted in 2017 and significantly reformed the Internal Revenue Code of 1986, as amended, or the
Code. In addition, as part of Congress’ response to the COVID-19 pandemic, the Families First Coronavirus Response Act, or FFCR Act, was enacted on March 18, 2020, and the Coronavirus Aid,
Relief, and Economic Security Act, or the CARES Act, was enacted on March 27, 2020. Both contain numerous tax provisions.
Regulatory guidance under the TCJA, the FFCR Act and the CARES Act is and continues to be forthcoming, and such guidance could ultimately increase or lessen impact of these laws on
our business and financial condition. It is also possible that Congress will enact additional legislation in connection with the COVID-19 pandemic, some of which could have an impact on our
company. In addition, it is uncertain if and to what extent various states will conform to the TCJA, the FFCR Act or the CARES Act. We urge investors to consult with their legal and tax advisers
regarding the implications of the TCJA, the FFCR Act and the CARES Act and other changes in tax laws on an investment in our common stock. Recent changes in tax law may adversely affect our
business or financial condition.
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We might not be able to utilize a significant portion of our net operating loss carryforwards and research and development tax credit carryforwards.
As of December 31, 2021, we had federal net operating loss carryforwards of $613.1 million, of which $502.6 million will, if not used, expire at various dates through 2037, and federal
research and development tax credit carryforwards of $12.6 million, which will, if not used, expire at various dates through 2041. To the extent that they expire unused, these net operating loss and
tax credit carryforwards will not be available to offset our future income tax liabilities. Federal net operating losses incurred in 2018 and in future years may be carried forward indefinitely, but the
deductibility of such carryforwards is limited to 80% of our taxable income in the year in which such carryforwards are used. As of December 31, 2021, we have recorded a full valuation allowance
to offset these deferred tax assets because the future realizability of such assets is uncertain.
In addition, under Section 382 of the Code and corresponding provisions of state law, if a corporation undergoes an “ownership change,” which is generally defined as a greater than 50%
change, by value, in its equity ownership over a three-year period, the corporation’s ability to use its pre-change net operating loss and credit carryforwards to reduce its tax liability for post-change
periods may be limited. We have not determined if we have experienced Section 382 ownership changes in the past and if a portion of our net operating loss and tax credit carryforwards is subject to
an annual limitation under Section 382. We also may experience ownership changes in the future as a result of shifts in our stock ownership, some of which may be outside of our control. In addition,
we have not conducted a detailed study to document whether our historical activities qualify to support the research and development credits currently claimed as a carryforward. A detailed study
could result in adjustment to our research and development credit carryforwards. If we determine that an ownership change has occurred and our ability to use our historical net operating loss and tax
credit carryforwards is materially limited, or if our research and development carryforwards are adjusted, our use of those attributes to offset future income tax liabilities would be limited.
ITEM 1B.
Unresolved Staff Comments
None.
ITEM 2.
Properties
We currently sublease our corporate headquarters, which consists of approximately 6,465 square feet of office space located at 30 Winter Street, Boston, Massachusetts. Our sublease
agreement, which was amended on November 17, 2021, continues through November 29, 2022, or the amended Winter Street Sublease. The amended Winter Street Sublease (i) reduced the square
feet of office space from 10,158 square feet to 6,465 square feet, (ii) provided that the security deposit of $0.3 million would be applied toward the remaining base rent payable to the landlord to
satisfy in full the base rent obligations through the expiration date of November 29, 2022, and (iii) provided that the landlord would make renovations to improve the space. The term of the amended
Winter Street Sublease remained the same and will continue through November 29, 2022. We believe that our existing facilities are sufficient for our current needs.
ITEM 3.
Legal Proceedings
As of the date of filing this Annual Report on Form 10-K, we are not party to any material legal proceedings that could have a material adverse effect on our business, operating results or
financial condition.
ITEM 4.
Mine Safety Disclosures
Not applicable.
PART II
ITEM 5.
Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities
Market Information
Our common stock is traded on the Nasdaq Capital Market under the symbol “AVEO”.
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Holders
As of March 9, 2022, there were approximately 34 holders of record of our common stock. We believe that the number of beneficial owners of our common stock at that date was substantially
greater.
Dividends
We have never declared or paid any cash dividends on our common stock and our ability to pay cash dividends is currently prohibited by the terms of our debt financing arrangements. We
currently intend to retain earnings, if any, for use in our business and do not anticipate paying cash dividends on our common stock in the foreseeable future. Payment of future dividends, if any, on
our common stock will be at the discretion of our board of directors after taking into account various factors, including our financial condition, operating results, anticipated cash needs, and plans for
expansion.
Purchase of Equity Securities
We did not purchase any of our equity securities during any month within the three months ended December 31, 2021.
Recent Sales of Unregistered Securities
None.
ITEM 6.
RESERVED.
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Item 7.    Management’s Discussion and Analysis of Financial Condition and Results of Operations.
You should read the following discussion and analysis of our financial condition and results of operations together with our consolidated financial statements and the related notes appearing
elsewhere in this report. Some of the information contained in this discussion and analysis or set forth elsewhere in this report, including information with respect to our plans and strategy for our
business and related financing, includes forward-looking statements that involve risks and uncertainties. You should read the “Risk Factors” section in Part 1, Item 1A of this report for a discussion
of important factors that could cause actual results to differ materially from the results described in or implied by the forward-looking statements contained in the following discussion and analysis.
Overview
We are a commercial stage, oncology-focused biopharmaceutical company committed to delivering medicines that provide a better life for patients with cancer. We currently market
FOTIVDA  (tivozanib) in the United States. FOTIVDA is our first commercial product and was approved by the FDA for marketing and sale in the United States on March 10, 2021 for the treatment
of adult patients with RCC, following two or more prior systemic therapies. We continue to develop tivozanib in immuno-oncology combinations in RCC and other indications, and we have other
investigational programs in clinical development.
FOTIVDA is an oral, next-generation VEGFR TKI. The FDA approval of FOTIVDA is based on our pivotal Phase 3 randomized, controlled, multi-center, open-label clinical trial comparing
tivozanib to an approved therapy, Nexavar  (sorafenib), in RCC patients whose disease had relapsed or become refractory to two or three prior systemic therapies, which we refer to as the TIVO-3
trial. The approval is also supported by three additional trials in RCC and includes safety data from over 1,000 clinical trial subjects.
FOTIVDA became commercially available in the United States on March 22, 2021 and is available to patients through a network of specialty pharmacies and distributors. We commercialize
FOTIVDA in the United States through the support of approximately 65 field-based employees, which includes approximately 50 oncology sales professionals. The field sales force is supported by
the AVEO ACE Patient Support program, which is an extensive patient and healthcare provider support program designed to optimize patient access and help patients navigate their treatment journey.
To date, we believe we have been very successful in securing payor coverage. Furthermore, the NCCN Guidelines recommend FOTIVDA as a subsequent therapy for patients with relapsed or
refractory advanced RCC with clear cell histology who received two or more prior systemic therapies.
Restrictions related to the ongoing COVID-19 pandemic have posed challenges for gaining in-person access to customers, prescribers and other healthcare professionals and certain
institutions remain closed to industry representatives. Notwithstanding these challenges, as of December 31, 2021, prescriptions for FOTIVDA and product revenues have increased quarter over
quarter since the beginning of our commercial launch. We aim to continue to deliver quarter over quarter net revenue and underlying prescription demand growth as we continue to execute on our
commercial strategy to support the adoption of FOTIVDA in appropriate patients.
We believe there is significant commercial opportunity for FOTIVDA in RCC in the United States. We estimate that the current U.S. market for relapsed or refractory advanced RCC therapy
is more than $1.7 billion, including $1.3 billion in the second line and $480.0 million in the third and fourth lines. As the TIVO-3 trial is the first positive Phase 3 clinical trial in RCC patients whose
disease had relapsed or become refractory to two or three prior systemic therapies as well as the first Phase 3 clinical trial in RCC to investigate a predefined subpopulation of patients who received
prior immunotherapy, a predominant standard of care for earlier lines of therapy, we believe that FOTIVDA could become a standard of care in the United States in the third and fourth line relapsed
or refractory advanced setting. Further, we intend to pursue opportunities in the second line relapsed or refractory advanced RCC setting. We and our collaboration partners are developing tivozanib
with ICIs and in combination with a HIF2α inhibitor to support tivozanib's potential utility in this earlier line of RCC therapy.
Based on FOTIVDA’s demonstrated anti-tumor activity, tolerability profile and reduction of regulatory T-cell production, we and our collaboration partners are developing tivozanib in
additional cancer indications with significant unmet medical needs including, HCC, and tumors that are resistant to immunotherapy, or immunologically cold tumors, in combination with ICIs. In
addition, we are evaluating tivozanib as a monotherapy in ovarian cancer and CCA. We and our collaboration partners or independent investigators sponsor the development of tivozanib through
preclinical studies and clinical trials conducted under collaboration agreements and IST agreements or our CRADA with NCI-SOP.
®
®
® 
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We are also seeking to advance our pipeline of four wholly owned IgG1, monoclonal antibody product candidates, ficlatuzumab, AV-380, AV-203 and AV-353. We aim to leverage our
existing collaborations and partnerships and enter into new strategic collaborations and partnerships to continue to advance each of our product candidates.
Recent Developments
On March 8, 2022, we entered into a Loan Amendment with Hercules, or the 2022 Loan Amendment. The 2022 Loan Amendment, among other things, makes the $5.0 million Tranche Four
funding available upon achieving $30.0 million in trailing three-month net product revenues from sales of FOTIVDA by no later than December 15, 2022, instead of being available at the discretion
of the Lenders by no later than June 30, 2022. Please see “Part II, Item 9b. Other Information — 2022 Amendment to 2020 Credit Facility” of this Annual Report for a further discussion of the 2022
Loan Amendment.
Financial Overview
We do not have a history of generating operating profits and, as of December 31, 2021, we had an accumulated deficit of $674.5 million. We anticipate that we will continue to incur
significant operating expenses for the foreseeable future as we seek to successfully commercialize FOTIVDA in the United States and continue our planned development activities for our clinical and
preclinical stage assets.
We may require substantial additional funding to continue to advance our pipeline of clinical and preclinical stage assets, and the timing and nature of these activities will be conducted
subject to the availability of sufficient financial resources, principally product sales of FOTIVDA in the United States. Please see “Part II, Item 7. Management’s Discussion and Analysis of Financial
Condition and Results of Operations — Liquidity and Capital Resources —Liquidity and Going Concern” of this Annual Report for a further discussion of our funding requirements.
Revenue
Prior to the commercial launch of FOTIVDA in March 2021, our revenues were historically generated primarily through collaborative research, development and commercialization
agreements. Payments to us under these arrangements typically include one or more of the following: non-refundable, upfront license fees; option exercise fees; funding of research and/or
development efforts; milestone payments; and royalties on future product sales. In November 2017, we began earning sales royalties upon EUSA’s commencement of the first commercial launch of
FOTIVDA.
On March 10, 2021, the FDA approved FOTIVDA in the United States for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic
therapies. We commenced commercial sales of our first product FOTIVDA in the United States on March 22, 2021. We expect that any revenue we generate will fluctuate from quarter to quarter and
year to year as a result of the timing and amount of the payments that we receive upon the sales of FOTIVDA and any future products, to the extent any are successfully commercialized, and license
fees, research and development reimbursements, milestones, royalties and other payments received under our strategic partnerships. If we or our collaboration partners fail to complete the
development of our product candidates in a timely manner or to obtain or maintain regulatory approval for them, our ability to generate future revenue, and our results of operations and financial
position, would be materially adversely affected.
Research and Development Expenses
Research and development expenses have historically consisted of expenses incurred in connection with the discovery and development of our product candidates. We recognize research and
development expenses as they are incurred. These expenses consist primarily of:
•
employee-related expenses, including salaries, bonuses, benefits, stock-based compensation and research-related overhead;
•
external development-related expenses, including clinical trials, preclinical studies, consultants and other outsourced services;
•
costs of acquiring and manufacturing drug development related materials and related distribution;
•
costs associated with our regulatory and quality assurance operations and medical affairs;
 
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•
upfront license payments, milestones, sublicense fees and royalties related to in-licensed products and technology; and
•
allocated expenses for facilities and information technology.
Research and development expenses is net of amounts reimbursed under our agreement with AstraZeneca for their respective share of development costs incurred by us under our joint
development plans.
We anticipate that research and development expenses will increase in 2022, principally related to the enrollment of the TiNivo-2 Trial for the treatment of RCC patients who have progressed
following one or two lines of prior immunotherapy, one of which must include an ICI, the manufacturing of ficlatuzumab clinical drug supply for a potential registrational clinical trial in HPV
negative R/M HNSCC patients that we plan to initiate in the first half of 2023, a Phase 1b clinical trial in AV-380 in cancer patients that we plan to initiate in the second half of 2022 and the related
manufacturing of AV-380 clinical drug supply, and co-funding pursuant to the NiKang Agreement for a Phase 2 clinical trial to evaluate tivozanib in combination with NKT2152 in ccRCC patients
who have not responded to or relapsed from prior therapies. These increases in 2022 will be partially offset by lower costs, principally related to the TIVO-3 Trial that closed in the second half of
2021 following the FDA’s approval of FOTIVDA on March 10, 2021. We anticipate that research and development expenses will be in the range of $60.0 million to $70.0 million in 2022 in support
of our existing pipeline plans. The timing and nature of contemplated activities in 2022 will be conducted subject to the availability of sufficient financial resources.
Currently, we track direct external development expenses and direct salary on a program-by-program basis and allocate general-related expenses, such as indirect compensation, benefits and
consulting fees, to each program based on the personnel resources allocated to such program. Facilities, IT costs and stock-based compensation are not allocated amongst programs and are considered
overhead.
Uncertainties of Estimates Related to Research and Development Expenses
The process of conducting preclinical studies and clinical trials necessary to obtain FDA approval for each of our product candidates is costly and time-consuming. The probability of success
for each product candidate and clinical trial may be affected by a variety of factors, including, among others, the risk benefit profile of the product candidates’ clinical activity, investment in the
program, competition, manufacturing capabilities and commercial viability.
At this time, we cannot reasonably estimate or know the nature, specific timing and estimated costs of the efforts that will be necessary to complete the development of our product
candidates, or the period, if any, in which material net cash inflows may commence from sales of any approved products. This uncertainty is due to the numerous risks and uncertainties associated
with developing drugs, including the uncertainty of:
•
our ability to establish and maintain strategic partnerships, the terms of those strategic partnerships and the success of those strategic partnerships, if any, including the timing and
amount of payments that we might receive from strategic partners;
•
the scope, progress, results and costs of preclinical development, laboratory testing and clinical trials for any product candidate;
•
the progress and results of our clinical trials;
•
the costs, timing and outcome of regulatory review of our product candidates;
•
the emergence of competing technologies and products and other adverse market developments;
•
the costs of preparing, filing and prosecuting patent applications and maintaining, enforcing and defending intellectual property-related claims; and
•
additional manufacturing requirements.
As a result of the uncertainties associated with developing drugs, including those discussed above, we are unable to determine the exact duration and completion costs of current or future
clinical stages of our product candidates, or when, or to what extent, we will generate revenues from the commercialization and sale of any of our product candidates for which we may obtain
regulatory approval. Development timelines, probability of success and development costs vary widely. We anticipate that we will make determinations as to which additional programs to pursue and
how much funding to direct to each program on an ongoing basis in response to the scientific and clinical success, if any, of each product
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candidate, as well as ongoing assessment of each product candidate’s commercial potential. We will need to raise substantial additional capital in the future in order to fund the development of our
preclinical and clinical product candidates.
Selling, General and Administrative Expenses
Selling, general and administrative expenses consist principally of compensation, benefits and travel for employees in executive, finance, legal, human resource and commercial functions.
Other selling, general and administrative expenses include professional fees for audit, tax, general legal, patent legal, investor relations, commercial, consulting services and directors’ fees, as well as
facility and information technology-related costs not otherwise included in research and development expenses.
We anticipate that selling, general and administrative expenses associated with the commercialization of FOTIVDA, principally related to our sales force, our marketing, market access and
commercial capabilities, and general and administrative support will increase in 2022, principally reflective of a full year of commercialization following the launch of FOTIVDA on March 22, 2021.
We anticipate that selling, general and administrative expenses will be approximately $70.0 million, including approximately $50.0 million in commercial expenses and approximately $20.0 million
in general and administrative expenses.
Interest Expense, Net
Interest expense consists of interest, amortization of debt discount and amortization of deferred financing costs associated with our loans payable, and is shown net of interest income, which
consists of interest earned on our cash, cash equivalents and marketable securities. The primary objective of our investment policy is capital preservation.
Income Taxes
We generated tax losses for the years ended December 31, 2021 and 2020, and since we maintain a full valuation allowance on all of our deferred tax assets, we have recorded no income tax
provision or benefit during the years ended December 31, 2021 and 2020.
Critical Accounting Policies and Significant Judgments and Estimates
Our discussion and analysis of our financial condition and results of operations are based on our consolidated financial statements and the notes thereto included elsewhere in this Annual
Report on Form 10-K, which have been prepared in accordance with accounting principles generally accepted in the United States, or GAAP. The preparation of financial statements in conformity
with GAAP requires us to make estimates and assumptions that affect certain reported amounts of assets and liabilities, disclosure of contingent assets and liabilities at the date of the financial
statements, the assessment of our ability to continue as a going concern, and the reported amounts of revenues and expenses during the reporting periods. Significant items subject to such estimates
and assumptions include revenue recognition, clinical trial costs and contract research accruals, measurement of trade receivables net, measurement of stock-based compensation and estimates of our
capital requirements over the next twelve months from the date of issuance of the consolidated financial statements. We base our estimates on historical experience and various other assumptions that
we believe to be reasonable under the circumstances. Material changes in these estimates could occur in the future. Changes in estimates are recorded or reflected in our disclosures in the period in
which they become known. Actual results may differ from our estimates if past experience or other assumptions do not turn out to be substantially accurate. Our significant accounting policies are
described in the notes to our consolidated financial statements appearing elsewhere in this Annual Report on Form 10-K.
Revenue Recognition
Prior to the commercial launch of FOTIVDA in March 2021, our revenues had historically been generated primarily through collaborative research, development and commercialization
agreements. The terms of these agreements generally contain multiple promised goods and services, which may include (i) licenses, or options to obtain licenses, to our technology, (ii) research and
development activities to be performed on behalf of the collaborative partner, and (iii) in certain cases, services in connection with the manufacturing of preclinical and clinical material. Payments to
us under these arrangements typically include one or more of the following: non-refundable, upfront license fees; option exercise fees; funding of research and/or development efforts; milestone
payments; and royalties on future product sales.
Collaboration Arrangements Within the Scope of ASC 808, Collaborative Arrangements
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We analyze our collaboration arrangements to assess whether such arrangements involve joint operating activities performed by parties that are both active participants in the activities and
exposed to significant risks and rewards dependent on the commercial success of such activities and are therefore within the scope of ASC Topic 808, Collaborative Arrangements, or ASC 808. This
assessment is performed throughout the life of the arrangement based on changes in the responsibilities of all parties in the arrangement.
For collaboration arrangements that are deemed to be within the scope of ASC 808, we first determine which elements of the collaboration are deemed to be within the scope of ASC 808 and
those that are more reflective of a vendor-customer relationship and therefore within the scope of ASC 606, Revenue from Contracts with Customers, or ASC 606. Our policy is generally to
recognize amounts received from collaborators in connection with joint operating activities that are within the scope of ASC 808 as a reduction in research and development expense.
Arrangements Within the Scope of ASC 606, Revenue from Contracts with Customers
Under ASC 606, we recognize revenue when our customers obtain control of promised goods or services, in an amount that reflects the consideration which we determine we expect to
receive in exchange for those goods or services. To determine revenue recognition for arrangements that we determine are within the scope of ASC 606, we perform the following five steps: (i)
identify the contract(s) with a customer; (ii) identify the performance obligation(s) in the contract; (iii) determine the transaction price; (iv) allocate the transaction price to the performance
obligation(s) in the contract; and (v) recognize revenue when (or as) we satisfy our performance obligation(s). As part of the accounting for these arrangements, we must make significant judgments,
including identifying performance obligations in the contract, estimating the amount of variable consideration to include in the transaction price and allocating the transaction price to each
performance obligation.
Once a contract is determined to be within the scope of ASC 606, we assess the goods or services promised within the contract and determine those that are performance obligations.
Arrangements that include rights to additional goods or services that are exercisable at a customer’s discretion are generally considered options. We assess if these options provide a material right to
the customer and if so, they are considered performance obligations. The exercise of a material right is accounted for as a contract modification for accounting purposes.
We assess whether each promised good or service is distinct for the purpose of identifying the performance obligations in the contract. This assessment involves subjective determinations
and requires management to make judgments about the individual promised goods or services and whether such are separable from the other aspects of the contractual relationship. Promised goods
and services are considered distinct provided that: (i) the customer can benefit from the good or service either on its own or together with other resources that are readily available to the customer
(that is, the good or service is capable of being distinct) and (ii) the entity’s promise to transfer the good or service to the customer is separately identifiable from other promises in the contract (that is,
the promise to transfer the good or service is distinct within the context of the contract). In assessing whether a promised good or service is distinct, we consider factors such as the research,
manufacturing and commercialization capabilities of the collaboration partner and the availability of the associated expertise in the general marketplace. We also consider the intended benefit of the
contract in assessing whether a promised good or service is separately identifiable from other promises in the contract. If a promised good or service is not distinct, an entity is required to combine
that good or service with other promised goods or services until it identifies a bundle of goods or services that is distinct.
The transaction price is then determined and allocated to the identified performance obligations in proportion to their standalone selling prices, or SSP, on a relative SSP basis. SSP is
determined at contract inception and is not updated to reflect changes between contract inception and when the performance obligations are satisfied. Determining the SSP for performance
obligations requires significant judgment. In developing the SSP for a performance obligation, we consider applicable market conditions and relevant entity-specific factors, including factors that
were contemplated in negotiating the agreement with the customer and estimated costs. We validate the SSP for performance obligations by evaluating whether changes in the key assumptions used
to determine the SSP will have a significant effect on the allocation of arrangement consideration between multiple performance obligations.
If the consideration promised in a contract includes a variable amount, we estimate the amount of consideration to which we will be entitled in exchange for transferring the promised goods
or services to a customer. We determine the amount of variable consideration by using the expected value method or the most likely amount method. We include the unconstrained amount of
estimated variable consideration in the transaction price. The amount included in the transaction price is constrained to the amount for which it is probable that a significant reversal of cumulative
revenue recognized will not occur. At the end of each subsequent reporting period, we re-evaluate the estimated variable consideration included in the transaction price and any related constraint, and
if necessary, adjust our estimate of the overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis in the period of adjustment.
89

In determining the transaction price, we adjust consideration for the effects of the time value of money if the timing of payments provides us with a significant benefit of financing. We do not
assess whether a contract has a significant financing component if the expectation at contract inception is such that the period between payment by the licensees and the transfer of the promised goods
or services to the licensees will be one year or less. We assess each of our revenue generating arrangements in order to determine whether a significant financing component exists and concluded that
a significant financing component does not exist in any of our arrangements.
We then recognize as revenue the amount of the transaction price that is allocated to the respective performance obligation when (or as) each performance obligation is satisfied at a point in
time or over time, and if over time based on the use of an output or input method.
Licenses of Intellectual Property: The terms of our license agreements include the license of functional intellectual property, given the functionality of the intellectual property is not expected to
change substantially as a result of our ongoing activities. If the license to our intellectual property is determined to be distinct from the other performance obligations identified in the arrangement, we
recognize revenues from the portion of the transaction price allocated to the license when the license is transferred to the licensee and the licensee is able to use and benefit from the license. For
licenses that are bundled with other promises (that is, for licenses that are not distinct from other promised goods and services in an arrangement), we utilize judgment to assess the nature of the
combined performance obligation to determine whether the combined performance obligation is satisfied over time or at a point in time and, if over time, the appropriate method of measuring
progress for purposes of recognizing revenue. We evaluate the measure of progress each reporting period and, if necessary, adjusts the measure of performance and related revenue recognition.
Research and Development Funding: Arrangements that include payment for research and development services are generally considered to have variable consideration. If and when we assess
the payment for these services is no longer subject to the constraint on variable consideration, the related revenue is included in the transaction price.
Milestone Payments: At the inception of each arrangement that includes non-refundable payments for contingent milestones, including preclinical research and development, clinical
development and regulatory, we evaluate whether the milestones are considered probable of being achieved and estimate the amount to be included in the transaction price using the most likely
amount method. If it is probable that a significant revenue reversal would not occur, the associated milestone value is included in the transaction price. Milestone payments that are not within the
control of us or the licensee, such as regulatory approvals, are not considered probable of being achieved until those approvals are received. At the end of each reporting period, we re-evaluate the
probability of the achievement of contingent milestones and the likelihood of a significant reversal of such milestone revenue, and if necessary, adjust our estimate of the overall transaction price.
Any such adjustments are recorded on a cumulative catch-up basis, which would affect collaboration and licensing revenue in the period of adjustment. This quarterly assessment may result in the
recognition of revenue related to a contingent milestone payment before the milestone event has been achieved.
Royalties: For arrangements that include sales-based royalties, including milestone payments based on the level of sales, and the license is deemed to be the predominant item to which the
royalties relate, we recognize revenue at the later of (i) when the related sales occur, or (ii) when the performance obligation to which some or all of the royalty has been allocated has been satisfied
(or partially satisfied).
The following table summarizes the total revenues earned in the years ended December 31, 2021, 2020, and 2019, respectively, by partner (in thousands). Refer to Note 4 “Collaborations and
License Agreements” of the notes to our consolidated financial statements included elsewhere in this Annual Report on Form 10-K regarding specific details of these collaboration and license
arrangements.
 
Years Ended
December 31,
 
2021
2020
2019
FOTIVDA U.S. product revenue, net
$
38,874 
$
— 
$
— 
Partnership revenue - KKC
— 
2,800 
25,000 
Partnership revenue - EUSA
3,421 
3,219 
3,795 
Total revenues
$
42,295 
$
6,019 
$
28,795 
Accrued Expenses and Accrued Clinical Trial Costs and Contract Research Liabilities
As part of the process of preparing our financial statements, we are required to estimate accrued expenses. This process involves identifying services which have been performed on our
behalf, and estimating the level of service
90

performed and the associated cost incurred for such service as of each balance sheet date in our financial statements. Given our current business, the primary area of uncertainty concerning accruals
which could have a material effect on our operating results is with respect to service fees paid to CMOs in conjunction with the production of commercial and clinical drug supplies and to CROs in
connection with our clinical trials. In connection with all of the foregoing service fees, our estimates are most affected by our understanding of the status and timing of services provided. The majority
of our service providers, including CMOs and CROs, invoice us in arrears for services performed. In the event that we do not identify some costs which have begun to be incurred, or we under or
overestimate the level of services performed or the costs of such services in a given period, our reported expenses for such period would be understated or overstated. We currently reflect the effects
of any changes in estimates based on changes in facts and circumstances directly in our operations in the period such change becomes known.
Our arrangements with CROs in connection with clinical trials often provide for payment prior to commencing the project or based upon predetermined milestones throughout the period
during which services are expected to be performed. We recognize expense relating to these arrangements based on the various services provided over the estimated time to completion. The date on
which services commence, the level of services performed on or before a given date, and the cost of such services are often determined based on subjective judgments. We make these judgments
based upon the facts and circumstances known to us based on the terms of the contract and our ongoing monitoring of service performance. During the years ended December 31, 2021, 2020, and
2019, we had arrangements with multiple CROs whereby these organizations commit to performing services for us over multiple reporting periods. We recognize the expenses associated with these
arrangements based on our expectation of the timing of the performance of components under these arrangements by these organizations. Generally, these components consist of the costs of setting
up the trial, monitoring the trial, closing the trial and preparing the resulting data. Costs related to patient enrollment in clinical trials are accrued as patients are enrolled in the trial.
With respect to financial reporting periods presented in this Annual Report on Form 10-K, the timing of our actual costs incurred have not differed materially from our estimated timing of
such costs.
Results of Operations
Comparison of Years Ended December 31, 2021, 2020 and 2019
Revenues (in thousands)
 
Years Ended
December 31,
2021 / 2020 Comparison
2020 / 2019 Comparison
 
2021
2020
2019
$
%
$
%
FOTIVDA U.S. product revenue, net
$
38,874 
$
— 
$
— 
$
38,874 
100 % $
— 
100 %
Partnership revenue - KKC
— 
2,800 
25,000 
(2,800)
(100)%
(22,200)
(89)%
Partnership revenue - EUSA
3,421 
3,219 
3,795 
202 
6 %
(576)
(15)%
Total revenues
$
42,295 
$
6,019 
$
28,795 
$
36,276 
603 % $
(22,776)
(79)%
Our total revenues increased by $36.3 million, or 603%, to $42.3 million in the year ended December 31, 2021 from $6.0 million in the same period in 2020, principally due to the
commencement of sales of our first commercial product FOTIVDA in the United States on March 22, 2021 for the treatment of adult patients with relapsed or refractory advanced RCC following two
or more prior systemic therapies.
Our total revenues decreased by $22.8 million, or 79%, to $6.0 million in the year ended December 31, 2020 from $28.8 million in the same period in 2019, principally due to payments
earned pursuant to the amendment to the KKC Agreement for KKC’s repurchase of the non-oncology rights to tivozanib in our territory, including the $25.0 million upfront payment earned in 2019
offset by a $2.8 million development milestone earned in 2020, as well as a $0.6 million decrease in revenues from EUSA.
Partnership revenues from KKC decreased by $2.8 million, or 100%, in the year ended December 31, 2021, compared to the same period in 2020 and decreased by $22.2 million, or 89%, in
the year ended December 31, 2020, compared to the same period in 2019. On August 2, 2020, we earned a $2.8 million development milestone payment from KKC for the acceptance of KKC’s IND
for a non-oncology formulation of tivozanib by the Pharmaceuticals and Medical Devices Agency of Japan. In the third quarter of 2020, we recognized this $2.8 million development milestone as
revenue in accordance with ASC 606. No milestones were earned in the year ended December 31, 2021.
91

On August 1, 2019, we entered into an amendment to the KKC Agreement pursuant to which KKC repurchased the non-oncology rights to tivozanib in our territory, excluding the rights we
have sublicensed to EUSA under the EUSA Agreement, and KKC made a $25.0 million non-refundable upfront payment to us that we received in September 2019. In the third quarter of 2019, we
recognized this $25.0 million upfront payment as revenue in accordance with ASC 606.
Partnership revenues from EUSA increased by $0.2 million, or 6%, in the year ended December 31, 2021 as compared to the same period in 2020, and decreased by $0.6 million, or 15%, in
the year ended December 31, 2020, from the same period in 2019.
FOTIVDA U. S. Product Revenue, Net (in thousands)
Years Ended
December 31,
2021 / 2020 Comparison
2020 / 2019 Comparison
2021
2020
2019
$
%
$
%
Gross product revenue
$
45,668 
$
— 
$
— 
$
45,668 
100 %
$
— 
— %
Discounts and allowances
(6,794)
— 
— 
(6,794)
100 %
— 
— %
Product revenue, net
$
38,874 
$
— 
$
— 
$
38,874 
100 %
$
— 
— %
We commenced sales of our first commercial product FOTIVDA in the United States on March 22, 2021 for the treatment of adult patients with relapsed or refractory advanced RCC
following two or more prior systemic therapies.
We anticipate FOTIVDA net product revenues will be in the range of $100.0 million to $110.0 million in 2022.
Cost of Products Sold (in thousands)
 
Years Ended December 31,
2021 / 2020 Comparison
2020 / 2019 Comparison
 
2021
2020
2019
$
%
$
%
Cost of products sold
$
4,737 
$
— 
$
— 
$
4,737 
100 %
$
— 
— %
Gross margin %
88 %
— %
— %
88 %
100 %
— %
— %
We commenced sales of our first commercial product FOTIVDA in the United States on March 22, 2021 for the treatment of adult patients with relapsed or refractory advanced RCC
following two or more prior systemic therapies. Cost of products sold is related to our product revenues for FOTIVDA and consists primarily of tiered royalty payments we are required to pay to
KKC on all net sales of tivozanib in our North American territory, which range from the low to mid-teens as a percentage of net sales. Cost of products sold also consists of shipping and other third-
party logistics and distribution costs for FOTIVDA. We consider regulatory approval of our product candidates to be uncertain and product manufactured prior to regulatory approval may not be sold
unless regulatory approval is obtained. As such, the manufacturing costs for FOTIVDA incurred prior to regulatory approval were not capitalized as inventory but were expensed as research and
development costs, which favorably impacted our gross margin. We anticipate that gross margins will continue to be in the mid-to-high 80  percentile in 2022.
th
92

Research and Development Expenses (in thousands)
 
Years Ended
December 31,
2021 / 2020 Comparison
2020 / 2019 Comparison
 
2021
2020
2019
$
%
$
%
Tivozanib
$
16,277 
$
17,435 
$
12,148 
$
(1,158)
(7)% $
5,287 
44 %
AV-380 Program in Cachexia
4,024 
2,550 
3,379 
1,474 
58 
(829)
(25)
Ficlatuzumab
3,663 
1,187 
1,143 
2,476 
209 
44 
4 
Overhead
2,334 
1,507 
1,288 
827 
55 
219 
17 
Total research and development expenses
$
26,298 
$
22,679 
$
17,958 
$
3,619 
16 % $
4,721 
26 %
Our total research and development expenses increased by $3.6 million, or 16%, to $26.3 million in the year ended December 31, 2021 from $22.7 million in the same period in 2020.
Our total research and development expenses increased by $4.7 million, or 26%, to $22.7 million in the year ended December 31,2020 from $18.0 million in the same period in 2019.
Tivozanib expenses decreased by $1.2 million, or 7%, in the year ended December 31, 2021 as compared to the same period in 2020, principally related to $10.2 million in total decreases for
costs incurred in the year ended December 31, 2020 that were not incurred in the same period in 2021, including (i) $2.3 million in connection with the completion and review support for the
tivozanib NDA for relapsed or refractory advanced RCC following two or more prior systemic therapies, (ii) the corresponding $2.9 million application user fee pursuant to the Prescription Drug
User Fee Act that was due upon the filing of the tivozanib NDA on March 31, 2020, (iii) $1.7 million in connection with drug substance manufacturing prior to marketing approval of tivozanib and
(iv) $3.3 million in connection with lower expenses for the TIVO-3 trial that was closed in the second half of 2021 following FDA approval of FOTIVDA on March 10, 2021. These decreases were
partially offset by $8.7 million in total increases for costs incurred in the year ended December 31, 2021 that were not incurred in the same period in 2020, including (i) $6.1 million in connection
with start-up activities for the TiNivo-2 Trial that was initiated in the first quarter of 2021, (ii) $2.1 million in connection with the medical affairs function in support of the commercial launch of
FOTIVDA and (iii) $0.5 million in consulting and other fees.
Tivozanib expenses increased by $5.3 million, or 44%, in the year ended December 31, 2020 as compared to 2019. The $5.3 million increase was principally due to increases totaling $7.4
million, including: (i) $3.4 million related to the tivozanib NDA for RCC, including $0.5 million related to the completion of the NDA submission and ongoing support of the FDA’s review of the
NDA and the $2.9 million application user fee pursuant to the PDUFA that was due upon the filing of the tivozanib NDA on March 31, 2020, (ii) $0.6 million related to the DEDUCTIVE trial that
was initiated in September 2019, net of cost sharing with AstraZeneca, and (iii) $3.4 million in commercial launch-readiness initiatives incurred in 2020 that were not incurred in 2019, including $1.7
million related to the conduct of certain post-commercial launch drug supply manufacturing, $1.3 million related to the buildout of our medical affairs function and $0.4 million related to other
commercial-launch readiness initiatives.
These increases were partially offset by decreases totaling $2.3 million, principally including: (i) $1.8 million related to lower expenses in connection with the TIVO-3 and TiNivo trials that
were nearing completion and (ii) $0.5 million related to fluctuations in the year-to-year sublicense fees due to KKC in connection with a milestone we earned under our EUSA Agreement in 2019 that
was not earned in 2020.
AV-380 expenses increased by $1.5 million, or 58%, in the year ended December 31, 2021 as compared to the same period in 2020, principally due to the conduct of the Phase 1 clinical trial of
AV-380 in healthy subjects that was initiated in the first quarter of 2021 and the commencement of related clinical drug supply manufacturing, partially offset by a decrease in preclinical development
costs incurred in the year ended December 31, 2020 that were not incurred in the same period in 2021.
AV-380 expenses decreased by $0.8 million, or 16%, in the year ended December 31, 2020 as compared to the same period in 2019, principally due to the $2.3 million time-based milestone
obligation due to St. Vincent’s under our license agreement with St. Vincent’s, in the first quarter of 2019 that was not incurred in 2020, partially offset by an increase of $1.5 million related to pre-
clinical development costs incurred in 2020 that were not incurred in 2019.
93

Ficlatuzumab expenses increased by $2.5 million, or 209%, in the year ended December 31, 2021 as compared to the same period in 2020, principally related to the commencement of certain
manufacturing activities in 2021 in support of planned clinical drug supply manufacturing in 2022 for a potential registrational clinical trial of ficlatuzumab in combination with cetuximab in patients
with HPV negative R/M HNSCC patients in the first half of 2023, partially offset by costs incurred in the first quarter of 2020 that were not incurred in 2021 in connection with the discontinued
CyFi-2 trial, net of cost sharing with Biodesix.
Ficlatuzumab expenses were flat in 2020 as compared to 2019. In March 2020, we decided to discontinue the CyFi-2 trial due to the urgent shift in priorities among clinical trial sites towards
efforts to combat the COVID-19 pandemic, which had impacted the trial enrollment timeline and the feasibility of completing the study within the shelf-life of the then available ficlatuzumab clinical
trial drug supply.
We anticipate that research and development expenses will increase in 2022, principally related to the enrollment of the TiNivo-2 Trial for the treatment of advanced refractory RCC, the
manufacturing of ficlatuzumab clinical drug supply for a potential registrational clinical trial in HPV negative R/M HNSCC patients that we plan to initiate in the first half of 2023, a Phase 1b clinical
trial in AV-380 in cancer patients that we plan to initiate in the second half of 2022 and the related manufacturing of AV-380 clinical drug supply, and co-funding pursuant to the NiKang Agreement
for a Phase 2 clinical trial to evaluate tivozanib in combination with NKT2152 in ccRCC patients who have not responded to or relapsed from prior therapies. These increases in 2022 will be partially
offset by lower costs, principally related to the TIVO-3 Trial that was closed in the second half of 2021 following the FDA’s approval of FOTIVDA on March 10, 2021. We anticipate that research
and development expenses will be in the range of $60.0 million to $70.0 million in 2022 in support of our existing pipeline plans. The timing and nature of contemplated activities in 2022 will be
conducted subject to the availability of sufficient financial resources.
Selling, General and Administrative Expenses (in thousands)
 
Years Ended December 31,
2021 / 2020 Comparison
2020 / 2019 Comparison
 
2021
2020
2019
$
%
$
%
Selling, general and administrative expenses
$
60,814 
$
22,217 
$
11,211 
$38,597
174 %
$
11,006 
98%
Selling, general and administrative expenses increased by $38.6 million, or 174%, to $60.8 million in the year ended December 31, 2021 from $22.2 million in the same period in 2020. The
$38.6 million increase principally included: (i) $30.4 million in commercial launch initiatives incurred in the year ended December 31, 2021 that were not incurred in the same period in 2020,
including $18.0 million in connection with compensation and recruiting costs related to the growth in our commercial infrastructure, including the hiring of the sales force, and $12.4 million in
connection with external commercial-launch activities in marketing, market access and commercial operations, (ii) $4.2 million in other professional fees and (iii) $4.0 million in other compensation-
related costs.
Selling, general and administrative expenses increased by $11.0 million, or 98%, to $22.2 million in 2020 from $11.2 million in 2019. The $11.0 million increase was principally due to $11.2
million in total increases, including: (i) $8.5 million in commercial launch-readiness initiatives incurred in 2020 that were not incurred in 2019, including $3.1 million in compensation costs related to
the growth in our commercial infrastructure and $5.4 million related to external commercial-launch readiness activities in marketing, market access and commercial operations, (ii) $2.3 million in
other professional fees, and (iii) $0.4 million in other compensation-related costs. These increases were partially offset by $0.2 million in lower facility costs resulting from our corporate headquarters
move in 2020 to 30 Winter Street in Boston, Massachusetts.
We anticipate that selling, general and administrative expenses associated with the commercialization of FOTIVDA, principally related to our sales force, our marketing, market access and
commercial capabilities, and general and administrative support will increase in 2022, principally reflective of a full year of commercialization following the launch of FOTIVDA on March 22, 2021.
We anticipate that selling, general and administrative expenses will be approximately $70.0 million, including approximately $50.0 million in commercial expenses and approximately $20.0 million
in general and administrative expenses.
94

Change in Fair Value of Expired PIPE Warrant Liability (in thousands)
 
Years Ended December 31,
2021 / 2020 Comparison
2020 / 2019 Comparison
 
2021
2020
2019
$
%
$
%
Change in fair value of expired PIPE Warrant liability
$
199 
$
4,898 
11,577 
$
(4,699)
(96 %)
$(6,679)
(58)%
In May 2016, we issued PIPE warrants, or the PIPE Warrants, in connection with a private placement financing and recorded the warrants as a liability. The PIPE Warrants were exercisable
for a period of five years from the date of issuance until their scheduled expiration on May 16, 2021. The PIPE Warrants were subject to revaluation at each balance sheet date and any changes in fair
value were recorded as a non-cash gain or (loss) in our Statement of Operations as a component of other income (expense).
In the year ended December 31, 2021, we recorded an approximate non-cash gain of $0.2 million in our Statement of Operations attributable to the decrease in the fair value of the PIPE
Warrant liability that resulted from the expiration of the PIPE Warrants on May 16, 2021.
In the year ended December 31, 2020, we recorded an approximate non-cash gain of $4.9 million in our Statement of Operations attributable to the decrease in the fair value of the PIPE
Warrant liability that resulted from a lower stock price of $5.77 on December 31, 2020 compared to the stock price of $6.20 on December 31, 2019, a decrease in our stock volatility rate and a shorter
remaining term as the PIPE Warrants approach expiration in May 2021.
In the year ended December 31, 2019, we recorded an approximate non-cash gain of $11.6 million in our Statement of Operations attributable to the decrease in the fair value of the PIPE
Warrant liability that principally resulted from a lower stock price of $6.20 on December 31, 2019 compared to the stock price of $16.00 on December 31, 2018.
Interest Expense, net (in thousands)
Years Ended December 31,
2021 / 2020 Comparison
2020 / 2019 Comparison
2021
2020
2019
$
%
$
%
Interest expense, net
$
(4,045)
$
(1,605)
$
(1,815)
$
(2,440)
152 %
$
210 
(12 %)
Interest expense, net increased by $2.4 million, or 152%, in the year ended December 31, 2021, as compared to the same period in 2020, principally due to higher loan balances under the
2020 Loan Amendment and 2021 Loan Amendment, as defined below, that were entered into with Hercules Capital Inc. and certain of its affiliates, or Hercules, on August 7, 2020 and February 1,
2021. respectively. See “Item 2. Management’s Discussion and Analysis of Financial Condition and Results of Operations — Liquidity and Capital Resources — Hercules Loan Facility” below for a
description of the 2020 Loan Amendment and 2021 Loan Amendment.
Interest expense, net decreased by $0.2 million, or 12%, in 2020 as compared to 2019. This decrease was principally due to the decrease in interest expense resulting from the paydown of
principal under our 2017 Loan Agreement with Hercules and a lower interest rate that ranged from 9.45% to 9.65% in 2020 as compared to the interest rate that ranged from 9.70% to 10.2% in 2019.
Principal payments to Hercules resumed during the period from August 1, 2019 through August 1, 2020.
We anticipate that interest expense, net will increase in 2022 due to the $40.0 million loan balance as of December 31, 2021 and the extended interest-only period through March 2023
pursuant to the 2020 Loan Amendment and 2021 Loan Amendment with Hercules.
Contractual Obligations and Commitments
Hercules Loan Facility
95

On August 7, 2020, we entered into the 2020 Loan Amendment with Hercules. The 2020 Loan Amendment provided us with the 2020 Loan Facility, an additional term loan of up to $35.0
million in four tranches to be used to refinance outstanding loans under the 2017 Loan Agreement and for general working capital purposes through the commercial launch of FOTIVDA, subject to
certain terms and conditions. The 2020 Loan Facility includes (i) $15.0 million in initial funding upon execution of the 2020 Loan Amendment to retire the outstanding balance of approximately $9.7
million under the 2017 Loan Agreement and to provide approximately $5.3 million in new loan funding, and (ii) up to $20.0 million in additional loan funding following FDA approval of FOTIVDA
and our net product revenues from sales of FOTIVDA, within certain time frames and subject to certain terms and conditions.
On February 1, 2021, we entered into the 2021 Loan Amendment with Hercules. The 2021 Loan Amendment increases the 2020 Loan Facility from up to $35.0 million to up to $45.0 million
upon FDA approval of FOTIVDA. The 2021 Loan Amendment makes certain changes to the 2020 Loan Amendment, including, among other things, increasing the amount of Tranche Two funding
for Performance Milestone I for FDA approval of FOTIVDA from $10.0 million to $20.0 million, thereby increasing the total amount of unfunded term loan commitments under the 2020 Loan
Facility from $20.0 million to $30.0 million following FDA approval of FOTIVDA and our net product revenues from sales of FOTIVDA, within certain time frames and subject to certain terms and
conditions. On March 8, 2022, we entered into a Loan Amendment with Hercules, or the 2022 Loan Amendment. The 2022 Loan Amendment makes the $5.0 million Tranche Four funding available
upon achieving $30.0 million in trailing three-month net product revenues from sales of FOTIVDA by no later than December 15, 2022, instead of being available at the discretion of the Lenders by
no later than June 30, 2022. For more information, see “Part II, Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations — Liquidity and Capital Resources
—Hercules Loan Facility” below, as well as Note 6, “—Hercules Loan Facility” of the Notes to our consolidated financial statements, each included elsewhere in this Annual Report on Form 10-K.
Collaborations and License Agreements
Under our license agreement with KKC, we are required to pay tiered royalty payments on net sales we make of FOTIVDA in our North American territory, which range from the low to mid-
teens as a percentage of net sales. We are also required to pay KKC 30% of certain amounts we receive from sublicensees, including upfront license fees, milestone payments and royalties, other than
amounts we receive in respect of research and development funding or equity investments, subject to certain limitations. Also, under our license agreement with St. Vincent’s, we are required to make
certain milestone payments upon the earlier of the achievement of specified development and regulatory milestones or a specified date for the first indication, and upon the achievement of specified
development and regulatory milestones for the second and third indications. We are also obligated to pay Biogen a percentage of milestone payments received by us from future partnerships after
March 28, 2016 and single digit royalty payments on net sales related to the sale of ErbB3 products, if any, up to a cumulative maximum amount of $50.0 million. In addition, we are obligated to pay
Biodesix a low double digit royalty on future product sales and 25% of future licensing revenue (excluding contributions to research and development expenses), less approximately $2.5 million that
Biodesix would be required to pay to us pursuant to the October 2016 amendment to the Biodesix Agreement. At this time, we cannot reasonably estimate when or if we may be required to make
other additional payments to KKC, St. Vincent’s, Biogen or Biodesix. For example, we are required to make future milestone payments to St. Vincent’s, up to an aggregate total of $14.4 million, upon
the earlier of the achievement of specified development and regulatory milestones or a specified date for the first indication and second indication, and upon the achievement of specified development
and regulatory milestones for the third indication, for licensed therapeutic products, some of which payments may be increased by a mid to high double digit percentage rate for milestone payments
made after we grant any sublicense under the license agreement, depending on the sublicensed territory. For more information, see Note 6, “—Collaborations and License Agreements” of the Notes to
our consolidated financial statements, included elsewhere in this Annual Report on Form 10-K.
Winter Street Lease
On March 5, 2020, we entered into a sublease agreement for office space located at 30 Winter Street in Boston, Massachusetts, or the Winter Street Sublease. Under the terms of the Winter
Street Sublease, we leased 10,158 square feet of office space for $47.00 per square foot, or approximately $0.5 million per year in base rent subject to certain operating expenses, taxes and annual
base rent increases of approximately 3%. On November 17, 2021, we amended the Winter Street Sublease to reduce the square feet of office space from 10,158 square feet to 6,465 square feet. The
amended Winter Street Sublease provided that (i) the security deposit of $0.3 million would be applied toward the remaining base rent payable to landlord to satisfy in full the base rent obligations
through the expiration date of November 29, 2022 and (ii) the landlord would make renovations to improve the space. The term of the amended Winter Street Sublease remained the same and will
continue through November 29, 2022.
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Other Funding Commitments
We enter into contracts in the normal course of business with CROs for preclinical research studies and clinical trials. We have contracts with CROs for our DEDUCTIVE and TiNivo-2 trials,
as well as our Phase 1b clinical trial of AV-380 in cancer patients. These contracts generally provide for termination on notice with no early termination fees. We also have a contract with a CMO for
the manufacture tivozanib (FOTIVDA ) in the United States, which includes minimum annual purchase requirements in the range of $0.5 million to $1.4 million through 2028. In addition, we have a
contract with a second CMO for the manufacture of clinical drug supply for ficlatuzumab and AV-380, for which we have manufacturing commitments in 2022 in the aggregate amount of
approximately $9.0 million. Additionally, we have license fee obligations of up to $2.0 million due to a former CMO for ficlatuzumab drug manufacturing.
Liquidity and Capital Resources
We have financed our operations to date primarily through private placements and public offerings of our common stock, license fees, milestone, royalty payments and research and
development funding from strategic partners, loan proceeds and sales revenues of our first commercial product FOTIVDA in the United States. As of December 31, 2021 we had cash, cash
equivalents and marketable securities of approximately $87.3 million. See “Part II, Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations — Liquidity and
Capital Resources —Liquidity and Going Concern” below and Note 1 to the consolidated financial statements included elsewhere in this Annual Report on Form 10-K for a further discussion of our
liquidity. Currently, our funds are invested in a United States government money market fund.
The following table sets forth the primary sources and uses of cash for each of the periods set forth below (in thousands):
For the Years Ended December 31,
2021
2020
2019
Net cash used in operating activities
$
(57,257) $
(37,983) $
(2,919)
Net cash (used in) provided by investing activities
(16,866)
17,704 
(17,917)
Net cash provided by financing activities
82,904 
52,255 
26,194 
Net increase in cash and cash equivalents
$
8,781 $
31,976 $
5,358 
Our operating activities used cash of $57.3 million, $38.0 million and $2.9 million in the years ended December 31, 2021, 2020 and 2019, respectively. Cash used in operations was
principally due to our net loss adjusted for non-cash items and changes in working capital.
Our investing activities used cash of $16.9 million and $17.9 million in the years ended December 31, 2021 and 2019, respectively, and provided cash of $17.7 million in the year ended
December 31, 2020, principally due to net changes in the purchases and maturities of marketable securities.
Our financing activities provided cash of $82.9 million, $52.3 million and $26.2 million in the years ended December 31, 2021, 2020 and 2019, respectively. In the year ended December 31,
2021, we raised approximately $83.1 million in funding, including approximately $51.7 million in net proceeds from the sale of approximately 6.9 million shares of our common stock in an
underwritten public offering in March 2021, approximately $24.9 million in new loan funding pursuant to the 2020 Loan Amendment and 2021 Loan Amendment with Hercules, net of transaction
costs, approximately $3.4 million in net proceeds from the sale of approximately 0.3 million shares of our common stock in March 2021 pursuant to our “at-the-market” sales agreement with SVB
Leerink LLC, or SVB Leerink, which we refer to as the SVB Leerink Sales Agreement, and approximately $3.1 million in proceeds from the exercise of Offering Warrants. In July 2021, we paid
approximately $0.8 million in an end-of-term loan payment pursuant to the December 2017 Loan Amendment with Hercules.
In the year ended December 31, 2020, we raised approximately $52.2 million, including approximately $47.7 million in net proceeds from the sale of approximately 9.7 million shares of our
common stock in an underwritten public offering in June 2020 and approximately $5.1 million in new loan funding pursuant to the 2020 Loan Amendment with Hercules, net of transaction costs, and
paid approximately $6.5 million in principal payments pursuant to our then December 2017 Loan Agreement with Hercules.
®
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In 2019, we raised approximately $30.3 million in net proceeds from the issuance of our common stock, including $7.5 million in net proceeds from the sale of approximately 1.3 million
shares of our common stock pursuant to the SVB Leerink Sales Agreement in February 2019 and approximately $22.8 million in net proceeds from the sale of approximately 2.2 million shares of our
common stock and warrants to purchase an aggregate of 2.5 million shares of our common stock in an underwritten public offering in April 2019, offset in part by approximately $4.1 million in debt-
related payments pursuant to our First Loan Agreement, including approximately $3.8 million in total principal payments during the period from August 2019 through December 2019 and a $0.3
million end-of-term fee in December 2019.
Hercules Loan Facility ($45 Million Loan Facility - $5 Million Committed Funding Remaining)
On May 28, 2010, the Company entered into a loan and security agreement, or the First Loan Agreement with Hercules. The First Loan Agreement was subsequently amended in March
2012, September 2014, May 2016 and amended and restated in December 2017, or the 2017 Loan Agreement.
On August 7, 2020, we entered into a first amendment to the 2017 Loan Agreement or the 2020 Loan Amendment, to provide us, subject to certain terms and conditions, with additional term
loans in an aggregate principal amount of up to $35.0 million, or the 2020 Loan Facility, to be used to repay in full the 2017 Loan Agreement and for general working capital purposes. The 2020
Loan Facility is available to us in four tranches, the first of which, in the amount of $15.0 million, was made available to us immediately upon the closing of the 2020 Loan Amendment. We used the
$15.0 million in proceeds of the first tranche as follows: approximately $9.7 million was used to repay the outstanding balance of the 2017 Loan Agreement in full, and approximately $5.3 million
was used for general working capital purposes. In connection with the 2020 Loan Amendment, we incurred approximately $0.3 million in loan issuance costs paid directly to Hercules, which are
accounted for as a loan discount. The 2020 Loan Amendment was accounted for as a loan modification in accordance with ASC 470-50.
The remaining $20.0 million of term loans is available to us under the 2020 Loan Facility subject to, among other terms and conditions, the achievement of the following milestones: (i)
Tranche Two in the initial amount of $10.0 million was available through June 30, 2021 upon achieving Performance Milestone I for FDA approval of FOTIVDA, (ii) the third tranche, or Tranche
Three, in the amount of $5.0 million, was initially available from July 1, 2021 through January 31, 2022 if we were to achieve $20.0 million in net product revenues from sales of FOTIVDA,
following FDA approval, by no later than December 31, 2021, or Performance Milestone II, and (iii) the fourth tranche, or Tranche Four, in the amount of $5.0 million, was initially available through
June 30, 2022 upon the achievement of both Performance Milestone I and Performance Milestone II, and upon Hercules consent to the advancement of Tranche Four.
The 2020 Loan Amendment also amended the 2017 Loan Agreement by: (i) extending maturity of the loans from July 1, 2021 until September 1, 2023, which is extendable to September 1,
2024 upon our option if the Tranche Three funding has occurred, (ii) providing for an interest-only period beginning on the closing date of 2020 Loan Amendment and ending December 31, 2021,
which period may be extended through September 30, 2022 provided we achieved Performance Milestone I, and further extendable through March 31, 2023 if the Tranche Three funding has
occurred, and (iii) revising the interest rate to the greater of 9.65% and an amount equal to 9.65% plus the prime rate minus 3.25% (subject to a 15% cap). Principal payments were initially scheduled
to commence on October 1, 2021, at the earliest, as described above. The interest rate as of December 31, 2021 was 9.65%.
Pursuant to the terms of the 2020 Loan Facility, principal will be repaid in equal monthly installments following the conclusion of the interest-only period. We may prepay all of the
outstanding principal and accrued interest under the 2020 Loan Facility, subject to a prepayment charge up to 3.0% in the first year following the closing of the 2020 Loan Amendment, decreasing to
2.0% in year two and 1.0% in year three. We are obligated to make an end-of-term payment of (i) 6.95% of the aggregate amount of loan funding received under the Loan Agreement on the earlier of
the maturity of the loans or the date on which we prepay the outstanding loan balance in full, and (ii) an approximate $0.8 million payment due on the earlier of July 1, 2021 or the date on which we
prepay the outstanding loan balance in full. This payment was made on July 1, 2021.
The 2020 Loan Facility includes (i) a financial covenant that we maintain minimum unrestricted cash positions of $10.0 million through the date the Second Tranche funding is received,
$15.0 million through the date the Third Tranche funding is received and $10.0 million thereafter through the maturity of the Loan Agreement, and (ii) an operating covenant that we achieve greater
than or equal to 75% of our forecasted net product revenues from our sales of tivozanib over a six-month trailing period, as defined and measured on a monthly basis, commencing upon the earlier to
occur of (x) the Third Tranche funding and (y) the month of April 2022. The 2020 Loan Facility also includes various other affirmative and negative covenants, including covenants to deliver certain
financial reports; to maintain insurance coverage; and to
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refrain from transferring assets, incurring additional indebtedness, engaging in mergers or acquisitions, paying dividends or making other distributions, making investments, creating liens, and
suffering a change in control, in each case subject to certain exceptions.
On February 1, 2021, we entered into the 2021 Loan Amendment. The 2021 Loan Amendment increased the aggregate principal amount of loans available under the 2020 Loan Facility from
up to $35.0 million to up to $45.0 million following FDA approval of FOTIVDA. The 2021 Loan Amendment also (i) increased Tranche Two funding upon achieving Performance Milestone I from
$10.0 million to $20.0 million, (ii) increased the amount of net product revenues from sales of FOTIVDA required for us to achieve Performance Milestone II from $20.0 million to $35.0 million, and
changed the deadline for achieving Performance Milestone II from December 31, 2021 to April 1, 2022, and (iii) increased the amount of unrestricted cash required for us to satisfy the minimum
financial covenant during the period between receiving Tranche Two funding and Tranche Three funding from $10.0 million to $15.0 million. In connection with the 2021 Loan Amendment, we
incurred approximately $0.1 million in loan issuance costs paid directly to Hercules, which are accounted for as a loan discount.
On March 11, 2021, we completed the $20.0 million drawdown of Tranche Two funding under the 2021 Loan Amendment that was made available in connection with the achievement of
Performance Milestone I upon FDA approval of FOTIVDA on March 10, 2021. The achievement of Performance Milestone I extended the interest-only period by twelve months from September 30,
2021 to September 30, 2022 and increased the amount of unrestricted cash required for us to satisfy the minimum financial covenant during the period between receiving Tranche Two funding and
Tranche Three funding from $10.0 million to $15.0 million.
On December 22, 2021, we completed the $5.0 million drawdown of Tranche Three funding under the 2021 Loan Amendment that was made available in connection with the achievement of
Performance Milestone II upon the achievement of $35.0 million in net product revenues from sales of FOTIVDA. The achievement of Performance Milestone II extended the interest-only period by
six months from September 30, 2022 to March 31, 2023, extended the loan maturity by one year from September 1, 2023 to September 1, 2024 and decreased the amount of unrestricted cash required
for us to satisfy the minimum financial covenant from $15.0 million to $10.0 million thereafter through the maturity of the Loan Agreement.
As of December 31, 2021, the total principal balance was $40.0 million, principal payments are scheduled to commence on April 1, 2023 and the corresponding end-of-term payments under
the 2020 Loan Facility, in the aggregate amount of approximately $2.8 million, are due upon the current loan maturity date of September 1, 2024. As of December 31, 2021, $5.0 million remains
available to us in committed funding under the 2020 Loan Facility for Tranche Four funding that was at our election and subject to the consent of Hercules. The unamortized discount to be recognized
over the remainder of the loan period was approximately $2.0 million and $1.2 million as of December 31, 2021 and December 31, 2020, respectively. Per the 2017 Loan Agreement, the end-of-term
payment of approximately $0.8 million was due and paid on July 1, 2021.
On March 8, 2022, we entered into the 2022 Loan Amendment. The 2022 Loan Amendment (i) changed the operating covenant to decrease the achievement of greater than or equal to 75%
of our forecasted net product revenues from our sales of tivozanib over a six-month trailing period to 65%, as defined and measured on a monthly basis, and extended the month of commencement
from April 2022 to June 2022, (ii) added a cash waiver, at our election, in the event our actual net product revenues from our sales of tivozanib over a six-month trailing period are below the monthly
minimum operating covenant of 65%, such that our unrestricted cash position is equal to or greater than the then total outstanding principal under the Loan Agreement for each day of such month,
(iii) changed Tranche Four funding, in the amount of $5.0 million, that was subject to the consent of Hercules to the achievement of $30.0 million in net product revenues from sales of FOTIVDA
over a trailing three-month period, or Performance Milestone III, and extended the availability of Tranche Four funding from June 30, 2022 to December 15, 2022, and (iv) increased the amount of
unrestricted cash required for us to satisfy the minimum financial covenant from $10.0 million to $15.0 million upon the earlier of receiving the Tranche Four funding or January 1, 2023, through the
maturity of the Loan Agreement.
Obligations under the 2020 Loan Facility are secured by substantially all of our assets, excluding intellectual property. The 2020 Loan Facility provides that certain events shall constitute a
default by us, including failure by us to pay amounts under the 2020 Loan Facility when due; breach or default in the performance of any covenant under the 2020 Loan Facility by us, subject to
certain cure periods; our insolvency and certain other bankruptcy proceedings involving us; our default of obligations involving indebtedness in excess of $0.5 million; and the occurrence of an event
or circumstance that would have a material adverse effect upon our business.
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We have determined that the risk of subjective acceleration under the material adverse events clause included in the 2020 Loan Facility is remote and, therefore, have classified the
outstanding principal amount in long-term liabilities based on the timing of scheduled principal payments. As of December 31, 2021, we are in compliance with all of the loan covenants and, through
the date of this filing, the lenders have not asserted any events of default under the 2020 Loan Facility. We do not believe that there has been a material adverse change as defined in the 2020 Loan
Facility.
Public Offering – March 2021
On March 26, 2021, we completed an underwritten public offering of 6,900,000 shares of our common stock, including the full exercise by the underwriters of their option to purchase an
additional 900,000 shares, at the public offering price of $8.00 per share for gross proceeds of approximately $55.2 million. The net offering proceeds to us were approximately $51.7 million after
deducting underwriting discounts and commissions and estimated offering expenses payable by us.
Public Offering – June 2020
On June 19, 2020, we completed an underwritten public offering of 9,725,000 shares of our common stock, including the partial exercise by the underwriters of their option to purchase an
additional 1,225,000 shares, at the public offering price of $5.25 per share for gross proceeds of approximately $51.1 million. Three stockholders each beneficially holding more than 5% of our
voting securities, including an entity affiliated with New Enterprise Associates and two other stockholders purchased an aggregate of 4,503,571 shares in this offering at the same public offering price
per share as the other investors. At such time, entities affiliated with New Enterprise Associates (collectively) beneficially held more than 5% of our voting securities. The net offering proceeds to us
were approximately $47.7 million after deducting underwriting discounts and commissions and estimated offering expenses payable by us.
Sales Agreement with SVB Leerink ($22 Million Availability Future Stock Sales)
In February 2018, we entered into the SVB Leerink Sales Agreement with SVB Leerink pursuant to which we may issue and sell shares of our common stock from time to time up to an
aggregate amount of $50.0 million, at our option, through SVB Leerink as our sales agent, with any sales of common stock through SVB Leerink being made by any method that is deemed an “at-
the-market offering” as defined in Rule 415 promulgated under the Securities Act of 1933, as amended, or in other transactions. Any such shares of common stock will be sold pursuant to a
prospectus supplement filed under the 2020 Shelf, as defined below. We agreed to pay SVB Leerink a commission of up to 3% of the gross proceeds of any sales of common stock pursuant to the
SVB Leerink Sales Agreement. We sold 470,777 shares, 1,251,555 shares, 1,070,175 shares and 330,688 shares pursuant to the SVB Leerink Sales Agreement, resulting in approximate proceeds net
of commissions of $10.3 million, $7.5 million, $5.9 million and $3.4 million in the fourth quarter of 2018, February 2019, November 2020 and March 2021, respectively. As of December 31, 2021,
approximately $22.2 million was available for issuance in connection with future stock sales pursuant to the SVB Leerink Sales Agreement.
Universal Shelf Registration Statement
On November 9, 2020, we filed a shelf registration statement on Form S-3 with the SEC, which covers the offering, issuance and sale of up to $300.0 million of our common stock, preferred
stock, debt securities, warrants and/or units, or the 2020 Shelf. The 2020 Shelf (File No. 333-249982) was declared effective by the SEC on November 18, 2020 and was filed to replace our then
existing shelf registration statement, which was terminated. As of December 31, 2021, there was approximately $213.0 million available for future issuance of our common stock, preferred stock,
debt securities, warrants and/or units.
Expired Offering Warrants from April 2019 Public Offering – Expiration Date of April 8, 2021
In April 2019, we completed an underwritten public offering of 2,173,913 shares of our common stock and warrants to purchase an aggregate of 2,500,000 shares of our common stock,
which we refer to herein as the Offering Warrants, including warrants to purchase an aggregate of 326,086 shares of our common stock sold pursuant to the underwriter’s partial exercise of its
overallotment option, at the public offering price of $11.40 per share and $0.10 per warrant for gross proceeds of approximately $25.0 million. The Offering Warrants were immediately exercisable
upon issuance at an exercise price of $12.50 per share, subject to adjustment in certain circumstances, and expired two years from the date of issuance on April 8, 2021. Any Offering Warrants that
had not been exercised for cash prior to their expiration were to be automatically exercised via cashless exercise on the expiration date. The shares and warrants were
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issued separately and were separately transferable. An entity affiliated with New Enterprise Associates purchased 434,782 shares and warrants to purchase an aggregate of 434,782 shares in this
offering at the same public offering price per share as the other investors. At such time, entities affiliated with New Enterprise Associates (collectively) beneficially held more than 5% of our voting
securities. The net offering proceeds to us were approximately $22.8 million after deducting underwriting discounts and commissions and estimated offering expenses payable by us.
In March 2021, the Offering Warrants exercisable for 247,391 shares of common stock had been exercised, for approximately $3.1 million in cash proceeds. On April 8, 2021, all of the
remaining 2,252,609 Offering Warrants expired and no shares of our common stock were issued via automatic cashless exercises of unexercised Offering Warrants on the date of expiration as the
$12.50 exercise price was greater than our closing stock price of $7.01 on April 8, 2021.
Expired Offering Warrants from May 2016 Private Placement – Expiration Date of May 16, 2021
In May 2016, we entered into a securities purchase agreement with a select group of qualified institutional buyers, institutional accredited investors and accredited investors pursuant to
which we sold 1,764,242 units, at a price of $9.65 per unit, for gross proceeds of approximately $17.0 million. Each unit consisted of one share of our common stock and a PIPE Warrant to purchase
one share of our common stock. The PIPE Warrants had an exercise price of $10.00 per share and expired five years from the date of issuance on May 16, 2021. Certain of our directors and executive
officers purchased an aggregate of 54,402 units in this offering at the same price as the other investors. The net offering proceeds to us were approximately $15.4 million after deducting placement
agent fees and other offering expenses payable by us. PIPE Warrants exercisable for 80,309 shares of common stock had been exercised for approximately $0.8 million in cash proceeds and all of the
1,683,933 PIPE Warrants that remained outstanding on May 16, 2021 expired.
Liquidity and Going Concern
We have devoted substantially all of our resources to our drug development efforts, comprised of research and development, manufacturing, conducting clinical trials for our product
candidates, protecting our intellectual property and general and administrative functions relating to these operations. Our future success is dependent on our ability to commercialize FOTIVDA in the
United States and develop our clinical stage assets and, ultimately, upon our ability to create shareholder value.
On March 10, 2021, the FDA approved FOTIVDA in the United States for the treatment of adult patients with relapsed or refractory advanced RCC following two or more prior systemic
therapies. We anticipate that we will continue to incur significant operating expenses for the foreseeable future as we commercialize FOTIVDA in the United States and continue our planned
development activities for our clinical and preclinical stage assets. Our future product revenues will depend upon the size of markets in which FOTIVDA, and any future products, have received
approval, and our ability to achieve sufficient market acceptance, reimbursement from third-party payers and adequate market share for FOTIVDA and any future products in those markets. The
likelihood of our long-term success must be considered in light of the expenses, difficulties and potential delays that may be encountered in the development and commercialization of new
pharmaceutical products, competitive factors in the marketplace and the complex regulatory environment in which we operate. Absent the realization of sufficient revenues from product sales to
support our cost structure, we may never attain or sustain profitability. We may require substantial additional funding to continue to advance our pipeline of clinical and preclinical stage assets, and
the timing and nature of these activities will be conducted subject to the availability of sufficient financial resources, principally product sales of FOTIVDA in the United States.
During the year ended December 31, 2021, we received an aggregate of approximately $116.6 million in funding, including approximately $58.2 million in equity funding, approximately
$24.9 million in net loan funding from Hercules, approximately $31.7 million in cash receipts from the product sales of FOTIVDA in the United States and approximately $1.8 million in partnership
cost sharing payments.
The approximate $58.2 million in equity funding included the $51.7 million in net proceeds from the sale of approximately 6.9 million shares of our common stock in an underwritten public
offering in March 2021, approximately $3.4 million in net proceeds from the sale of approximately 0.3 million shares of our common stock in March 2021 pursuant to our SVB Leerink Sales
Agreement, and approximately $3.1 million in proceeds from the exercise of Offering Warrants.
The approximate $24.9 million in net loan funding from Hercules included $25.0 million in new loan funding pursuant to the 2020 Loan Amendment and 2021 Loan Amendment upon FDA
approval of FOTIVDA and upon
 
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achievement of $35.0 million in net product revenues from sales of FOTIVDA, net of payments of approximately $0.1 million in transaction costs related to the 2021 Loan Amendment.
We believe that our $87.3 million in cash, cash equivalents and marketable securities as of December 31, 2021, along with net product revenues from product sales of FOTIVDA in the
United States, would enable us to maintain our current operations for more than 12 months following the filing of this Annual Report on Form 10-K.
In 2022, we anticipate FOTIVDA net product revenues will be in the range of $100.0 million to $110.0 million. In 2022, we anticipate that research and development expenses will be in the
range of $60.0 million to $70.0 million and selling, general and administrative expenses will be approximately $70.0 million, including approximately $50.0 million in commercial expenses and
approximately $20.0 million in general and administrative expenses. We anticipate that gross margins will continue to be in the mid-to-high 80  percentile in 2022.
However, there are numerous risks and uncertainties associated with research, development and commercialization of pharmaceutical products, including, without limitation, risks related to
our ability to generate product revenue from sales of FOTIVDA in the United States, which became commercially available in the United States on March 22, 2021. Accordingly, our future funding
requirements may vary from our current expectations and will depend on many factors, including, but not limited to:
•
the cost of commercialization activities of FOTIVDA in the United States and any of our product candidates that may be approved for sale, including marketing, sales and
distribution costs;
•
the cost of manufacturing FOTIVDA in the United States, our product candidates and any additional products we may successfully commercialize;
•
the impact of COVID-19 on our operations, business and prospects;
•
our ability to establish and maintain strategic partnerships, licensing or other arrangements and the financial terms of such agreements;
•
the number and characteristics of the product candidates we pursue;
•
the scope, progress, results and costs of researching and developing our product candidates, and of conducting preclinical and clinical trials;
•
the timing of, and the costs involved in, completing our clinical trials and obtaining regulatory approvals for our product candidates;
•
the costs involved in preparing, filing, prosecuting, maintaining, defending and enforcing patent claims, including litigation costs and the outcome of such litigation;
•
the absence of any breach, acceleration event or event of default under our 2020 Loan Facility, or under any other agreements with third parties;
•
the cost and outcome of any legal actions against us;
•
the timing, receipt and amount of sales of, or royalties on, tivozanib and our future products, if any; and
•
general economic, industry and market conditions.
We may require substantial additional funding to continue to advance our pipeline of clinical and preclinical stage assets. We may seek to sell additional equity or debt securities or obtain
additional credit facilities. The sale of additional equity or convertible debt securities may result in additional dilution to our stockholders. If we raise additional funds through the issuance of debt
securities or preferred stock or through additional credit facilities, these securities and/or the loans under credit facilities could provide for rights senior to those of our common stock and could
contain covenants that would restrict our operations. Additional funds may not be available when we need them, on terms that are acceptable to us, or at all. For example, we may never achieve the
milestone specified in the 2020 Loan Facility that would allow us to access the remaining $5.0 million in available credit. We also expect to seek additional funds through arrangements with
collaborators, licensees or other third parties. These arrangements would generally require us to relinquish or encumber rights to some of our technologies or product candidates, and we may not be
able to enter into such arrangements on acceptable terms, if at all. If we are unable to raise substantial additional funding to advance our pipeline of clinical and preclinical stage assets, whether on
terms that are acceptable to us, or at all or if we were to default under the 2020 Loan
th
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Facility, and Hercules accelerated the then remaining principal payments and fees due under the loan, then we may be required to:
•
delay, limit, reduce or terminate our clinical trials, preclinical studies or other development activities for one or more of our product candidates; and/or
•
delay, limit, reduce or terminate our establishment of sales and marketing capabilities or other activities that may be necessary to commercialize our product candidates, if approved.
ITEM 7A.
Quantitative and Qualitative Disclosures About Market Risk.
We are a smaller reporting company, as defined by Rule 12b-2 of the Securities Exchange Act of 1934, as amended, and are not required to provide the information required under this Item
7A.
ITEM 8.
Financial Statements and Supplementary Data
AVEO PHARMACEUTICALS, INC.
INDEX TO CONSOLIDATED FINANCIAL STATEMENTS
Report of Independent Registered Public Accounting Firm (PCAOB ID: 42)
104
 
 
Consolidated Balance Sheets as of December 31, 2021 and 2020
106
 
 
Consolidated Statements of Operations for the Years Ended December 31, 2021, 2020 and 2019
107
 
 
Consolidated Statements of Comprehensive Income (Loss) for the Years Ended December 31, 2021, 2020 and 2019
108
 
 
Consolidated Statements of Stockholders’ Equity (Deficit) for the Years Ended December 31, 2021, 2020 and 2019
109
 
 
Consolidated Statements of Cash Flows for the Years Ended December 31, 2021, 2020 and 2019
110
 
 
Notes to Consolidated Financial Statements
111
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Report of Independent Registered Public Accounting Firm
To the Stockholders and the Board of Directors of AVEO Pharmaceuticals, Inc.
Opinion on the Financial Statements
We have audited the accompanying consolidated balance sheets of AVEO Pharmaceuticals, Inc. (the Company) as of December 31, 2021 and 2020, the related consolidated statements of operations,
comprehensive income (loss), stockholder’s equity and cash flows for each of the three years in the period ended December 31, 2021, and the related notes (collectively referred to as the
“consolidated” financial statements). In our opinion, the consolidated financial statements present fairly, in all material respects, the financial position of the Company at December 31, 2021 and
2020, and the results of its operations and its cash flows for each of the three years in the period ended December 31, 2021, in conformity with U.S. generally accepted accounting principles.
We have also audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the Company’s internal control over financial reporting as of
December 31, 2021, based on criteria established in Internal Control – Integrated Framework issued by the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework)
and our report dated March 14, 2022 expressed an unqualified opinion thereon.
Basis for Opinion
These financial statements are the responsibility of the Company's management. Our responsibility is to express an opinion on the Company’s financial statements based on our audits. We are a
public accounting firm registered with the PCAOB and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and
regulations of the Securities and Exchange Commission and the PCAOB.
We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether the financial
statements are free of material misstatement, whether due to error or fraud. Our audits included performing procedures to assess the risks of material misstatement of the financial statements, whether
due to error or fraud, and performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in the financial
statements. Our audits also included evaluating the accounting principles used and significant estimates made by management, as well as evaluating the overall presentation of the financial
statements. We believe that our audits provide a reasonable basis for our opinion.
Critical Audit Matter
The critical audit matter communicated below is a matter arising from the current period audit of the financial statements that was communicated or required to be communicated to the audit
committee and that: (1) relates to accounts or disclosures that are material to the financial statements and (2) involved our especially challenging, subjective or complex judgments. The
communication of the critical audit matter does not alter in any way our opinion on the consolidated financial statements, taken as a whole, and we are not, by communicating the critical audit matter
below, providing a separate opinion on the critical audit matter or on the accounts or disclosures to which it relates.
104

Product discounts and allowances
Description of the Matter
As discussed in Note 3 to the consolidated financial statements, the Company recognizes revenues at its net sales price, which includes estimates of
variable consideration for which reserves are established primarily from discounts, chargebacks, rebates, co-pay assistance, returns and other
allowances. The calculation of reserves for chargebacks and rebates involves subjective management assumptions. Reserves for product sales
discounts and allowances, which include reserves for customer chargebacks and rebates, totaled $2.4 million and were recorded as reductions to trade
receivables or accrued expenses as of December 31, 2021, depending on the nature of the contract and the related settlement. 
Auditing the Company’s measurement of reserves for customer chargebacks and rebates was complex and judgmental because the estimates involve
subjective management assumptions about product arrangements and the end users of the drug at the time of distribution. The reductions to gross
product revenue are sensitive to changes in these assumptions. As FOTIVDA is the Company’s first commercial product, the Company does not have
the historical experience to make those estimates and relies on industry data and any known trends in making this estimate.
How we addressed the
matter in our audit
We obtained an understanding, evaluated the design and tested the operating effectiveness of internal controls that addressed the identified risks
related to the Company’s process for recording the reserves for customer chargebacks and rebates. For example, we tested controls over
management’s review of the various customer chargeback and rebate calculations, the significant assumptions about the percentage of discounts
applied, and the completeness and accuracy of the data used in the calculation and estimates.
To test the Company's reserves for customer chargebacks and rebates, our audit procedures included, among others, assessing the methodologies used
to determine the reserves and testing the significant assumptions discussed above, including the underlying data used in developing the significant
assumptions. We evaluated management’s significant assumptions by (i) comparing the assumptions used to calculate the reserves to external data (ii)
testing contracted rates and payment data, (iii) evaluating the sensitivity of the estimated discounts and allowances calculations based on changes in
the significant assumptions, (iv) comparing the actual results to previous estimates, and (v) assessing information subsequent to the balance sheet date
to determine whether there were any new information that would require adjustment.
/s/ Ernst & Young LLP
We have served as the Company’s auditor since 2003.
Boston, Massachusetts
March 14, 2022
105

AVEO PHARMACEUTICALS, INC.
Consolidated Balance Sheets
(In thousands, except par value amounts)
December 31,
2021
December 31,
2020
Assets
Current assets:
Cash and cash equivalents
$
70,542 
$
61,761 
Marketable securities
16,784 
— 
Trade receivables, net
9,811 
— 
Partnership receivables
1,790 
1,197 
Inventory
1,656 
— 
Clinical trial retainers
1,181 
355 
Other prepaid expenses and other current assets
2,972 
2,195 
Total current assets
104,736 
65,508 
Property and equipment, net
276 
343 
Operating lease right-of-use asset
178 
903 
Other assets
151 
158 
Total assets
$
105,341 
$
66,912 
Liabilities and stockholders’ equity
Current liabilities:
Accounts payable
$
2,712 
$
3,380 
Accrued clinical trial costs and contract research
5,046 
4,550 
Accrued compensation and benefits
4,963 
3,082 
Other accrued liabilities
5,421 
1,381 
Operating lease liability
11 
369 
Loans payable, net of discount
— 
1,056 
Deferred revenue
578 
1,974 
Deferred research and development reimbursements
— 
164 
PIPE Warrant liability
— 
199 
Other liabilities (Note 6)
— 
790 
Total current liabilities
18,731 
16,945 
Loans payable, net of current portion and discount
37,960 
12,716 
Deferred revenue, non-current
— 
578 
Operating lease liability, non-current
— 
336 
Other liabilities, non-current (Note 6)
2,780 
1,043 
Total liabilities
59,471 
31,618 
Stockholders’ equity:
Preferred stock, $.001 par value: 5,000 shares authorized at December 31, 2021 and December 31, 2020; no shares issued and outstanding at
each of December 31, 2021 and December 31, 2020
— 
— 
Common stock, $.001 par value: 50,000 shares authorized at December 31, 2021 and December 31, 2020; 34,475 shares issued and
outstanding at December 31, 2021 and 26,883 issued and outstanding at December 31, 2020
34 
27 
Additional paid-in capital
720,386 
656,472 
Accumulated other comprehensive loss
(3)
— 
Accumulated deficit
(674,547)
(621,205)
Total stockholders’ equity
45,870 
35,294 
Total liabilities and stockholders’ equity
$
105,341 
$
66,912 
See accompanying notes.
106

AVEO PHARMACEUTICALS, INC.
Consolidated Statements of Operations
(In thousands, except per share amounts)
Years Ended December 31,
2021
2020
2019
Revenues:
FOTIVDA U.S. product revenue, net
$
38,874 
$
— 
$
— 
Partnership licensing and royalty revenue
3,421 
6,019 
28,795 
42,295 
6,019 
28,795 
Operating expenses:
Cost of products sold
4,737 
— 
— 
Research and development
26,298 
22,679 
17,958 
Selling, general and administrative
60,814 
22,217 
11,211 
91,849 
44,896 
29,169 
Loss from operations
(49,554)
(38,877)
(374)
Other income (expense), net:
Interest expense, net
(4,045)
(1,605)
(1,815)
Change in fair value of PIPE Warrant liability
199 
4,898 
11,577 
Other income
58 
— 
— 
(3,788)
3,293 
9,762 
Net income (loss)
$
(53,342)
$
(35,584)
$
9,388 
Basic net income (loss) per share
Net income (loss) per share
$
(1.63)
$
(1.66)
$
0.61 
Weighted average number of common shares outstanding
32,661 
21,402 
15,331 
Diluted net income (loss) per share
Net income (loss) per share
$
(1.63)
$
(1.66)
$
0.61 
Weighted average number of diluted shares outstanding
32,661 
21,402 
15,376 
See accompanying notes.
107

AVEO PHARMACEUTICALS, INC.
Consolidated Statements of Comprehensive Income (Loss)
(In thousands)
Years Ended December 31,
2021
2020
2019
Net income (loss)
$
(53,342)
$
(35,584)
$
9,388 
Other comprehensive loss:
Unrealized loss on available-for-sale securities
(3)
— 
(1)
Comprehensive income (loss)
$
(53,345)
$
(35,584)
$
9,387 
See accompanying notes.
108

AVEO PHARMACEUTICALS, INC.
Consolidated Statements of Stockholders’ Equity
(In thousands)
Common Shares
Additional
Paid-in
Capital
Accumulated
Other
Comprehensive
Income
Accumulated
Deficit
Total
Stockholders'
Equity
Shares
Par Value
Balance at December 31, 2018
12,648 
$
13 
$
567,768 
$
1 
$
(595,009)
$
(27,227)
Issuance of common stock and warrants in a public offering,
excluding to related parties (net of issuance costs of
$2.2 million)
1,739 
2 
17,765 
— 
— 
17,767 
Issuance of common stock and warrants in a public offering, to
related parties
435 
— 
5,000 
— 
— 
5,000 
Issuance of common stock from the SVB Leerink sales
agreement (net of issuance costs of $0.2 million)
1,251 
1 
7,511 
— 
— 
7,512 
Stock-based compensation expense related to equity- classified
awards
— 
— 
2,358 
— 
— 
2,358 
Exercise of stock options
8 
— 
49 
— 
— 
49 
Change in unrealized gain (loss) on investments
— 
— 
— 
(1)
— 
(1)
Net income
— 
— 
— 
— 
9,388 
9,388 
Balance at December 31, 2019
16,081 
$
16 
$
600,451 
$
— 
$
(585,621)
$
14,846 
Issuance of common stock in a public offering, excluding to
related parties (net of issuance costs of $3.4 million)
5,221 
5 
24,074 
— 
— 
24,079 
Issuance of common stock in a public offering, to related
parties
4,504 
5 
23,639 
— 
— 
23,644 
Issuance of common stock from the SVB Leerink sales
agreement (net of issuance costs of $0.2 million)
1,070 
1 
5,916 
— 
— 
5,917 
Stock-based compensation expense related to equity- classified
awards
— 
— 
2,355 
— 
— 
2,355 
Exercise of stock options
1 
— 
5 
— 
— 
5 
Issuance of common stock under employee stock purchase plan
6 
— 
32 
— 
— 
32 
Net loss
— 
— 
— 
— 
(35,584)
(35,584)
Balance at December 31, 2020
26,883 
$
27 
$
656,472 
$
— 
$
(621,205)
$
35,294 
Issuance of common stock in a public offering (net of issuance
costs of $3.5 million)
6,900 
7 
51,711 
— 
— 
51,718 
Issuance of common stock from the SVB Leerink sales
agreement (net of issuance costs of $0.1 million)
331 
— 
3,377 
— 
— 
3,377 
Issuance of common stock in connection with warrant exercises
247 
— 
3,092 
— 
— 
3,092 
Issuance of common stock under employee stock purchase plan
112 
— 
577 
— 
— 
577 
Exercise of stock options
2 
15 
15 
Stock-based compensation expense related to equity-classified
awards
— 
— 
5,142 
— 
— 
5,142 
Unrealized gain or (loss) on available-for-sale investments
— 
— 
— 
(3)
— 
(3)
Net loss
— 
— 
— 
— 
(53,342)
(53,342)
Balance at December 31, 2021
34,475 
$
34 
$
720,386 
$
(3)
$
(674,547)
$
45,870 
See accompanying notes.
109

AVEO PHARMACEUTICALS, INC.
Consolidated Statements of Cash Flows
(In thousands)
For the Years Ended December 31,
2021
2020
2019
Operating activities
Net income (loss)
$
(53,342) $
(35,584) $
9,388 
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation and amortization
67 
21 
— 
Stock-based compensation
5,142 
2,355 
2,358 
Non-cash interest expense
1,010 
469 
567 
Non-cash change in fair value of PIPE Warrant liability
(199)
(4,898)
(11,577)
Amortization of premium and discount on investments
78 
(106)
(44)
Changes in operating assets and liabilities:
Trade receivables, net
(9,811)
— 
— 
Partnership receivables
(593)
433 
1,395 
Inventory
(1,656)
— 
— 
Prepaid expenses and other current assets
(1,603)
(1,326)
(742)
Operating lease right-of-use asset
832 
(1,060)
— 
Other non-current assets
(100)
— 
— 
Accounts payable
(667)
1,914 
(2,033)
Accrued clinical trial costs and contract research
496 
(1,130)
(574)
Accrued compensation and benefits
1,881 
1,798 
238 
Other accrued liabilities
4,040 
329 
(600)
Operating lease liability
(358)
369 
— 
Deferred revenue
(1,974)
(1,974)
(934)
Deferred research and development reimbursements
(164)
71 
(361)
Operating lease liability, non-current
(336)
336 
— 
Net cash used in operating activities
(57,257)
(37,983)
(2,919)
Investing activities
Purchases of marketable securities
(28,166)
(36,133)
(17,917)
Proceeds from maturities and sales of marketable securities
11,300 
54,200 
— 
Purchases of property and equipment
— 
(363)
— 
Net cash (used in) provided by investing activities
(16,866)
17,704 
(17,917)
Financing activities
Proceeds from issuance of common stock, net of issuance costs
55,095 
29,996 
25,279 
Proceeds from issuance of common stock and warrants to related parties
— 
23,644 
5,000 
Proceeds from warrant exercises
3,092 
— 
— 
Proceeds from issuance of stock for stock-based compensation arrangements
592 
38 
49 
Proceeds from issuance of loan payable
25,000 
5,329 
— 
Payment on principal of loan payable (Note 6)
— 
(6,497)
(3,834)
Payment of loan maturity fees (Note 6)
(790)
— 
(300)
Payment of debt issuance costs
(85)
(255)
— 
Net cash provided by financing activities
82,904 
52,255 
26,194 
Net increase in cash and cash equivalents
8,781 
31,976 
5,358 
Cash and cash equivalents at beginning of period
61,761 
29,785 
24,427 
Cash and cash equivalents at end of period
$
70,542 $
61,761 $
29,785 
Supplemental cash flow information
Cash paid for interest
$
2,888 $
1,337 $
1,971 
Right-of-use asset obtained in exchange for operating lease liabilities
$
— $
1,225 $
— 
See accompanying notes.
110

AVEO Pharmaceuticals, Inc.
Notes to Consolidated Financial Statements
December 31, 2021
(1) Organization
AVEO Pharmaceuticals, Inc. (the “Company”) is a commercial stage, oncology-focused biopharmaceutical company committed to delivering medicines that provide a better life for patients
with cancer. The Company currently markets FOTIVDA  (tivozanib) in the United States. FOTIVDA is the Company's first commercial product and was approved by the U.S. Food and Drug
Administration ("FDA") for marketing and sale in the United States on March 10, 2021 for the treatment of adult patients with relapsed or refractory advanced renal cell carcinoma (“RCC”)
following two or more prior systemic therapies. The Company continues to develop tivozanib in immuno-oncology combinations in RCC and other indications, and the Company has other
investigational programs in clinical development.
FOTIVDA is an oral, next-generation vascular endothelial growth factor receptor (“VEGFR”) tyrosine kinase inhibitor (“TKI”). The FDA approval of FOTIVDA is based on the Company’s
pivotal Phase 3 randomized, controlled, multi-center, open-label clinical trial comparing tivozanib to an approved therapy, Nexavar® (sorafenib), in RCC patients whose disease had relapsed or
become refractory to two or three prior systemic therapies, which the Company refers to as the TIVO-3 trial. The approval is also supported by three additional trials in RCC and includes safety data
from over 1,000 clinical trial subjects.
FOTIVDA became commercially available in the United States on March 22, 2021 and is available to patients through a network of specialty pharmacies and distributors. The Company
commercializes FOTIVDA in the United States through the support of approximately 65 field-based employees, which includes approximately 50 oncology sales professionals. The field sales force is
supported by the AVEO ACE Patient Support program, which is an extensive patient and healthcare provider support program designed to optimize patient access and help patients navigate their
treatment journey. To date, the Company believes it has been very successful in securing payor coverage. Furthermore, the NCCN Clinical Practices Guidelines in Oncology ("NCCN Guidelines")
recommended FOTIVDA as a subsequent therapy for patients with relapsed or refractory advanced RCC with clear cell histology who received two or more prior systemic therapies.
Based on FOTIVDA’s demonstrated anti-tumor activity, tolerability profile and reduction of regulatory T-cell production, the Company and its collaboration partners are is developing
tivozanib in additional cancer indications with significant unmet medical needs including, hepatocellular carcinoma (“HCC”), and tumors that are resistant to immunotherapy, or immunologically
cold tumors, in combination with immune checkpoint inhibitors ("ICIs"). In addition, the Company is evaluating tivozanib as a monotherapy in ovarian cancer and cholangiocarcinoma ("CCA"). The
Company and the Company's collaboration partners or independent investigators sponsor the development of tivozanib through preclinical studies and clinical trials conducted under collaboration
agreements and investigator sponsored trial ("IST") agreements or the Company's Cooperative Research and Development Agreement ("CRADA") with the National Cancer Institute’s Surgical
Oncology Program ("NCI-SOP").
The Company is also seeking to advance its pipeline of four wholly owned immunoglobulin G1 (“IgG1”) monoclonal antibody product candidates, ficlatuzumab, AV-380, AV-203 and AV-
353. The Company aims to leverage its existing collaborations and partnerships and enter into new strategic collaborations and partnerships to continue to advance each of its product candidates.
As used throughout these consolidated financial statements, the terms “AVEO,” and the “Company” refer to the business of AVEO Pharmaceuticals, Inc. and its three wholly owned
subsidiaries, AVEO Pharma Limited, AVEO Pharma (Ireland) Limited and AVEO Securities Corporation.
Liquidity and Going Concern
In accordance with Accounting Standards Update (“ASU”) No. 2014-15, Disclosure of Uncertainties about an Entity’s Ability to Continue as a Going Concern (Subtopic 205-40), the
Company has evaluated whether there are conditions and events, considered in the aggregate, that raise substantial doubt about the Company’s ability to continue as a going concern within one year
after the date that the consolidated financial statements are issued. The Company’s financial statements have been prepared on the basis of continuity of operations, realization of assets and the
satisfaction of liabilities
®
111

in the ordinary course of business. Through December 31, 2021, the Company has financed its operations primarily through private placements and public offerings of its common stock, license fees,
milestone payments and research and development funding from strategic partners, FOTIVDA commercial sales receipts and debt facilities. The Company has devoted substantially all of its
resources to its drug development efforts, comprising research and development, manufacturing, conducting clinical trials for its product candidates, commercializing FOTIVDA, protecting its
intellectual property and general and administrative functions relating to these operations.
The future success of the Company is dependent on its ability to commercialize FOTIVDA in the United States and to develop its portfolio assets and, ultimately, upon the Company’s ability
to create shareholder value. On March 10, 2021, the FDA approved FOTIVDA in the United States for the treatment of adult patients with relapsed or refractory advanced RCC following two or more
prior systemic therapies. The Company’s future product revenues will depend upon the size of markets in which FOTIVDA, and any future products, have received approval, and its ability to achieve
sufficient market acceptance, reimbursement from third-party payors and adequate market share for FOTIVDA and any future products in those markets. The likelihood of the Company’s long-term
success must be considered in light of the expenses, difficulties and potential delays that may be encountered in the development and commercialization of new pharmaceutical products, competitive
factors in the marketplace and the complex regulatory environment in which the Company operates. Absent the realization of sufficient revenues from product sales to support the Company’s cost
structure, the Company may never attain or sustain profitability.
The Company has incurred recurring losses and cash outflows from operations since its inception, including an accumulated deficit of $674.5 million as of December 31, 2021. The
Company anticipates that it will continue to incur significant operating expenses for the foreseeable future as it commercializes FOTIVDA in the United States and continues its planned development
activities for its clinical and preclinical stage assets. The Company may require substantial additional funding to continue to advance its pipeline of clinical and preclinical stage assets, and the timing
and nature of these activities will be conducted subject to the availability of sufficient financial resources, principally product sales of FOTIVDA in the United States.
As of March 14, 2022, the date of issuance of these consolidated financial statements, the Company expects that its cash, cash equivalents and marketable securities of $87.3 million as of
December 31, 2021, along with net product revenues from product sales of FOTIVDA in the United States, will be sufficient to fund its current operations for more than twelve months from the date
of filing this Annual Report on Form 10-K.
Management’s expectations with respect to its ability to fund current planned operations is based on estimates that are subject to risks and uncertainties, including, without limitation, risks
related to its ability to generate product revenue from sales of FOTIVDA in the United States, which became commercially available in the United States on March 22, 2021. If actual results are
different from management’s estimates, the Company may need to seek additional strategic or financing opportunities sooner than would otherwise be expected. However, there is no guarantee that
any of these strategic or financing opportunities would be executed or executed on favorable terms, and some could be dilutive to existing stockholders. If the Company is unable to obtain additional
funding on a timely basis, it may be forced to significantly curtail, delay or discontinue one or more of its planned research or development programs or be unable to expand its operations or
otherwise capitalize on its commercialization of its product and product candidates.
(2) Basis of Presentation
These consolidated financial statements include the accounts of the Company and its wholly owned subsidiaries, AVEO Pharma Limited, AVEO Pharma (Ireland) Limited and AVEO
Securities Corporation. The Company has eliminated all significant intercompany accounts and transactions in consolidation.
(3) Significant Accounting Policies
Revenue Recognition
Under Accounting Standards Codification (“ASC”) 606, Revenue from Contracts with Customers, the Company recognizes revenue when its customers obtain control of promised goods or
services, in an amount that reflects the consideration which the Company determines it expects to receive in exchange for those goods or services. To determine revenue recognition for arrangements
that the Company determines are within the scope of ASC 606, the Company performs the following five steps: (i) identify the contract(s) with a customer; (ii) identify the performance obligation(s)
in the contract; (iii) determine the transaction price; (iv) allocate the transaction price to the performance obligation(s) in the contract; and (v) recognize revenue when (or as) the Company satisfies its
performance obligation(s). As part of the
 
112

accounting for these arrangements, the Company must make significant judgments, including identifying performance obligations in the contract, estimating the amount of variable consideration to
include in the transaction price and allocating the transaction price to each performance obligation.
Net Product Revenue
On March 10, 2021, the FDA approved FOTIVDA in the United States for the treatment of adult patients with relapsed or refractory advanced RCC after two prior systemic therapies.
FOTIVDA became commercially available on March 22, 2021. FOTIVDA is the Company’s first commercial product. The Company sells its products principally through a limited distribution
network comprised of two specialty pharmacies, Biologics and Onco360, and the following specialty distributors: Amerisource Specialty Distribution, Oncology Supply, McKesson Plasma and
Biologics, McKesson Specialty and Cardinal Specialty (collectively with the specialty pharmacies, the "Customers" and each a "Customer"). These Customers subsequently resell the Company’s
products to health care providers and patients. In addition to distribution agreements with Customers, the Company enters into arrangements with health care providers and payors that provide for
government-mandated and/or privately-negotiated rebates, chargebacks and discounts with respect to the purchase of the Company’s products. Revenues from product sales are recognized when the
Customer obtains control of the Company’s product, which occurs at a point in time, typically upon delivery to the Customer.
Product Sales Discounts and Allowances
The Company records revenues from product sales at the net sales price (transaction price), which includes estimates of variable consideration for which reserves are established primarily
from discounts, chargebacks, rebates, co-pay assistance, returns and other allowances that are offered within contracts between the Company and its Customers, health care providers, payors and
other indirect customers relating to the sales of its products. These reserves are based on the amounts earned or to be claimed on the related sales and are classified as reductions of trade receivables
(if the amount is deductible by the Customer from payments to the Company) or a current liability (if the amount is payable by the Company to a third party or Customer). Where appropriate, these
estimates take into consideration a range of possible outcomes that are probability-weighted for relevant factors such as current contractual and statutory requirements, specific known market events
and trends, industry data, forecasted Customer buying and payment patterns, and the Company’s historical experience that will develop over time as FOTIVDA is the Company’s first commercial
product. Overall, these reserves reflect the Company’s best estimates of the amount of consideration to which it is entitled based on the terms of its contracts. The amount of variable consideration
that is included in the transaction price may be constrained, and is included in the net sales price only to the extent that it is probable that a significant reversal in the amount of the cumulative revenue
recognized will not occur in a future period. Actual amounts of consideration ultimately received may differ from the Company’s estimates. If actual results in the future vary from the Company’s
estimates, the Company will adjust these estimates, which would affect net product revenues and earnings in the period such variances become known.
Chargebacks: Chargebacks are discounts that occur when contracted customers purchase directly from a specialty distributor. Contracted customers, which currently consist primarily of
Public Health Service institutions, Federal government entities purchasing via the Federal Supply Schedule, Group Purchasing Organizations and health maintenance organizations, generally
purchase the product at a discounted price. The specialty distributor, in turn, charges back to the Company the difference between the price initially paid by the specialty distributor and the discounted
price paid to the specialty distributor by its contracted customer. The allowance for chargebacks is based on actual chargebacks received and an estimate of sales by the specialty distributor to its
contracted customers.
Discounts for Prompt Payment: The Customers receive a discount of 2% for prompt payment. The Company expects its Customers will earn 100% of their prompt payment discounts and,
therefore, the Company deducts the full amount of these discounts from total product sales when revenues are recognized.
Rebates: Allowances for rebates include mandated discounts under the Medicaid Drug Rebate Program, Medicare Part D Coverage Gap Discounts Program, other government programs and
commercial contracts. Rebate amounts owed after the final dispensing of the product to a benefit plan participant are based upon contractual agreements or legal requirements with public sector
benefit providers, such as Medicaid. In addition, in the United States during 2020, the Medicare Part D prescription drug benefit mandated participating manufacturers to fund 70% of the Medicare
Part D insurance coverage gap for prescription drugs sold to eligible patients. The allowance for rebates is based on statutory or contractual discount rates and expected utilization. The Company’s
estimates for the expected utilization of rebates are based on Customer and payer data received from the specialty pharmacies and distributors and historical utilization rates that will develop over
time as FOTIVDA is the Company’s first commercial product. Rebates are generally invoiced by the
 
113

payor and paid in arrears, such that the accrual balance consists of an estimate of the amount expected to be incurred for the current quarter’s shipments to the Customers, plus an accrual balance for
known prior quarters’ unpaid rebates. If actual future rebates vary from estimates, the Company may need to adjust its accruals, which would affect net product revenues in the period of adjustment.
Co-payment Assistance: Patients who have commercial insurance and meet certain eligibility requirements may receive co-payment assistance. The Company accrues a liability for co-
payment assistance based on actual program participation and estimates of program redemption using Customer data provided by the third party that administers the copay program.
Other Customer Credits: The Company pays fees to its Customers for account management, data management and other administrative services. To the extent the services received are
distinct from the sale of products to its Customers, the Company classifies these payments in selling, general and administrative expenses in its Consolidated Statements of Income.
The following table summarizes net product revenues for FOTIVDA in the United States earned in the years ended December 31, 2021, 2020 and 2019, respectively (in thousands):
Years Ended
December 31,
2021
2020
2019
Product revenues:
Gross product revenues
$
45,668 
$
— 
$
— 
Discounts and allowances
(6,794)
— 
— 
Net product revenues
$
38,874 
$
— 
$
— 
The following table summarizes the percentage of total product revenues for FOTIVDA in the United States by any Customer who individually accounted for 10% or more of total product
revenues earned in the years ended December 31, 2021, 2020 and 2019, respectively:
 
Years Ended
December 31,
 
2021
2020
2019
OncoMed Specialty, LLC (Onco360)
22 %
— 
— 
Affiliates of McKesson Corporation
42 %
— 
— 
Affiliates of AmerisourceBergen Corporation
27 %
— 
— 
Product Sales Discounts and Allowances
The activities and ending allowance balances for each significant category of discounts and allowances for FOTIVDA (which constitute variable consideration) for the year ended
December 31, 2021 were as follows (in thousands):
Chargebacks, Discounts for
Prompt Pay and Other
Allowances
Rebates, Customer Fees /
Credits
and Co-Pay Assistance
Totals
Balance at December 31, 2020
$
— 
$
— 
$
— 
Provision related to sales made in:
Current period
4,196 
2,598 
6,794 
Prior periods
— 
— 
— 
Payments and customer credits issued
(3,003)
(1,428)
(4,431)
Balance at December 31, 2021
$
1,193 
$
1,170 
$
2,363 
114

The allowances for chargebacks, discounts for prompt payment and other allowances are recorded as a reduction of trade receivables, net, and the remaining reserves are recorded as rebates
and fees due to customers in other current accrued liabilities in the accompanying Consolidated Balance Sheets.
Collaboration Revenues
The Company’s historical revenues have been generated primarily through collaborative research, development and commercialization agreements. The terms of these agreements generally
contain multiple promised goods and services, which may include (i) licenses, or options to obtain licenses, to the Company’s technology, (ii) research and development activities to be performed on
behalf of the collaborative partner and (iii) in certain cases, services in connection with the manufacturing of preclinical and clinical material. Payments to the Company under these arrangements
typically include one or more of the following: non-refundable, upfront license fees; option exercise fees; funding of research and/or development efforts; milestone payments; and royalties on future
product sales.
Collaboration Arrangements Within the Scope of ASC 808, Collaborative Arrangements
The Company analyzes its collaboration arrangements to assess whether such arrangements involve joint operating activities performed by parties that are both active participants in the
activities and exposed to significant risks and rewards dependent on the commercial success of such activities and are therefore within the scope of ASC Topic 808, Collaborative Arrangements
(“ASC 808”). This assessment is performed throughout the life of the arrangement based on changes in the responsibilities of all parties in the arrangement. For collaboration arrangements that are
deemed to be within the scope of ASC 808, the Company first determines which elements of the collaboration are deemed to be within the scope of ASC 808 and those that are more reflective of a
vendor-customer relationship and therefore within the scope of ASC 606. The Company’s policy is generally to recognize amounts received from collaborators in connection with joint operating
activities that are within the scope of ASC 808 as a reduction in research and development expense.
Arrangements Within the Scope of ASC 606, Revenue from Contracts with Customers
Once a contract is determined to be within the scope of ASC 606, the Company assesses the goods or services promised within the contract and determines those that are performance
obligations. Arrangements that include rights to additional goods or services that are exercisable at a customer’s discretion are generally considered options. The Company assesses if these options
provide a material right to the customer and if so, they are considered performance obligations. The exercise of a material right is accounted for as a contract modification for accounting purposes.
The Company assesses whether each promised good or service is distinct for the purpose of identifying the performance obligations in the contract. This assessment involves subjective
determinations and requires management to make judgments about the individual promised goods or services and whether such are separable from the other aspects of the contractual relationship.
Promised goods and services are considered distinct provided that: (i) the customer can benefit from the good or service either on its own or together with other resources that are readily available to
the customer (that is, the good or service is capable of being distinct) and (ii) the entity’s promise to transfer the good or service to the customer is separately identifiable from other promises in the
contract (that is, the promise to transfer the good or service is distinct within the context of the contract). In assessing whether a promised good or service is distinct, the Company considers factors
such as the research, manufacturing and commercialization capabilities of the collaboration partner and the availability of the associated expertise in the general marketplace. The Company also
considers the intended benefit of the contract in assessing whether a promised good or service is separately identifiable from other promises in the contract. If a promised good or service is not
distinct, an entity is required to combine that good or service with other promised goods or services until it identifies a bundle of goods or services that is distinct.
The transaction price is then determined and allocated to the identified performance obligations in proportion to their standalone selling prices (“SSP”) on a relative SSP basis. SSP are
determined at contract inception and are not updated to reflect changes between contract inception and when the performance obligations are satisfied. Determining SSP for performance obligations
requires significant judgment. In developing SSP for a performance obligation, the Company considers applicable market conditions and relevant entity-specific factors, including factors that were
contemplated in negotiating the agreement with the customer and estimated costs. The Company validates SSP for performance obligations by evaluating whether changes in the key assumptions
used to determine SSP will have a significant effect on the allocation of arrangement consideration between multiple performance obligations.
115

If the consideration promised in a contract includes a variable amount, the Company estimates the amount of consideration to which it will be entitled in exchange for transferring the
promised goods or services to a customer. The Company determines the amount of variable consideration by using the expected value method or the most likely amount method. The Company
includes the unconstrained amount of estimated variable consideration in the transaction price. The amount included in the transaction price is constrained to the amount for which it is probable that a
significant reversal of cumulative revenue recognized will not occur. At the end of each subsequent reporting period, the Company re-evaluates the estimated variable consideration included in the
transaction price and any related constraint, and if necessary, adjusts its estimate of the overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis in the period of
adjustment.
In determining the transaction price, the Company adjusts consideration for the effects of the time value of money if the timing of payments provides the Company with a significant benefit
of financing. The Company does not assess whether a contract has a significant financing component if the expectation at contract inception is such that the period between payment by the licensees
and the transfer of the promised goods or services to the licensees will be one year or less. The Company assessed each of its revenue generating arrangements in order to determine whether a
significant financing component exists and concluded that a significant financing component does not exist in any of its arrangements.
The Company then recognizes as revenue the amount of the transaction price that is allocated to the respective performance obligation when (or as) each performance obligation is satisfied
at a point in time or over time, and if over time based on the use of an output or input method.
Licenses of Intellectual Property: The terms of the Company’s license agreements include the license of functional intellectual property, given the functionality of the intellectual property is
not expected to change substantially as a result of the Company’s ongoing activities. If the license to the Company’s intellectual property is determined to be distinct from the other performance
obligations identified in the arrangement, the Company recognizes revenues from the portion of the transaction price allocated to the license when the license is transferred to the licensee and the
licensee is able to use and benefit from the license. For licenses that are bundled with other promises (that is, for licenses that are not distinct from other promised goods and services in an
arrangement), the Company utilizes judgment to assess the nature of the combined performance obligation to determine whether the combined performance obligation is satisfied over time or at a
point in time and, if over time, the appropriate method of measuring progress for purposes of recognizing revenue. The Company evaluates the measure of progress each reporting period and, if
necessary, adjusts the measure of performance and related revenue recognition.
Research and Development Funding: Arrangements that include payment for research and development services are generally considered to have variable consideration. If and when the
Company assesses the payment for these services is no longer subject to the constraint on variable consideration, the related revenue is included in the transaction price.
Milestone payments: At the inception of each arrangement that includes non-refundable payments for contingent milestones, including preclinical research and development, clinical
development and regulatory, the Company evaluates whether the milestones are considered probable of being achieved and estimates the amount to be included in the transaction price using the most
likely amount method. If it is probable that a significant revenue reversal would not occur, the associated milestone value is included in the transaction price. Milestone payments that are not within
the control of the Company or the licensee, such as regulatory approvals, are not considered probable of being achieved until those approvals are received. At the end of each reporting period, the
Company re-evaluates the probability of the achievement of contingent milestones and the likelihood of a significant reversal of such milestone revenue, and if necessary, adjusts its estimate of the
overall transaction price. Any such adjustments are recorded on a cumulative catch-up basis, which would affect collaboration and licensing revenue in the period of adjustment. This quarterly
assessment may result in the recognition of revenue related to a contingent milestone payment before the milestone event has been achieved.
Royalties: For arrangements that include sales-based royalties, including milestone payments based on the level of sales, and the license is deemed to be the predominant item to which the
royalties relate, the Company recognizes revenue at the later of (i) when the related sales occur or (ii) when the performance obligation to which some or all of the royalty has been allocated has been
satisfied (or partially satisfied).
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The following table summarizes the total collaboration revenues earned in the years ended December 31, 2021, 2020 and 2019, respectively, by partner (in thousands). Refer to Note 4,
“Collaborations and License Agreements” regarding specific details.
Years Ended
December 31,
2021
2020
2019
EUSA
$
3,421 
$
3,219 
$
3,795 
KKC
— 
2,800
25,000
Total
$
3,421 
$
6,019 
$
28,795 
Trade Receivables
Trade receivables, net, includes amounts billed to Customers for product sales of FOTIVDA. The Company records trade receivables net of chargebacks, cash discounts for prompt payment
and any allowances for credit losses. The Company considers its historical losses, if any, adjusted to account for current conditions, and reasonable and supportable forecasts of future economic
conditions affecting its customers to estimate credit losses. The Customers are specialty pharmacies and specialty distributors, and accordingly, the Company considers the risk of potential credit
losses to be low.
Cost of Products Sold
Cost of products sold is related to the Company's product revenues for FOTIVDA and consists primarily of tiered royalty payments the Company is required to pay to Kyowa Kirin Co.
(“KKC”) on all net sales of tivozanib in the Company’s North American territory, which range from the low to mid-teens as a percentage of net sales. Refer to Note 4, “Collaborations and License
Agreements” regarding specific details. Cost of products sold also consists of shipping and other third-party logistics and distribution costs for the Company’s products. The Company considered
regulatory approval of its product candidate to be uncertain and product manufactured prior to regulatory approval could not have been sold unless regulatory approval was obtained. As such, the
manufacturing costs for FOTIVDA incurred prior to regulatory approval were not capitalized as inventory, but were expensed as research and development costs. In 2021, the Company conducted
resupply manufacturing of tivozanib in connection with upcoming drug expirations beginning in the fourth quarter of 2022. As of December 31, 2021, the Company capitalized approximately
$1.7 million of manufacturing costs as Inventory on the Consolidated Balance Sheet, all of which was classified as work in process.
Research and Development Expenses
Research and development expenses are charged to expense as incurred. Research and development expenses consist of costs incurred in performing research and development activities,
including (i) internal costs for salaries, bonuses, benefits, stock-based compensation, research-related overhead and allocated expenses for facilities and information technology, and (ii) external costs
for clinical trials, drug manufacturing and distribution, preclinical studies, upfront license payments, milestones and sublicense fees related to in-licensed products and technology, consultants and
other contracted services.
Expired Warrants Issued in Connection with Private Placement – Expiration Date of May 16, 2021
In May 2016, the Company issued warrants to purchase an aggregate of 1,764,242 shares of common stock in connection with a private placement financing and recorded the warrants as a
liability (the “PIPE Warrants”). The remaining 1,683,933 PIPE Warrants expired on May 16, 2021, as scheduled five years from the date of issuance. The Company accounts for warrant instruments
that either conditionally or unconditionally obligate the issuer to transfer assets as liabilities regardless of the timing of the redemption feature or price, even though the underlying shares may be
classified as permanent or temporary equity. Refer to Note 7, “Common Stock—Private Placement – May 2016” for further discussion of the private placement financing.
The PIPE Warrants contained a provision giving the warrant holder the option to receive cash, equal to the fair value of the remaining unexercised portion of the warrant, as cash settlement
in the event that there had been a fundamental transaction (contractually defined to include various merger, acquisition or stock transfer activities). Due to this provision, ASC 480, Distinguishing
Liabilities from Equity required that these warrants be classified as a liability and not as equity. Accordingly, the Company recorded a warrant liability in the amount of approximately $9.3 million
upon issuance of the
117

PIPE Warrants. The fair value of these warrants had been determined using the Black-Scholes pricing model. These warrants were subject to revaluation at each balance sheet date and any changes in
fair value were recorded as a non-cash gain or (loss) in the Statement of Operations as a component of other income (expense), net until the expiration of the warrants.
The Company recorded a non-cash gain of approximately $0.2 million in the year ended December 31, 2021, in its Statement of Operations attributable to the decrease in fair value of the
warrant liability that resulted from the expiration of the PIPE Warrants on May 16, 2021.
The Company recorded a non-cash gain of approximately $3.1 million in the year ended December 31, 2020, in its Statement of Operations attributable to the decreases in the fair value of
the warrant liability that resulted from changes in the Company’s stock price as of December 31, 2020 relative to prior periods, decreases in the Company’s stock volatility rate and a shorter
remaining term as the PIPE Warrants approached their expiration in May 2021. No PIPE Warrants were exercised during the years ended December 31, 2021 and 2020.
The following table rolls forward the fair value of the Company’s PIPE Warrant liability, the fair value of which is determined by using Level 3 inputs for the years ended December 31,
2021, 2020 and 2019 (in thousands):
Fair value at December 31, 2018
$
16,674 
Decrease in fair value
(11,577)
Fair value at December 31, 2019
$
5,097 
Decrease in fair value
(4,898)
Fair value at December 31, 2020
$
199 
Decrease in fair value
(199)
Fair value at December 31, 2021
$
— 
The key assumptions used to value the PIPE Warrants were as follows:
Issuance
December 31,
2018
December 31,
2019
December 31,
2020
Expected price volatility
76.25%
82.64 %
133.07 %
56.79 %
Expected term (in years)
5.00
2.5
1.5
0.50
Risk-free interest rates
1.22%
2.47 %
1.59 %
0.09 %
Stock price
$
8.90 
$
16.00 
$
6.20 
$
5.77 
Dividend yield
—
—
—
—
Cash and Cash Equivalents
The Company considers all highly liquid investments with original maturities of three months or less at the date of purchase and an investment in a United States government money market
fund to be cash equivalents. Changes in the balance of cash and cash equivalents may be affected by changes in investment portfolio maturities, as well as actual cash disbursements to fund
operations.
The Company’s cash is deposited in highly-rated financial institutions in the United States. The Company invests in United States government money market funds, high-grade, short-term
commercial paper, corporate bonds and other United States government agency securities, which management believes are subject to minimal credit and market risk. The carrying values of the
Company’s cash and cash equivalents approximate fair value due to their short-term maturities.
The Company did not have any restricted cash balances at December 31, 2021.
Marketable Securities
Marketable securities consist primarily of investments which have expected average maturity dates in excess of three months. The Company invests in high-grade corporate obligations,
including commercial paper, and United States
118

government and government agency obligations that are classified as available-for-sale. Since these securities are available to fund current operations they are classified as current assets on the
consolidated balance sheets.
Marketable securities are stated at fair value, including accrued interest, with their unrealized gains and losses included as a component of accumulated other comprehensive income or loss,
which is a separate component of stockholders’ equity. The fair value of these securities is based on quoted prices and observable inputs on a recurring basis. The cost of marketable securities is
adjusted for amortization of premiums and accretion of discounts, with such amortization and accretion recorded as a component of interest expense, net. Realized gains and losses are determined on
the specific identification method. Unrealized gains and losses are included in other comprehensive loss until realized, at which point they would be recorded as a component of interest expense, net.
Below is a summary of cash, cash equivalents and marketable securities at December 31, 2021 and December 31, 2020 (in thousands):
Amortized
Cost
Unrealized
Gains
Unrealized
Losses
Fair
Value
December 31, 2021
Cash and cash equivalents:
Cash and money market funds
$
70,542 
$
— 
$
— 
$
70,542 
Total cash and cash equivalents
70,542 
— 
— 
70,542 
Marketable securities:
Corporate debt securities due within 1 year
$
16,787 
$
— 
$
(3)
$
16,784 
Total marketable securities
16,787 
— 
(3)
16,784 
Total cash, cash equivalents and marketable securities
$
87,329 
$
— 
$
(3)
$
87,326 
December 31, 2020
Cash and cash equivalents:
Cash and money market funds
$
61,761 
$
— 
$
— 
$
61,761 
Total cash, cash equivalents and marketable securities
$
61,761 
$
— 
$
— 
$
61,761 
Concentrations of Credit Risk
Financial instruments that potentially subject the Company to credit risk primarily consist of cash and cash equivalents, marketable securities and accounts receivable. The Company
maintains deposits in highly-rated, federally-insured financial institutions in excess of federally insured limits. The Company’s investment strategy is focused on capital preservation. The Company
invests in instruments that meet the high credit quality standards outlined in the Company’s investment policy. This policy also limits the amount of credit exposure to any one issue or type of
instrument.
The Company’s trade receivables, net, includes amounts billed to Customers for product sales of FOTIVDA. The Customers are a limited group of specialty pharmacies and specialty
distributors, and accordingly, the Company considers the risk of potential credit losses to be low.
The Company’s partnership receivables include amounts due to the Company from licensees and collaborators. The Company has not experienced any material losses related to partnership
receivables from individual licensees or collaborators.
Fair Value Measurements
The fair value of the Company’s financial assets and liabilities reflects the Company’s estimate of amounts that it would have received in connection with the sale of the assets or paid in
connection with the transfer of the liabilities in an orderly transaction between market participants at the measurement date. In connection with measuring the fair value of its assets and liabilities, the
Company seeks to maximize the use of observable inputs (market data obtained from sources
119

independent from the Company) and to minimize the use of unobservable inputs (the Company’s assumptions about how market participants would price assets and liabilities). The following fair
value hierarchy is used to classify assets and liabilities based on the observable inputs and unobservable inputs used in order to value the assets and liabilities:
Level 1. Quoted prices in active markets for identical assets or liabilities. An active market for an asset or liability is a market in which transactions for the asset or liability occur with
sufficient frequency and volume to provide pricing information on an ongoing basis.
Level 2. Observable inputs other than Level 1 inputs. Examples of Level 2 inputs include quoted prices in active markets for similar assets or liabilities and quoted prices for identical assets
or liabilities in markets that are not active.
Level 3. Unobservable inputs based on the Company’s assessment of the assumptions that market participants would use in pricing the asset or liability.
Financial assets and liabilities are classified in their entirety within the fair value hierarchy based on the lowest level of input that is significant to the fair value measurement. The Company
measures the fair value of its marketable securities by taking into consideration valuations obtained from third-party pricing sources. The pricing services utilize industry standard valuation models,
including both income and market-based approaches, for which all significant inputs are observable, either directly or indirectly, to estimate fair value. These inputs include reported trades of and
broker-dealer quotes on the same or similar securities, issuer credit spreads, benchmark securities and other observable inputs.
As of December 31, 2021, the Company had financial assets valued based on Level 1 inputs consisting of cash and cash equivalents in a United States government money market fund and
had financial assets based on Level 2 inputs consisting of high-grade debt securities, including commercial paper. During the year ended December 31, 2021, the Company did not have any transfers
of financial assets between Levels 1 and 2.
As of December 31, 2021, the Company did not have any financial liabilities recorded at fair value.
The loan payable (discussed in Note 6), which is classified as a Level 3 liability, has a variable interest rate and the carrying value approximates its fair value. As of December 31, 2021, the
carrying value was approximately $38.0 million.
The following table summarizes the financial assets and liabilities measured at fair value on a recurring basis at December 31, 2021 and December 31, 2020 (in thousands):
Fair Value Measurements as of December 31, 2021
Level 1
Level 2
Level 3
Total
Financial assets carried at fair value:
Cash and money market funds
$
70,542 
$
— 
$
— 
$
70,542 
Total cash and cash equivalents
$
70,542 
$
— 
$
— 
$
70,542 
Marketable securities:
Corporate debt securities due within 1 year
$
— 
$
16,784 
$
— 
$
16,784 
Total marketable securities
$
— 
$
16,784 
$
— 
$
16,784 
Total cash, cash equivalents and marketable securities
$
70,542 
$
16,784 
$
— 
$
87,326 
Fair Value Measurements as of December 31, 2020
Level 1
Level 2
Level 3
Total
Financial assets carried at fair value:
Cash and money market funds
$
61,761 
$
— 
$
— 
$
61,761 
Total cash, cash equivalents and marketable securities
$
61,761 
$
— 
$
— 
$
61,761 
Financial liabilities carried at fair value:
Total PIPE Warrant liability
$
— 
$
— 
$
199 
$
199 
120

Basic and Diluted Net Loss per Common Share
Basic net income (loss) per share attributable to the Company’s common stockholders is based on the weighted-average number of common shares outstanding during the period. Diluted net
income (loss) per share attributable to the Company’s common stockholders is based on the weighted-average number of common shares outstanding during the period plus additional weighted-
average common equivalent shares outstanding during the period when the effect is dilutive.
For the years ended December 31, 2021 and 2020, diluted net loss per share is the same as basic net loss per share as the inclusion of weighted-average shares of common stock issuable
upon the exercise of outstanding stock options and warrants until the expirations of the Offering Warrants on April 8, 2021 and the PIPE Warrants on May 16, 2021 would be anti-dilutive.
For the year ended December 31, 2019, diluted net income per share (i) includes common equivalent shares issuable upon the exercise of in-the-money stock options, as determined using the
treasury stock method, as the average market prices of the Company’s common stock during the respective period exceeded the exercise prices of certain stock options, and (ii) excludes the
incremental common shares issuable upon the exercise of the PIPE Warrants, Offering Warrants and out-of-the money stock options as their effect would be anti-dilutive. In the year ended
December 31, 2019, the average market prices of the Company’s common stock were below the exercise prices of $10.00 and $12.50 per share for the PIPE Warrants and Offering Warrants,
respectively.
The following table summarizes the computation of basic and diluted net loss per share for the years ended December 31, 2021, 2020 and 2019, respectively (in thousands except per share
amounts):
Years Ended December 31,
2021
2020
2019
Basic and diluted net income (loss) attributable to common stockholders
$
(53,342)
$
(35,584)
$
9,388 
Weighted-average shares of common stock outstanding
32,661
21,402
15,331
Dilutive securities:
Incremental common shares issuable upon the exercise of dilutive stock options
—
—
45
Weighted-average number of common shares outstanding and dilutive share equivalents outstanding
32,661
21,402
15,376
Basic net income (loss) per share
$
(1.63)
$
(1.66)
$
0.61 
Diluted net income (loss) per share
$
(1.63)
$
(1.66)
$
0.61 
The following table summarizes outstanding securities not included in the computation of diluted net loss per common share as the effect would have been anti-dilutive for the years ended
December 31, 2021, 2020 and 2019, respectively (in thousands):
Outstanding at
December 31,
2021
2020
2019
Stock options outstanding
3,156 
1,797 
1,168 
Offering Warrants outstanding (warrants expired April 8, 2021)
— 
2,500 
2,500 
PIPE Warrants outstanding (warrants expired May 16, 2021)
— 
1,684 
1,684 
Total
3,156 
5,981 
5,352 
Stock-Based Compensation
Under the Company’s stock-based compensation programs, the Company periodically grants stock options and restricted stock to employees, directors and nonemployee consultants. The
Company also issues shares under an employee
121

stock purchase plan. The fair value of each award is recognized in the Company’s statements of operations over the requisite service period for such award.
Awards that vest as the recipient provides service are expensed on a straight-line basis over the requisite service period. The Company uses the Black-Scholes option pricing model to value
stock option awards without market conditions, which requires the Company to make certain assumptions regarding the expected volatility of its common stock price, the expected term of the option
grants, the risk-free interest rate and the dividend yield with respect to its common stock. The Company calculates volatility using its historical stock price data. Due to the lack of the Company’s own
historical data, the Company elected to use the “simplified” method for “plain vanilla” options to estimate the expected term of the Company’s stock option grants. Under this approach, the weighted-
average expected life is presumed to be the average of the vesting term and the contractual term of the option. The risk-free interest rate used for each grant is based on the United States Treasury
yield curve in effect at the time of grant for instruments with a similar expected life. The Company utilizes a dividend yield of zero based on the fact that the Company has never paid cash dividends
and has no present intention to pay cash dividends.
The fair value of equity-classified awards to employees and directors is measured at fair value on the date the awards are granted. During the years ended December 31, 2021, 2020 and
2019, the Company recorded the following stock-based compensation expense (in thousands):
Years Ended
December 31,
2021
2020
2019
Research and development
$
1,218 
$
499 
$
662 
Selling, general and administrative
3,924 
1,856 
1,696 
Total
$
5,142 
$
2,355 
$
2,358 
Income Taxes
The Company provides for income taxes using the asset-liability method. Under this method, deferred tax assets and liabilities are recognized based on differences between financial
reporting and tax bases of assets and liabilities, and are measured using the enacted tax rates and laws that will be in effect when the differences are expected to reverse. The Company calculates its
provision for income taxes on ordinary income based on its projected annual tax rate for the year. Uncertain tax positions are recognized if the position is more-likely-than-not to be sustained upon
examination by a tax authority. Unrecognized tax benefits represent tax positions for which reserves have been established. The Company maintains a full valuation allowance on all deferred tax
assets.
Segment and Geographic Information
Operating segments are defined as components of an enterprise engaging in business activities for which discrete financial information is available and regularly reviewed by the chief
operating decision maker in deciding how to allocate resources and in assessing performance. The Company views its operations and manages its business in one operating segment principally in the
United States. As of December 31, 2021, 2020 and 2019, the Company has no net assets located outside of the United States.
Use of Estimates
The preparation of financial statements in conformity with GAAP requires management to make estimates and assumptions that affect certain reported amounts of assets and liabilities,
disclosure of contingent assets and liabilities at the date of the financial statements, the assessment of the Company’s ability to continue as a going concern and the reported amounts of revenues and
expenses during the reporting periods. Significant items subject to such estimates and assumptions include revenue recognition, clinical trial costs and contract research accruals, measurement of
trade receivables net, measurement of stock-based compensation and estimates of the Company’s capital requirements over the next twelve months from the date of issuance of the consolidated
financial statements. The Company bases its estimates on historical experience and various other assumptions that management believes to be reasonable under the circumstances. Material changes in
these estimates could occur in the future. Changes in estimates are recorded or reflected in the
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Company’s disclosures in the period in which they become known. Actual results could differ from those estimates if past experience or other assumptions do not turn out to be substantially accurate.
Accrued Clinical Trial Costs and Contract Research Liabilities
During each of the years ended December 31, 2021, 2020 and 2019, the Company had arrangements with multiple contract research organizations (“CROs”) whereby these organizations
commit to performing services for the Company over multiple reporting periods. The Company recognizes the expenses associated with these arrangements based on its expectation of the timing of
the performance of components under these arrangements by these organizations. Generally, these components consist of the costs of setting up the trial, monitoring the trial, closing the trial and
preparing the resulting data. Costs related to patient enrollment in clinical trials are accrued as patients are enrolled in the trial.
In addition to fees earned by the CROs to manage the Company’s clinical trials, the CROs are also responsible for managing payments to the clinical trial sites on the Company’s behalf.
There can be significant lag time in clinical trial sites invoicing the CROs. The date on which services are performed, the level of services performed and the cost of such services are often
determined based on subjective judgments. The Company makes these judgments based upon the facts and circumstances known to it, such as the terms of the contract and its knowledge of activity
that has been incurred, including the number of active clinical sites, the number of patients enrolled, the activities to be performed for each patient, including patient treatment and any imaging, if
applicable, and the duration for which the patients will be enrolled in the trial. In the event that the Company does not identify some costs which have begun to be incurred, or the Company under or
overestimates the level of services performed or the costs of such services in a given period, its reported expenses for such period would be understated or overstated. The Company currently reflects
the effects of any changes in estimates based on changes in facts and circumstances directly in its operations in the period such change becomes known.
With respect to financial reporting periods presented in this Annual Report on Form 10-K, the timing of the Company’s actual costs incurred have not differed materially from its estimated
timing of such costs.
Recently Adopted Accounting Pronouncements
In December 2019, the FASB issued ASU 2019-12, Income Taxes (Topic 740): Simplifying the Accounting for Income Taxes (“ASU 2019-12”), which is intended to simplify the accounting
for income taxes. ASU 2019-12 removes certain exceptions to the general principles in Topic 740 and also clarifies and amends existing guidance to improve consistent application. The Company
adopted ASU 2019-02 effective January 1, 2021. The adoption of this standard did not have a material impact on the Company’s consolidated financial statements.
(4) Collaborations and License Agreements
Collaboration Agreement
AstraZeneca
In December 2018, the Company entered into a clinical supply agreement (the “AstraZeneca Agreement”) with a wholly owned subsidiary of AstraZeneca to evaluate the safety and efficacy
of AstraZeneca’s IMFINZI (durvalumab), a human monoclonal antibody directed against PD-L1, in combination with tivozanib as a first-line treatment or following bevacizumab and atezolizumab
treatment for patients with advanced, unresectable HCC in an open-label, multi-center, randomized Phase 1b/2 clinical trial (the “DEDUCTIVE trial”). The Company serves as the study sponsor;
each party contributes the clinical supply of its study drug; key decisions are made by both parties by consensus; and external study costs are otherwise shared equally.
The Company is accounting for the joint development activities under the AstraZeneca Agreement as a joint risk-sharing collaboration in accordance with ASC 808 because both the
Company and AstraZeneca are active participants in the oversight of the DEDUCTIVE trial via their participation on a joint steering committee and are exposed to significant risk and rewards in
connection with the activity based on their obligation to share in the costs. AstraZeneca does not meet the definition of a “Customer,” thus the joint development activities under the AstraZeneca
Agreement are not accounted for under ASC 606.
Payments from AstraZeneca with respect to its share of the external costs for the DEDUCTIVE trial incurred by the Company pursuant to a joint development plan are recorded as a
reduction in research and development expenses due to the joint risk-sharing nature of the activities that is not representative of a vendor-customer relationship.
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The Company records reimbursements from AstraZeneca for external study costs as a reduction in research and development expense during the period that reimbursable expenses are
incurred. As a result of the cost sharing provisions in the AstraZeneca Agreement, the Company’s research and development expenses were reduced by approximately $0.9 million, $1.1 million, and
$0.5 million in the years ended December 31, 2021, 2020 and 2019, respectively. The amount due to the Company from AstraZeneca pursuant to the cost-sharing provision was approximately $0.8
million as of December 31, 2021.
Out-License Agreements
EUSA
In December 2015, the Company entered into a license agreement with EUSA (the “EUSA Agreement”), under which the Company granted to EUSA the exclusive, sublicensable right to
develop, manufacture and commercialize tivozanib in the territories of Europe (excluding Russia, Ukraine and the Commonwealth of Independent States), Latin America (excluding Mexico), Africa
and Australasia (collectively, the “EUSA Licensed Territories”) for all diseases and conditions in humans, excluding non-oncologic diseases or conditions of the eye.
EUSA made research and development reimbursement payments to the Company of $2.5 million upon the execution of the EUSA Agreement during the year ended December 31, 2015 and
$4.0 million in September 2017 upon its receipt of marketing approval from the European Commission in August 2017 for FOTIVDA (tivozanib) for the treatment of RCC. In September 2017,
EUSA elected to opt-in to co-develop the Phase 2 clinical trial of tivozanib in combination with nivolumab in the first-line and the second-line treatment of RCC (the “TiNivo trial”). As a result of
exercising its opt-in right, EUSA made an additional research and development reimbursement payment to the Company of $2.0 million. This $2.0 million payment was received in October 2017, in
advance of the completion of the TiNivo trial, and represented EUSA’s approximate 50% share of the total costs of the TiNivo trial. The Company is also eligible to receive an additional research and
development reimbursement payment from EUSA, in the amount of $20.0 million, for the Company’s Phase 3 randomized, controlled, multi-center, open-label clinical trial comparing tivozanib to an
approved therapy, sorafenib (Nexavar ), in RCC patients whose disease had relapsed or become refractory to two or three prior systemic therapies, including subjects with prior checkpoint inhibitor
therapy (the “TIVO-3 trial”), if EUSA elects to opt-in to that study.
The Company is entitled to receive milestone payments of $2.0 million per country upon reimbursement approval for RCC, if any, in each of France, Germany, Italy, Spain and the United
Kingdom (collectively, the “EU5”). The Company is also entitled to receive an additional $2.0 million for the grant of marketing approval for RCC, if any, in three of the licensed countries outside of
the EU, as mutually agreed by the parties, of which approvals have been obtained in New Zealand in July 2019 and in South Africa in September 2020. In February 2018, November 2018 and
February 2019, EUSA obtained reimbursement approval from the National Institute for Health and Care Excellence (“NICE”) in the United Kingdom, the German Federal Association of the
Statutory Health Insurances (“GKV-SV”) in Germany and the Ministry of Health, Consumer Affairs and Social Welfare (“MSCBS”) in Spain, respectively, for the first-line treatment of RCC.
Accordingly, the Company earned a $2.0 million milestone payment with respect to reimbursement approval in the United Kingdom that was received in March 2018, a $2.0 million milestone
payment with respect to reimbursement approval in Germany that was received in December 2018 and a $2.0 million milestone payment with respect to reimbursement approval in Spain that was
received in May 2019. The Company is also eligible to receive a payment of $2.0 million per indication in connection with a filing by EUSA with the European Medicines Agency (“EMA”) for
marketing approval, if any, for tivozanib for the treatment of each of up to three additional indications and $5.0 million per indication in connection with the EMA’s grant of marketing approval for
each of up to three additional indications, as well as potentially up to $335.0 million upon EUSA’s achievement of certain sales thresholds. The Company is also eligible to receive tiered double-digit
royalties on net sales, if any, of licensed products in the EUSA Licensed Territories ranging from a low double digit up to mid-twenty percent depending on the level of annual net sales. No milestone
payments nor any research and development reimbursement payments were earned in the years ended December 31, 2021 and 2020.
Pursuant to the KKC Agreement (as defined below), the Company is required to pay KKC a 30% sublicense fee related to earned milestone payments and royalties from EUSA. However,
research and development reimbursement payments by EUSA are excluded from the 30% sublicense fee due to KKC, subject to certain limitations. If EUSA elects to opt-in to the TIVO-3 trial, only
approximately $8.7 million of the final $20.0 million research and development payment by EUSA would be subject to the 30% sublicense fee due to KKC. The $2.0 million milestone payments the
Company earned in each of February 2018, November 2018 and February 2019 upon EUSA’s reimbursement approval for FOTIVDA from the NICE in the United Kingdom, the GKV-SV in
Germany and the MSCBS in Spain, respectively, for the first-line treatment of RCC were subject to the 30% KKC sublicense fee, or $0.6 million, each. The sublicense fees for
®
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EUSA’s reimbursement approvals in the United Kingdom, Germany and Spain were paid in April 2018, January 2019 and June 2019, respectively.
EUSA is obligated to use commercially reasonable efforts to seek regulatory approval for and commercialize tivozanib throughout the EUSA Licensed Territories in RCC. EUSA has
responsibility for all activities and costs associated with the further development, manufacture, regulatory filings and commercialization of tivozanib in the EUSA Licensed Territories.
Accounting Under ASC 606
Under ASC 606, the upfront consideration and regulatory milestones included in the transaction price are being recognized as collaboration and licensing revenue over the Company’s
substantive performance period from contract execution in December 2015 through April 2022. Under ASC 606, upon the achievement of a regulatory milestone, the amount that represents the
cumulative catch-up for the period from contract execution in December 2015 through the date of the milestone achievement is recognized as collaboration and licensing revenue, with the balance
classified as deferred revenue and recognized as collaboration and licensing revenue over the remainder of the performance period, currently estimated through April 2022.
None of the remaining regulatory-related milestones are included in the transaction price as these milestone amounts were fully constrained. As part of its evaluation of the constraint, the
Company considered multiple factors: (i) the remaining reimbursement and marketing approvals in RCC are outside of the control of EUSA and vary on a country-by-country basis; (ii) milestones
related to the submission filings for EMA approval of tivozanib in up to three additional indications are contingent upon the success of future clinical trials in additional indications, if any, and are
outside of the control of EUSA; (iii) milestones related to the marketing approval by the EMA for tivozanib in up to three additional indications are contingent upon the success of the corresponding
future clinical trials, if any, and are outside of the control of EUSA; and (iv) efforts by EUSA.
Any consideration related to sales-based milestones (including royalties) will be recognized when the related sales occur as these amounts have been determined to relate predominantly to
the license granted to EUSA and therefore are recognized at the later of when the performance obligation is satisfied (or partially satisfied) or the related sales occur. The Company will re-evaluate
the transaction price, including its estimated variable consideration for milestones included in the transaction price and all constrained amounts, in each reporting period and as uncertain events are
resolved or other changes in circumstances occur.
In November 2017, the Company began earning sales royalties upon EUSA’s commencement of the first commercial launch of FOTIVDA with the initiation of product sales in Germany.
EUSA has received reimbursement approval for and commercially launched FOTIVDA in Germany, the United Kingdom and Spain, as well as in some additional non-EU5 countries. EUSA is
working to secure reimbursement approval in Italy and France and commercially launch FOTIVDA in additional EUSA licensed territories. The Company recognized royalty revenue of
approximately $1.4 million, $1.2 million and $0.9 million in the years ended December 31, 2021, 2020 and 2019, respectively.
The Company recognized total revenues under the EUSA Agreement of approximately $3.4 million, $3.2 million and $3.8 million in the years ended December 31, 2021, 2020 and 2019,
respectively. As of December 31, 2021, there was approximately $0.6 million in total deferred revenue that is expected to continue to be recognized as collaboration and licensing revenue over the
duration of the Company’s performance period, currently estimated through April 2022.
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The following table summarizes the revenues earned in connection with the EUSA Agreement under ASC 606 for the years ended December 31, 2021, 2020 and 2019 (in thousands):
Years Ended
December 31,
Revenue Type
Date Achieved
2021
2020
2019
Collaboration and Licensing Revenue:
Amounts in contract liabilities at the beginning of the period:
Upfront payment
December 2015
$
395 $
395 $
395 
R&D payment - EMA approval in RCC
August 2017
631 
631 
631 
Milestone - UK reimbursement approval
February 2018
316 
316 
316 
Milestone - German reimbursement approval
November 2018
316 
316 
316 
Milestone - Spanish reimbursement approval
February 2019
316 
316 
1,276 
$
1,974 $
1,974 $
2,934 
Partnership Royalties
1,447 
1,245 
861 
Total
$
3,421 $
3,219 $
3,795 
The following table summarizes changes in the Company’s accounts receivable and contract liabilities (deferred revenue) in connection with the EUSA Agreement for the year ended
December 31, 2021 (in thousands):
Contract Assets
Beginning
Balance
January 1,
2021
Additions
Deductions
Ending
Balance
December 31, 2021
Partnership receivables
$
392 
$
1,447 
$
(1,079)
$
760 
Deferred Revenue
Contract Liabilities
Transaction
Price
Date Achieved
Date Paid
Beginning
Balance
January 1,
2021
Additions
Deductions
Ending
Balance
December 31, 2021
Amounts in contract liabilities at the beginning of the period:
 
 
 
 
 
Upfront payment
$
2,500 
December 2015
December 2015
$
512 
$
— 
$
395 
$
117 
R&D payment - EMA approval in RCC
4,000 
August 2017
September 2017
817 
— 
631 
186 
Milestone - UK reimbursement approval
2,000 
February 2018
March 2018
408 
— 
316 
92 
Milestone - German reimbursement
 approval
2,000 
November 2018
December 2018
407 
— 
316 
91 
Milestone - Spanish reimbursement
 approval
2,000 
February 2019
May 2019
408 
— 
316 
92 
Total
$
12,500 
$
2,552 
$
— 
$
1,974 
$
578 
Biodesix
In April 2014, the Company entered into a worldwide co-development and collaboration agreement (the “Biodesix Agreement”) with Biodesix, Inc. (“Biodesix”) to develop and
commercialize ficlatuzumab, the Company’s potent humanized IgG1 monoclonal antibody that targets HGF. Under the Biodesix Agreement, prior to the first commercial sale of ficlatuzumab, each
party had the right to elect to discontinue its funding obligation for further development or
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commercialization efforts with respect to ficlatuzumab in exchange for reduced economics in the program, which is referred to as an “Opt-Out.” In September 2020, the Company regained full global
rights to ficlatuzumab, effective December 2, 2020, when Biodesix exercised its “Opt-Out” rights under the Biodesix Agreement.
Pursuant to the terms of the Biodesix Agreement, as a result of Biodesix’s election to Opt-Out, Biodesix will (i) continue to be responsible for reimbursement of development costs with
respect to the ongoing open label Phase 2 investigator-sponsored clinical trial of ficlatuzumab in combination with ERBITUX® (cetuximab) in HNSCC (the “Phase 2 HNSCC Trial”), (ii) cease to be
entitled to 50% sharing of profits resulting from commercialization of ficlatuzumab, (iii) be entitled to a low double digit royalty on future product sales and 25% of future licensing revenue less
approximately $2.5 million that Biodesix would be required to pay to the Company pursuant to the October 2016 amendment to the Biodesix Agreement and excluding contributions to research and
development expenses and (iv) remain responsible for development obligations under the Biodesix Agreement with respect to VeriStrat. Biodesix and the Company also remain obligated to negotiate
a commercialization agreement to delineate their rights and obligations in the event of any commercialization of VeriStrat with ficlatuzumab. As a result of Biodesix’s decision to Opt-Out, the
Company now has worldwide licensing rights and sole decision-making authority with respect to further development and commercialization of ficlatuzumab. The payment obligations between the
parties under the Biodesix Agreement are in effect until completion of the Phase 2 HNSCC Trial.
CANbridge
In March 2016, the Company entered into a collaboration and license agreement (the “CANbridge Agreement”) with CANbridge Life Sciences, Ltd. (“CANbridge”). Under the terms of the
CANbridge Agreement, the Company granted CANbridge the exclusive right to develop, manufacture and commercialize AV-203, the Company’s potent humanized IgG1 monoclonal antibody that
targets ErbB3 (also known as HER3), for the diagnosis, treatment and prevention of disease in all countries outside of North America.
In March 2021, CANbridge exercised its right to terminate for convenience the CANbridge Agreement. Under the terms of the CANbridge Agreement, the transfer of the AV-203 program
was completed in September 2021 and the Company regained worldwide rights to the AV-203 program.     
Biogen Idec International GmbH
In March 2009, the Company entered into an exclusive option and license agreement with Biogen regarding the development and commercialization of the Company’s discovery-stage
ErbB3-targeted antibodies, including AV-203, for the potential treatment and diagnosis of cancer and other diseases outside of North America (the “Biogen Agreement”). Under the Biogen
Agreement, the Company was responsible for developing ErbB3 antibodies through completion of the first Phase 2 clinical trial designed in a manner that, if successful, would generate data sufficient
to support advancement to a Phase 3 clinical trial.
In March 2014, the Company and Biogen amended the Biogen Agreement (the “Biogen Amendment”). Pursuant to the Biogen Amendment, Biogen agreed to the termination of its rights and
obligations under the Biogen Agreement, including Biogen’s option to (i) obtain a co-exclusive (with the Company) worldwide license to develop and manufacture ErbB3 targeted antibodies and (ii)
obtain exclusive commercialization rights to ErbB3 products in countries in the world other than North America. As a result, the Company has worldwide rights to AV-203. Pursuant to the Biogen
Amendment, the Company is obligated to use reasonable efforts to seek a collaboration partner for the purpose of funding further development and commercialization of ErbB3 targeted antibodies.
The Company is also obligated to pay Biogen a percentage of milestone payments received by the Company from future partnerships after March 28, 2016 and single digit royalty payments on net
sales related to the sale of ErbB3 products, if any, up to a cumulative maximum amount of $50.0 million.
In-License Agreements
St. Vincent’s
In July 2012, the Company entered into a license agreement with St. Vincent’s, under which the Company obtained an exclusive, worldwide sublicensable right to research, develop,
manufacture and commercialize products for human therapeutic, preventative and palliative applications that benefit from inhibition or decreased expression or activity of GDF15, which is also
referred to as MIC-1 (the “St. Vincent’s Agreement”). Under the St. Vincent’s Agreement, St. Vincent’s also granted the Company non-exclusive rights for certain related diagnostic products and
research tools.
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In order to sublicense certain necessary intellectual property rights to Novartis in August 2015, the Company amended and restated the St. Vincent’s Agreement and made an additional
upfront payment to St. Vincent’s of $1.5 million. As of December 31, 2021, the Company is required to make future milestone payments, up to an aggregate total of $14.4 million, upon the earlier of
the achievement of specified development and regulatory milestones or a specified date for the first indication, and upon the achievement of specified development and regulatory milestones for the
second and third indications, for licensed therapeutic products, some of which payments may be increased by a mid to high double-digit percentage rate for milestone payments made after the
Company grants any sublicense, depending on the sublicensed territory. In February 2022, the Company paid.a $2.3 million time-based milestone obligation that became due to St. Vincent’s in
January 2022. The Company will also be required to pay St. Vincent’s tiered royalty payments equal to a low-single-digit percentage of any net sales it or its sublicensees make from licensed
therapeutic products. The royalty rate escalates within the low-single-digit range during each calendar year based on increasing licensed therapeutic product sales during such calendar year.
The St. Vincent’s Agreement remains in effect until the later of 10 years after the date of first commercial sale of licensed therapeutic products in the last country in which a commercial sale is
made, or expiration of the last-to-expire valid claim of the licensed patents, unless we elect, or St. Vincent’s elects, to terminate the St. Vincent’s Agreement earlier. We have the right to terminate the
St. Vincent’s Agreement on six months’ notice if we terminate our GDF15 research and development programs as a result of the failure of a licensed therapeutic product in preclinical or clinical
development, or if we form the reasonable view that further GDF15 research and development is not commercially viable, and we are not then in breach of any of our obligations under the St.
Vincent’s Agreement.
Kyowa Kirin Co. (KKC)
In December 2006, the Company entered into an agreement with KKC (the “KKC Agreement”), under which it obtained an exclusive, sublicensable license to develop, manufacture and
commercialize tivozanib in all territories in the world except for Asia and the Middle East, where KKC retained the rights to tivozanib. Under the KKC Agreement, the Company obtained exclusive
rights to tivozanib in its territory under certain KKC patents, patent applications and know-how for the diagnosis, prevention and treatment of all human diseases and conditions (the “Field”). On
August 1, 2019, the Company entered into an amendment to the KKC Agreement pursuant to which KKC repurchased the non-oncology rights to tivozanib in the Company’s territory, excluding the
rights the Company has sublicensed to EUSA under the EUSA Agreement. The Company has upfront, milestone and royalty payment obligations to KKC under the KKC Agreement related to the
amended Field for oncology development by the Company, and following the amendment, KKC also has upfront, milestone and royalty payment obligations to the Company related to non-oncology
development by KKC in the Company’s territory. Pursuant to the amendment to the KKC Agreement, KKC made a non-refundable upfront payment to the Company in the amount of $25.0 million
that was received in September 2019, and KKC waived the one-time milestone payment of $18.0 million which would have otherwise been payable by the Company upon obtaining marketing
approval on March 10, 2021 for tivozanib in the United States. KKC is required to make milestone payments to the Company of up to an aggregate of $390.7 million upon the successful achievement
of certain development and sales milestones of tivozanib in non-oncology indications.
KKC Agreement
Upon entering into the KKC Agreement, the Company made an upfront payment in the amount of $5.0 million. In March 2010, the Company made a milestone payment to KKC in the
amount of $10.0 million in connection with the dosing of the first patient in the Company’s TIVO-1 trial. In December 2012, the Company made a $12.0 million milestone payment to KKC in
connection with the acceptance by the FDA of the Company’s 2012 New Drug Application filing for tivozanib. Pursuant to the amendment to the KKC Agreement, KKC waived the one-time
milestone payment of $18.0 million which would have otherwise been payable by the Company upon obtaining marketing approval on March 10, 2021 for tivozanib in the United States. Each
milestone under the KKC Agreement was a one-time only payment obligation. The Company has no remaining development and commercialization milestone payments due to KKC under the KKC
Agreement.
The Company is also required to pay tiered royalty payments on net sales it makes of tivozanib in its North American territory, which range from the low to mid-teens as a percentage of net
sales. The royalty rate escalates within this range based on increasing tivozanib sales. The Company’s royalty payment obligations in a particular country in its territory begin on the date of the first
commercial sale of tivozanib in that country, and end on the later of 12 years after the date of first commercial sale of tivozanib in that country or the date of the last to expire of the patents covering
tivozanib that have been issued in that country. On March 10, 2021, the FDA approved FOTIVDA in the United States for the treatment of adult patients with relapsed or refractory advanced RCC
following two or more prior systemic therapies. On
 
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March 22, 2021, the Company commenced product sales of FOTIVDA in the United States. In the years ended December 31, 2021, the Company recognized approximately $4.7 million in royalties
due to KKC on net product sales of FOTIVDA in the United States in its Statement of Operations as a component of cost of products sold.
If the Company sublicenses any of its rights to tivozanib to a third party, as it has done with EUSA, the sublicense defines the payment obligations of the sublicensee, which may vary from
the milestone and royalty payment obligations under the KKC Agreement relating to rights the Company retains. The Company is required to pay KKC a fixed 30% of amounts the Company receives
from its sublicensees, including upfront license fees, milestone payments and royalties, but excluding amounts the Company receives for research and development reimbursement payments or equity
investments, subject to certain limitations.
In connection with the EUSA Agreement, the Company is required to pay KKC the 30% sublicense fee related to earned milestone payments and royalties from EUSA. However, research
and development reimbursement payments by EUSA are excluded from the 30% sublicense fee, subject to certain limitations. If EUSA elects to opt-in to the TIVO-3 trial, only approximately $8.7
million of the final $20.0 million research and development payment by EUSA would be subject to the 30% sublicense fee due to KKC. Refer to the section above, “Out License Agreements –
EUSA”, for further discussion of the actual 30% sublicense fees incurred and paid to-date to KKC.
The Company and KKC each have access to and can benefit from the other party’s clinical data and regulatory filings with respect to tivozanib and biomarkers identified in the conduct of
activities under the KKC Agreement, as related to the amended Field for oncology development. Under the KKC Agreement, the Company is obligated to use commercially reasonable efforts to
develop and commercialize tivozanib in its territory.
The KKC Agreement will remain in effect until the expiration of all of the Company’s royalty and sublicense revenue obligations, determined on a product-by-product and country-by-
country basis, unless terminated earlier. If the Company fails to meet its obligations under the KKC Agreement and is unable to cure such failure within specified time periods, KKC can terminate the
KKC Agreement, resulting in a loss of our rights to tivozanib and an obligation to assign or license to KKC any intellectual property or other rights the Company may have in tivozanib, including its
regulatory filings, regulatory approvals, patents and trademarks for tivozanib.
August 1, 2019 Amendment to the KKC Agreement
In addition to the non-refundable upfront payment to the Company pursuant to the amendment to the KKC Agreement in the amount of $25.0 million and the waiver of the $18.0 million
milestone for United States approval of tivozanib, the Company earned and received a $2.8 million development milestone payment in August 2020 pursuant to the amendment to the KKC
Agreement upon the acceptance of KKC’s investigational new drug, or IND, application for a non-oncology use of tivozanib by the Pharmaceuticals and Medical Devices Agency of Japan on August
2, 2020. KKC is also required to make remaining milestone payments to the Company of up to an aggregate of $387.9 million upon the successful achievement of certain development and sales
milestones of tivozanib in non-oncology indications. KKC is required to make tiered royalty payments to the Company on net sales of tivozanib in non-oncology indications in the Company’s
territory, which range from high single digit to low double digits as a percentage of net sales. The royalty rate escalates within this range based on increasing tivozanib sales, subject to certain
adjustments. KKC’s royalty payment obligations in a particular country in the Company’s territory begin on the date of the first commercial sale of tivozanib in that country, and end on the later of
the expiration date of the last valid claim of a patent application or patent owned by KKC covering tivozanib or 10 years after the date of first commercial sale of tivozanib in non-oncology
indications in that country. No milestone payments were earned in the year ended December 31, 2021. During the year ended December 31, 2020, the Company received a $2.8 million development
milestone payment.
If KKC sublicenses any of its rights to tivozanib to a third-party, KKC is required to pay the Company a percentage of amounts received from the respective sublicensees related to the
Company’s territory, including upfront license fees, milestone payments and royalties, but excluding amounts received in respect of research and development reimbursement payments or equity
investments, subject to certain limitations.
Accounting Analysis Under the August 1, 2019 Amendment to the KKC Agreement
Following the repurchase of non-oncology rights by KKC, the amended KKC Agreement is accounted for as two distinct agreements: (i) the KKC Agreement by which the Company has
upfront, milestone and royalty payment obligations to KKC related to the Company’s oncology development of tivozanib in the amended Field for the Company’s territory that continues to be
accounted for under ASC 730, Research and Development, and (ii) the amended KKC
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Agreement by which KKC has upfront, milestone and royalty payment obligations to the Company related to its non-oncology development of tivozanib for the Company’s territory that will be
accounted for under ASC 606.
The Company evaluated the amendment to the KKC Agreement under ASC 606 and determined that KKC met the definition of a “Customer” as the Company considers the licensing or sale
of intellectual property rights to be an output of the Company’s ordinary activities and is central to the operations of the Company. The Company determined that the amendment to the KKC
Agreement contained a single performance obligation related to the Company’s transfer of rights to non-oncology intellectual property and know-how to KKC, excluding the rights the Company has
sublicensed to EUSA under the EUSA Agreement. In addition, the Company determined that the $25.0 million non-refundable upfront payment received from KKC in September 2019 constituted
the amount of the consideration to be included in the transaction price and attributed this amount to the Company’s single performance obligation. The Company satisfied this performance obligation
during the third quarter of 2019. Accordingly, the Company recognized the $25.0 million in consideration as revenue in the third quarter of 2019. The Company concluded the performance obligation
was satisfied at a point in time because any know-how or clinical data generated from the Company’s ongoing oncology development of tivozanib would not benefit KKC’s non-oncology
development of tivozanib.
In the third quarter of 2020, the Company increased the transaction price to $27.8 million to include the $2.8 million development milestone that was earned in August 2020 upon the
acceptance of KKC’s IND application for a non-oncology use of tivozanib by the Pharmaceuticals and Medical Devices Agency of Japan. Accordingly, the Company recognized the $2.8 million in
consideration as revenue in the third quarter of 2020 as the Company did not have any ongoing performance obligations under the amendment to the KKC Agreement.
None of KKC’s remaining development and regulatory milestones to the Company related to its non-oncology development of tivozanib for the Company’s territory were included in the
transaction price, as these milestone amounts were fully constrained. As part of its evaluation of the constraint, the Company considered multiple factors: (i) regulatory approvals are outside of the
control of KKC; (ii) certain development and regulatory milestones are contingent upon the success of future clinical trials, if any, which is out of the control of KKC; and (iii) efforts by KKC. Any
consideration related to development and regulatory milestones owed by KKC to the Company will be recognized when the corresponding milestones are no longer constrained as the Company does
not have any ongoing performance obligations. Any consideration related to sales-based milestones (including royalties) will be recognized when the related sales occur as these amounts have been
determined to relate predominantly to the intellectual property transferred to KKC and therefore are recognized at the later of when the performance obligation is satisfied or the related sales occur.
(5) Other Accrued Liabilities
Other accrued expenses consisted of the following (in thousands):
 
December 31,
2021
December 31,
2020
FOTIVDA U.S. Product Royalties
2,011 
— 
FOTIVDA Federal Rebates, Customer Credits and Co-Pay Assistance
1,170 
— 
Professional Fees
1,107 
1,061 
Other
1,133 
320 
Total
5,421 
1,381 
(6) Hercules Loan Facility
On May 28, 2010, the Company entered into a loan and security agreement (the “First Loan Agreement”) with Hercules Capital Inc. and certain of its affiliates (“Hercules”). The First Loan
Agreement was subsequently amended in March 2012, September 2014, May 2016 and amended and restated in December 2017 (the “2017 Loan Agreement” and as amended by the 2020 Loan
Amendment (as defined below) and the 2021 Loan Amendment (as defined below), the “Loan Agreement”).
On August 7, 2020, the Company entered into a first amendment to the 2017 Loan Agreement (the “2020 Loan Amendment”) to provide the Company, subject to certain terms and
conditions, with an additional term loan in an aggregate principal amount of up to $35.0 million (the “2020 Loan Facility”) in up to four tranches to be used to refinance outstanding loans under the
2017 Loan Agreement, and for general working capital purposes. The Company received the
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initial $15.0 million of the 2020 Loan Facility upon the closing of the 2020 Loan Amendment, of which approximately $9.7 million was used to retire the then outstanding balance under the 2017
Loan Agreement and of which approximately $5.3 million was new loan funding which was used for general working capital purposes.
The remainder of the loan amount is available to the Company, at its option, subject to certain terms and conditions, including upon the achievement of the following milestones: (i) the
second tranche in the initial amount of $10.0 million (“Tranche Two”) was available through June 30, 2021 upon achieving FDA approval of FOTIVDA (“Performance Milestone I”), (ii) the third
tranche of $5.0 million (“Tranche Three”) was initially available from July 1, 2021 through January 31, 2022 assuming the Company was to achieve $20.0 million in net product revenues from sales
of FOTIVDA, by no later than December 31, 2021 (“Performance Milestone II”), and (iii) the fourth tranche of $5.0 million (“Tranche Four”) was initially available through June 30, 2022 contingent
upon the achievement of both Performance Milestone I and Performance Milestone II, and subject to the consent of Hercules.
The 2020 Loan Amendment also amended the 2017 Loan Agreement by: (i) extending maturity until September 1, 2023, which is extendable to September 1, 2024 at the Company’s option
assuming the Tranche Three funding has occurred, (ii) providing for an interest-only period beginning on the closing date of 2020 Loan Amendment and ending on September 30, 2021, which period
may be extended through September 30, 2022 provided the Company achieves Performance Milestone I and further extendable through March 31, 2023 after the Tranche Three funding has occurred,
if at all, and (iii) revising the per annum interest rate to the greater of (x) 9.65% and (y) an amount equal to 9.65% plus the prime rate as reported in the Wall Street Journal minus 3.25% as determined
daily, provided however, that the per annum interest rate shall not exceed 15%. Principal payments were scheduled to commence on October 1, 2021 at the earliest, as described above. The interest
rate as of December 31, 2021 was 9.65%.
Per the terms of the 2020 Loan Facility, principal will be repaid in equal monthly installments following the conclusion of the interest-only period. The Company may prepay all of the
outstanding principal and accrued interest under the 2020 Loan Facility, subject to a prepayment charge up to 3.0% in the first year following the closing of the 2020 Loan Amendment, decreasing to
2.0% in year two and 1.0% in year three. The Company is obligated to make an end-of-term payment of 6.95% of the aggregate amount of loan funding received under the 2020 Loan Facility on the
earlier of the maturity of the loan or the date on which the Company prepays any outstanding loan balance. The approximate $0.8 million end-of-term payment under the 2017 Loan Agreement
continued to be due and was paid on July 1, 2021. In connection with the 2020 Loan Amendment, the Company incurred approximately $0.3 million in loan issuance costs paid directly to Hercules,
which are accounted for as a loan discount. The 2020 Loan Amendment was accounted for as a loan modification in accordance with ASC 470-50.
The 2020 Loan Facility includes various financial and operating covenants, including that the Company maintain an unrestricted cash position of at least $10.0 million through the date the
Third Tranche funding is received and at least $5.0 million thereafter through the maturity of the loan. The Company was also required to achieve greater than or equal to 75% of its forecasted net
product revenues from its sales of tivozanib over a six month trailing period, as defined and measured on a monthly basis, effective upon the earlier of receiving Third Tranche funding and the month
of April 2022.
On February 1, 2021, the Company entered into the second amendment to the 2017 Loan Agreement (the “2021 Loan Amendment”), which increased the 2020 Loan Facility from up to
$35.0 million to up to $45.0 million following FDA approval of FOTIVDA. The 2021 Loan Amendment makes certain changes to the 2020 Loan Amendment, including, among other things, (i)
increasing Tranche Two funding upon achieving Performance Milestone I from $10.0 million to $20.0 million, thereby increasing the total amount of then unfunded term loan commitments under the
2020 Loan Facility from $20.0 million to $30.0 million, (ii) increasing the amount of net product revenues from sales of FOTIVDA required to achieve Performance Milestone II from $20.0 million
to $35.0 million and changing the deadline for achieving Performance Milestone II from December 31, 2021 to April 1, 2022 and (iii) increasing the amount of the financial covenant for the
maintenance of an unrestricted cash position from at least $10.0 million to at least $15.0 million from the date the Tranche Two funding is received until the date the Tranche Three funding is
received and at least $10.0 million thereafter through the maturity of the Loan Agreement. In connection with the 2021 Loan Amendment, the Company incurred approximately $0.1 million in loan
issuance costs paid directly to Hercules, which are accounted for as a loan discount.
On March 11, 2021, the Company completed the $20.0 million drawdown of Tranche Two funding under the 2021 Loan Amendment that was made available in connection with the
achievement of Performance Milestone I upon FDA approval of FOTIVDA on March 10, 2021. The achievement of Performance Milestone I extended the interest-only period by twelve months
from September 30, 2021 to September 30, 2022 and increased the amount of unrestricted cash
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required for the Company to satisfy the minimum financial covenant during the period between receiving Tranche Two funding and Tranche Three funding from $10.0 million to $15.0 million.
On December 22, 2021, the Company completed the $5.0 million drawdown of Tranche Three funding under the 2021 Loan Amendment that was made available in connection with the
achievement of Performance Milestone II upon the achievement of $35.0 million in net product revenues from sales of FOTIVDA. The achievement of Performance Milestone II extended the
interest-only period by six months from September 30, 2022 to March 31, 2023, extended the loan maturity by one year from September 1, 2023 to September 1, 2024 and decreased the amount of
unrestricted cash required for the Company to satisfy the minimum financial covenant from $15.0 million to $10.0 million thereafter through the maturity of the Loan Agreement.
As of December 31, 2021, the total principal balance was $40.0 million, principal payments are scheduled to commence on April 1, 2023 and the corresponding end-of-term payments under
the 2020 Loan Facility, in the aggregate amount of approximately $2.8 million, are due upon the current loan maturity date of September 1, 2024. As of December 31, 2021, $5.0 million remains
available to the Company in committed funding under the 2020 Loan Facility, in Tranche Four funding that was at our election and subject to the consent of Hercules. The unamortized discount to be
recognized over the remainder of the loan period was approximately $2.0 million and $1.2 million as of December 31, 2021 and December 31, 2020, respectively. Per the 2017 Loan Agreement, the
end-of-term payment of approximately $0.8 million was paid on July 1, 2021, as scheduled.
On March 8, 2022, the Company entered into the 2022 Loan Amendment. The 2022 Loan Amendment (i) changed the operating covenant to decrease the achievement of greater than or
equal to 75% of the Company's forecasted net product revenues from its sales of tivozanib over a six-month trailing period to 65%, as defined and measured on a monthly basis, and extended the
month of commencement from April 2022 to June 2022, (ii) added a cash waiver, at the Company's election, in the event its actual net product revenues from its sales of tivozanib over a six-month
trailing period are below the monthly minimum operating covenant of 65%, such that the Company's unrestricted cash position is equal to or greater than the then total outstanding principal under the
Loan Agreement for each day of such month, (iii) changed Tranche Four funding, in the amount of $5.0 million, that was subject to the consent of Hercules to the achievement of $30.0 million in net
product revenues from sales of FOTIVDA over a trailing three-month period, or Performance Milestone III, and extended the availability of Tranche Four funding from June 30, 2022 to December
15, 2022, and (iv) increased the amount of unrestricted cash required for the Company to satisfy the minimum financial covenant from $10.0 million to $15.0 million upon the earlier of receiving the
Tranche Four funding or January 1, 2023, through the maturity of the Loan Agreement.
The 2020 Loan Facility is secured by substantially all of the Company’s assets, excluding intellectual property. The 2020 Loan Facility provides that certain events shall constitute a default
by the Company, including failure by the Company to pay amounts under the 2020 Loan Amendment when due; breach or default in the performance of any covenant under the 2020 Loan
Amendment by the Company, subject to certain cure periods; insolvency of the Company and certain other bankruptcy proceedings involving the Company; default by the Company of obligations
involving indebtedness in excess of $500,000; and the occurrence of an event or circumstance that would have a material adverse effect upon the business of the Company. As of December 31, 2021,
the Company was in compliance with all loan covenants, Hercules has not asserted any events of default and the Company does not believe that there has been a material adverse effect as defined in
the 2020 Loan Amendment.
The Company has determined that the risk of subjective acceleration under the material adverse events clause is remote and therefore has classified the outstanding principal as a long-term
liability based on the timing of scheduled principal payments.
132

Future minimum payments under the loans payable outstanding as of December 31, 2021 are as follows (in thousands):
Year Ending December 31:
 Amount
2022
$
3,885 
2023
22,528 
2024
24,406 
$
50,819 
Less amount representing interest
(8,039)
Less unamortized discount
(2,040)
Less deferred charges
(2,780)
Less loans payable current, net of discount
— 
Loans payable, net of current portion and discount
$
37,960 
(7) Common Stock
As of December 31, 2021, the Company had 50,000,000 authorized shares of common stock, $0.001 par value, of which 34,474,710 shares were issued and outstanding.
Public Offering – March 2021
On March 26, 2021, the Company completed an underwritten public offering of 6,900,000 shares of its common stock, including the full exercise by the underwriters of their option to
purchase an additional 900,000 shares, at the public offering price of $8.00 per share for gross proceeds of approximately $55.2 million. The net offering proceeds to the Company were
approximately $51.7 million after deducting underwriting discounts and commissions and estimated offering expenses payable by the Company.
Universal Shelf Registration Statement
On November 9, 2020, the Company filed a shelf registration statement on Form S-3 with the SEC, which covers the offering, issuance and sale of up to $300.0 million of its common stock,
preferred stock, debt securities, warrants and/or units (the “2020 Shelf”). The 2020 Shelf (File No. 333-249982) was declared effective by the SEC on November 18, 2020 and was filed to replace the
Company’s then existing shelf registration statement, which was terminated. As of December 31, 2021, there was approximately $213.0 million available for future issuance of common stock,
preferred stock, debt securities, warrants and/or units.
Public Offering – June 2020
On June 19, 2020, the Company completed an underwritten public offering of 9,725,000 shares of its common stock, including the partial exercise by the underwriters of their option to
purchase an additional 1,225,000 shares, at the public offering price of $5.25 per share for gross proceeds of approximately $51.1 million. Three stockholders beneficially holding more than 5% of
the Company’s voting securities, including an entity affiliated with New Enterprise Associates and two other stockholders, purchased an aggregate of 4,503,571 shares in this offering at the same
public offering price per share as the other investors. At such time, entities affiliated with New Enterprise Associates (collectively) beneficially held more than 5% of the Company’s voting securities.
The net offering proceeds to the Company were approximately $47.7 million after deducting underwriting discounts and commissions and estimated offering expenses payable by the Company.
Reverse Stock Split – February 2020
On February 13, 2020, the holders of a majority of the Company’s outstanding shares of common stock approved the reverse stock split and gave the Company’s board of directors
discretionary authority to select a ratio for the split ranging from 1-for-5 to 1-for-15. The Company’s board of directors approved the reverse stock split at a ratio of 1-for-10 on February 13, 2020. On
February 19, 2020, the Company effected a reverse stock split of its outstanding shares of common stock at a ratio of one-for-ten pursuant to a Certificate of Amendment to its Certificate of
Incorporation filed with the Secretary of State of the State of Delaware. The reverse stock split was reflected on Nasdaq beginning with the opening
133

of trading on February 20, 2020. The primary purpose of the reverse stock split was to enable the Company to regain compliance with the $1.00 minimum bid price requirement for continued listing
on Nasdaq.
The reverse stock split affected all issued and outstanding shares of the Company’s common stock, as well as the number of authorized shares of the Company’s common stock and the number
of shares of common stock available for issuance under the Company’s equity incentive plans. The reverse stock split reduced the number of shares of the Company’s issued and outstanding common
stock from approximately 160.8 million to approximately 16.1 million. In addition, the reverse stock split effected a reduction in the number of shares of the Company’s common stock issuable upon
the exercise of stock options and warrants outstanding immediately prior to the reverse stock split, with a proportional increase in the respective exercise prices. The reverse stock split proportionately
reduced the number of authorized shares of the Company’s common stock from 500.0 million shares to 50.0 million. The reverse stock split did not change the par value of the Company’s common
stock or the authorized number of shares of the Company’s preferred stock. All share and per share amounts give effect to the reverse stock split on a retroactive basis.
Expired Offering Warrants from April 2019 Public Offering – Expiration Date of April 8, 2021
In April 2019, the Company completed an underwritten public offering of 2,173,913 shares of its common stock and warrants to purchase an aggregate of 2,500,000 shares of its common
stock (“the Offering Warrants”), including warrants to purchase an aggregate of 326,086 shares of its common stock sold pursuant to the underwriter’s partial exercise of its overallotment option, at
the public offering price of $11.40 per share and $0.10 per warrant for gross proceeds of approximately $25.0 million. The Offering Warrants were immediately exercisable upon issuance at an
exercise price of $12.50 per share, subject to adjustment in certain circumstances, and expired two years from the date of issuance on April 8, 2021. Any Offering Warrants that had not been exercised
for cash prior to their expiration were to be automatically exercised via cashless exercise on the expiration date. The shares and warrants were issued separately and were separately transferable. An
entity affiliated with New Enterprise Associates purchased 434,782 shares and warrants to purchase an aggregate of 434,782 shares in this offering at the same public offering price per share as the
other investors. At such time, entities affiliated with New Enterprise Associates (collectively) beneficially held more than 5% of the Company’s voting securities. The net offering proceeds to the
Company were approximately $22.8 million after deducting underwriting discounts and commissions and estimated offering expenses payable by the Company. The Company determined the shares
of common stock and the Offering Warrants represented freestanding financial instruments. In addition, the Company conducted an assessment of the classification of the Offering Warrants and,
based on their terms, concluded the Offering Warrants were equity-classified. Accordingly, the net offering proceeds of $22.8 million were recorded within stockholders’ equity (deficit).
Public Offering – April 2019
In April 2019, the Company completed an underwritten public offering of 2,173,913 shares of its common stock and warrants to purchase an aggregate of 2,500,000 shares of its common stock
(“the 2019 Offering Warrants”), including warrants to purchase an aggregate of 326,086 shares of its common stock sold pursuant to the underwriter’s partial exercise of its overallotment option, at
the public offering price of $11.40 per share and $0.10 per warrant for gross proceeds of approximately $25.0 million. The 2019 Offering Warrants were immediately exercisable upon issuance at an
exercise price of $12.50 per share, subject to adjustment in certain circumstances, and will expire two years from the date of issuance upon their scheduled expiration on April 8, 2021. Any 2019
Offering Warrants that have not been exercised for cash prior to their expiration shall be automatically exercised via cashless exercise on the expiration date. The shares and warrants were issued
separately and are separately transferable. An entity affiliated with New Enterprise Associates purchased 434,782 shares and warrants to purchase an aggregate of 434,782 shares in this offering at the
same public offering price per share as the other investors. At such time, entities affiliated with New Enterprise Associates (collectively) beneficially held more than 5% of the Company’s voting
securities. The net offering proceeds to the Company were approximately $22.8 million after deducting underwriting discounts and commissions and estimated offering expenses payable by the
Company. As of December 31, 2020, 2019 Offering Warrants to purchase 2,500,000 shares of the Company’s common stock were outstanding. The Company determined the shares of common stock
and the 2019 Offering Warrants represented freestanding financial instruments. In addition, the Company conducted an assessment of the classification of the Offering Warrants and, based on their
terms, concluded the 2019 Offering Warrants are equity-classified. Accordingly, the net offering proceeds of $22.8 million have been recorded within stockholders’ equity (deficit).
In March 2021, 2019 Offering Warrants exercisable for 247,391 shares of common stock were exercised for approximately $3.1 million in cash proceeds. On April 8, 2021, all of the
remaining 2,252,609 2019 Offering Warrants expired and no shares of the Company’s common stock were issued via automatic cashless exercises of unexercised 2019
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Offering Warrants on the date of expiration as the $12.50 exercise price was greater than the Company’s closing stock price of $7.01 on April 8, 2021.
Sales Agreement with SVB Leerink
In February 2018, the Company entered into a sales agreement with SVB Leerink LLC (“SVB Leerink” and the “SVB Leerink Sales Agreement”) pursuant to which the Company may issue
and sell shares of its common stock from time to time up to an aggregate amount of $50.0 million, at its option, through SVB Leerink as its sales agent, with any sales of common stock through SVB
Leerink being made by any method that is deemed an “at-the-market offering” as defined in Rule 415 promulgated under the Securities Act of 1933, as amended (the “Securities Act”), or in other
transactions pursuant to an effective shelf registration statement on Form S-3. The Company agreed to pay SVB Leerink a commission of up to 3% of the gross proceeds of any sales of common
stock pursuant to the SVB Leerink Sales Agreement. The Company sold 470,777 shares, 1,251,555 shares, 1,070,175 shares and 330,688 shares pursuant to the SVB Leerink Sales Agreement,
resulting in proceeds net of commissions of approximately $10.3 million, $7.5 million, $5.9 million and $3.4 million in the fourth quarter of 2018, February 2019, November 2020 and March 2021,
respectively. As of December 31, 2021, approximately $22.2 million was available for issuance in connection with future stock sales pursuant to the SVB Leerink Sales Agreement.
Expired PIPE Warrants from May 2016 Private Placement – Expiration Date of May 16, 2021
In May 2016, the Company entered into a securities purchase agreement with a select group of qualified institutional buyers, institutional accredited investors and accredited investors
pursuant to which the Company sold 1,764,242 units, at a price of $9.65 per unit, for gross proceeds of approximately $17.0 million. Each unit consisted of one share of the Company’s common stock
and a warrant to purchase one share of the Company’s common stock (the “PIPE Warrants”). The PIPE Warrants had an exercise price of $10.00 per share and expired five years from the date of
issuance on May 16, 2021. Certain of the Company’s directors and executive officers purchased an aggregate of 54,402 units in this offering at the same price as the other investors. The net offering
proceeds to the Company were approximately $15.4 million after deducting placement agent fees and other offering expenses payable by the Company. PIPE Warrants exercisable for 80,309 shares
of common stock had been exercised for approximately $0.8 million in cash proceeds and all of the remaining 1,683,933 PIPE Warrants expired on May 16, 2021.
(8) Stock-based Compensation
Stock Incentive Plan
The Company previously maintained the 2010 Stock Incentive Plan (the “2010 Plan”) for employees, consultants, advisors and directors, as amended in March 2013, June 2014 and June
2017.
In April 2019, the Company’s board of directors adopted the 2019 Equity Incentive Plan (the “2019 Plan”) and on June 12, 2019 the stockholders approved the 2019 Plan at the Annual
Meeting of Stockholders. The 2019 Plan provides similar terms as the 2010 Plan, including: (i) a provision for the grant of equity awards such as stock options and restricted stock; (ii) that the
exercise price of incentive stock options cannot be less than 100% of the fair market value of the common stock on the date of the grant for participants who own less than 10% of the total combined
voting power of stock of the Company and not less than 110% for participants who own more than 10% of the total combined voting power of the stock of the Company; (iii) that options and
restricted stock granted under the 2019 Plan vest over periods as determined by the board of directors, which generally are equal to four years; and (iv) that options granted under the 2019 Plan expire
over periods as determined by the board of directors, which generally are ten years from the date of grant. In April 2020, the board of directors adopted an amendment to the 2019 Plan to increase the
total number of shares reserved under the Plan by 1,300,000 shares, among other things. This amendment was approved by stockholders at the Annual Meeting of Stockholders held on June 10, 2020.
In April 2021, the board of directors adopted an additional amendment to the 2019 Plan to increase the total number of shares reserved under the Plan by 2,200,000. This amendment was approved by
stockholders at the Annual Meeting of Stockholders held on June 9, 2021.
Awards may be made under the 2019 Plan for up to the sum of (i) 4,500,000 shares of common stock and (ii) such additional number of shares of common stock (up to 1,068,901 shares) as
is equal to (x) the number of shares of common stock reserved for issuance under the 2010 Plan that were available for grant under the 2010 Plan immediately prior to the date the 2019 Plan was
approved by the Company’s stockholders and (y) the number of shares of common stock subject to awards outstanding under the 2010 Plan, which awards expire, terminate or are otherwise
surrendered, cancelled, forfeited or repurchased by the Company pursuant to a contractual repurchase right. As of December 31, 2021,
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there were 2,401,114 shares of common stock available for future issuance under the 2019 Plan and no shares of common stock available for future issuance under the 2010 Plan.
The following table summarizes stock option activity during the year ended December 31, 2021:
Options
Weighted-
Average
Exercise
Price
Weighted-
Average
Remaining
Contractual
Term
Aggregate
Intrinsic
Value
Outstanding at January 1, 2021
1,816,690 
$
11.04 
7.53 $
170,000 
Granted
1,751,218 
8.37 
Exercised
(2,479)
5.97 
Forfeited
(409,050)
11.87 
Outstanding at December 31, 2021
3,156,379 
$
9.45 
7.55 $
5,720 
Exercisable at December 31, 2021
1,357,101 
$
11.72 
5.82 $
1,907 
The aggregate intrinsic value is based upon the Company’s closing stock price of $4.69 on December 31, 2021.
The fair value of stock options, subject only to service or performance conditions, that are granted to employees is estimated on the date of grant using the Black-Scholes option-pricing
model. The following tables summarize the assumptions used in the Black-Scholes option-pricing model in the years ended December 31, 2021, 2020 and 2019:
 
Years Ended
December 31,
 
2021
2020
2019
Volatility factor
56.17% - 102.66%
94.37% - 102.48%
88.27% - 98.81%
Expected term (in years)
0.25 - 6.25
5.50 - 6.25
5.50 - 6.25
Risk-free interest rates
0.06% - 1.33%
0.31% - 1.67%
1.43% - 2.55%
Dividend yield
—
—
—
Based upon these assumptions, the weighted-average grant date fair value of stock options granted during the years ended December 31, 2021, 2020 and 2019 was $6.49, $4.54 and $5.70
respectively.
As of December 31, 2021, there was $10.1 million of total unrecognized stock-based compensation expense related to stock options granted to employees under the Plan. The expense is
expected to be recognized over a weighted-average period of 2.88 years. The intrinsic value of options exercised was a nominal amount in the years ended December 31, 2021, 2020 and 2019,
respectively.
Employee Stock Purchase Plan
In February 2010, the board of directors adopted the 2010 Employee Stock Purchase Plan (the “ESPP”), as amended in March 2013 and in November 2017. In April 2021, the board of
directors adopted an amendment to the 2010 ESPP Plan to increase the total number of shares reserved under the Plan by 500,000 shares, pursuant to which the Company may sell up to an aggregate
of 576,400 shares of Common Stock. This amendment was approved by stockholders at the Annual Meeting of Stockholders held on June 9, 2021. The ESPP allows eligible employees to purchase
common stock at a price per share equal to 85% of the lower of the fair market value of the common stock at the beginning or end of each six-month period during the term of the ESPP. As of
December 31, 2021, there were 412,403 shares available for future issuance under the ESPP.
Pursuant to the ESPP, the Company sold a total of 111,456 shares of common stock during the year ended December 31, 2021 at purchase prices of $4.38 and $4.40, which represents 85% of
the closing price of the Company’s common stock on December 1, 2020 and December 14, 2021. The Company sold a total of 5,971 shares of common stock during the year ended December 31,
2020 at purchases prices of $6.46 and $4.57, which represents 85% of the closing price of the Company’s common stock on December 1, 2019 and November 30, 2020, respectively. The Company
did not sell any shares of common stock pursuant to the ESPP during the year ended December 31, 2019. The total stock-based
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compensation expense recorded as a result of the ESPP was $0.3 million during the year ended December 31, 2021, and a nominal amount during the years ended 2020 and 2019, respectively.
(9) Commitments and Contingencies
Operating Leases
On March 5, 2020, the Company entered into the Winter Street Sublease to relocate the Company’s corporate headquarters previously located at One Broadway in Cambridge, Massachusetts
for $47.00 per square foot, or approximately $0.5 million per year in base rent, subject to certain operating expenses, taxes and annual base rent increases of approximately 3%. On November 17,
2021, the Company amended the Winter Street Sublease to reduce the square feet of office space from 10,158 square feet to 6,465 square feet. The amended Winter Street Sublease provided that (i)
the security deposit of $0.3 million would be applied toward the remaining base rent payable to the landlord to satisfy in full the base rent obligations through the expiration date of November 29,
2022 and (ii) the landlord would make renovations to improve the space. The amended Winter Street Sublease term remained the same and continues through November 29, 2022.
Previously, the Company leased office space under a month-to-month lease. Rent expense under the operating leases amounted to $0.6 million, $0.6 million and $0.8 million for the years
ended December 31, 2021, 2020 and 2019, respectively.
Manufacturing Commitments
The Company has entered into a contract with a clinical manufacturing organization (“CMO”) for the manufacture of tivozanib (FOTIVDA) in the United States, which includes minimum
annual purchase requirements in the range of $0.5 million to $1.4 million through 2028. In addition, the Company has a contract with a second CMO for the manufacture of clinical drug supply for
ficlatuzumab and AV-380, for which the Company has manufacturing commitments in 2022 in the aggregate amount of approximately $9.0 million. Additionally, the Company has license fee
obligations of up to $2.0 million due to a former CMO for ficlatuzumab drug manufacturing.
Employment Agreements
On March 8, 2021, the Company adopted the Executive Severance and Change in Control Benefits Plan (the "Severance Benefits Plan") for certain of our employees, including each of our
executive officers. The severance benefits provided in the Severance Benefits Plan supersede the separation benefits provided under the terms of any covered employee’s severance and change in
control agreement and our Key Employee Change in Control Benefits Plan. Under the terms of the Severance Benefits Plan, if the executive’s employment is terminated without cause or if the
executive terminates his employment for good reason, such executive will be entitled to receive severance equal to his or, her base salary, benefits and prorated bonuses for a period of time equal to
12 months or, for the chief executive officer base salary for a period of time equal to 12 months and a bonus amount subject to a specified calculation. In addition, if any covered employee’s
employment is terminated by the Company without cause or by the employee for good reason on the date of or within 18 months following a change of control, such covered employee will be
entitled to receive severance for a period of time ranging from 9 months to 24 months, depending upon the position of the covered employee.
(10) Income Taxes
The Company accounts for income taxes under the provisions of ASC 740. The Company recorded no tax provision for the years ended December 31, 2021 and 2020, respectively, due to
generating taxable losses in all filing jurisdictions.
A reconciliation of the expected income tax benefit computed using the federal statutory income tax rate to the Company’s effective income tax rate is as follows for the years ended
December 31, 2021, 2020 and 2019:
137

Years Ended December 31,
2021
2020
2019
Income tax computed at federal statutory tax rate
21.0 
%
21.0 
%
21.0 
%
State taxes, net of federal benefit
3.6 
%
6.7 
%
1.3 
%
Research and development credits
1.6 
%
1.5 
%
(4.2)
%
PIPE Warrants
0.1 
%
2.9 
%
(25.9)
%
Other permanent differences
(0.9)
%
(0.5)
%
1.8 
%
Other
(0.5)
%
(1.1)
%
5.7 
%
Change in valuation allowance
(24.9)
%
(30.5)
%
0.3 
%
Total
— 
%
— 
%
— 
%
With limited exceptions, the Company has incurred net operating losses from inception. At December 31, 2021 the Company had domestic federal, state, and United Kingdom (UK) net
operating loss carryforwards of approximately $613.1 million, $508.4 million, and $6.0 million respectively, available to reduce future taxable income. The federal net operating loss carryforwards
expire beginning in 2022 and continue through 2037 and the state loss carryforwards begin to expire in 2030 and continue through 2041. The Company’s federal net operating losses include
$110.5 million, which do not expire. The foreign net operating loss carryforwards in the UK does not expire. The Company also had federal and state research and development tax credit
carryforwards of approximately $12.7 million and $4.3 million, respectively, available to reduce future tax liabilities and which expire at various dates. The federal credits expire beginning in 2023
through 2040 and the state credits expire beginning in 2022 through 2036. The net operating loss and research and development carryforwards are subject to review and possible adjustment by the
Internal Revenue Service and may be limited in the event of certain changes in the ownership interest of significant stockholders.
The Company’s net deferred tax assets as of December 31, 2021 and 2020 are as follows (in thousands):
December 31,
2021
2020
(in thousands)
Deferred tax assets:
NOL carryforwards
$
160,833 
$
148,689 
Research and development credits
16,088 
15,271 
Deferred revenue and R&D reimbursements
149 
742 
Other temporary differences
5,930 
5,001 
Total deferred tax assets:
183,000 
169,703 
Valuation allowance
(183,000)
(169,703)
Total
$
— 
$
— 
A full valuation allowance has been recorded in the accompanying consolidated financial statements to offset these deferred tax assets because the future realizability of such assets is
uncertain. This determination is based primarily on the Company’s historical and expected future losses. The valuation allowance increased by $13.3 million and $10.9 million during the years ended
December 31, 2021 and 2020, respectively, which was primarily due to the generation of net operating losses and tax credits.
The Company applies the provisions of ASC 740, Income Taxes, for the financial statement recognition, measurement, presentation and disclosure of uncertain tax positions taken or expected
to be taken in income tax returns. Unrecognized tax benefits represent tax positions for which reserves have been established. A full valuation allowance has been provided against the Company’s
deferred tax assets, so that the effect of the unrecognized tax benefits is to reduce the gross amount of the deferred tax asset and the corresponding valuation allowance. Since the Company has
incurred net operating losses since inception, it has never been subject to a revenue agent review. The Company is currently open to examination under the statute of limitations by the Internal
Revenue Service and state jurisdictions for the tax years ended 2018 through 2021. Carryforward tax attributes generated in years past may still be adjusted upon future examination if
138

they have or will be used in a future period. The Company is currently not under examination by the Internal Revenue Service or any other jurisdictions for any tax years.
Utilization of the net operating loss carryforwards and research and development tax credit carryforwards may be subject to an annual limitation under Section 382 of the Internal Revenue
Code of 1986, as amended (the “Internal Revenue Code”), and corresponding provisions of state law, due to ownership changes that have occurred previously or that could occur in the future. These
ownership changes may limit the amount of carryforwards that can be utilized annually to offset future taxable income. In general, an ownership change, as defined by Section 382, results from
transactions increasing the ownership of certain shareholders or public groups in the stock of a corporation by more than 50% over a three-year period. The Company has not recently conducted a
study to assess whether a change of control has occurred or whether there have been multiple changes of control since the last study was completed due to the significant complexity and cost
associated with such a study. If the Company has experienced a change of control, as defined by Section 382, at any time since the last study was completed, utilization of the net operating loss
carryforwards or research and development tax credit carryforwards would be subject to an annual limitation under Section 382, which is determined by first multiplying the value of the Company’s
stock at the time of the ownership change by the applicable long-term tax-exempt rate, and then could be subject to additional adjustments, as required. Any limitation may result in expiration of a
portion of the net operating loss carryforwards or research and development tax credit carryforwards before utilization.
The Company may from time to time be assessed interest or penalties by major tax jurisdictions. The Company recognizes interest and penalties related to uncertain tax positions in income tax
expense. No interest and penalties have been recognized by the Company to date.
The Company anticipates that the amount of unrecognized tax benefits recorded will not change in the next twelve months.
The following is a reconciliation of the Company’s gross uncertain tax positions at December 31, 2021, 2020 and 2019:
Years Ended December 31,
2021
2020
2019
(in thousands)
Amount established upon adoption
$
1,078 
$
1,200 
$
1,200 
Additions for current year tax provisions
— 
— 
— 
Additions for prior year tax provisions
— 
— 
— 
Reductions of prior year tax provisions
(113)
(122)
— 
Balance as of end of year
$
965 
$
1,078 
$
1,200 
(11) Employee Benefit Plan
In 2002, the Company established the AVEO Pharmaceuticals, Inc. 401(k) Plan (the “401(k) Plan”) for its employees, which is designed to be qualified under Section 401(k) of the Code.
Eligible employees are permitted to contribute to the 401(k) Plan within statutory and 401(k) Plan limits. The Company makes matching contributions of 50% of the first 5% of employee
contributions. The Company made matching contributions of $0.3 million, $0.1 million and $0.1 million for each of the years ended December 31, 2021, 2020 and 2019, respectively.
139

(12) Quarterly Results (Unaudited)
Three Months Ended
March 31, 2021
June 30, 2021
September 30, 2021
December 31, 2021
(in thousands, expect per share data)
(unaudited)
Revenues:
FOTIVDA U.S. product revenue, net*
$
1,066 
$
6,735 
$
14,318 
$
16,755 
Partnership licensing and royalty revenue
854
821
855
891
1,920
7,556
15,173
17,646
Operating expenses:
Cost of products sold*
138
822
1,744
2,033
Research and development
5,797
6,878
7,502
6,121
Selling, general and administrative*
15,100
14,920
15,142
15,652
21,035
22,620
24,388
23,806
Loss from operations
(19,115)
(15,064)
(9,215)
(6,160)
Other income (expense), net:
Interest expense, net
(611)
(1,128)
(1,153)
(1,153)
Change in fair value of PIPE Warrant liability
(2,396)
2,595 
— 
— 
Other income
— 
— 
— 
58
Other income (expense), net
(3,007)
1,467 
(1,153)
(1,095)
Net income (loss)
$
(22,122)
$
(13,597)
$
(10,368)
$
(7,255)
Net loss per share - basic and diluted
$
(0.81)
$
(0.40)
$
(0.30)
$
(0.21)
Weighted average number of common shares outstanding
27,429
34,362
34,374
34,384
*FOTIVDA is the Company's first commercial product and was approved by the FDA for marketing and sale in the United States on March 10, 2021 for the treatment of adult patients with
relapsed or refractory advanced RCC following two or more prior systemic therapies.
140

Three Months Ended
March 31, 2020
June 30, 2020
September 30, 2020
December 31, 2020
(in thousands, expect per share data)
(unaudited)
Partnership licensing and royalty revenue
$
784 
$
749 
$
3,600 
$
886 
Operating expenses:
Research and development
7,826 
4,419 
5,860 
4,574 
Selling, general and administrative
3,672 
3,737 
5,800 
9,008 
11,498 
8,156 
11,660 
13,582 
Loss from operations
(10,714)
(7,407)
(8,060)
(12,696)
Other income (expense), net:
Interest expense, net
(315)
(349)
(419)
(522)
Change in fair value of PIPE Warrant liability
2,648 
450 
86 
1,714 
Other income (expense), net
2,333 
101 
(333)
1,192 
Net income (loss)
$
(8,381)
$
(7,306)
$
(8,393)
$
(11,504)
Net loss per share - basic and diluted
$
(0.52)
$
(0.42)
$
(0.33)
$
(0.44)
Weighted average number of common shares outstanding
16,081 
17,364 
25,808 
26,252 
(13) Legal Proceedings
As of the date of filing this Annual Report on Form 10-K, there are no material outstanding legal proceedings against the Company or its current officers or directors.
ITEM 9.
Changes in and Disagreements with Accountants on Accounting and Financial Disclosure
None.
Item 9A.    Controls and Procedures.
Evaluation of Disclosure Controls and Procedures
Our management, with the participation of our Chief Executive Officer and Chief Financial Officer, evaluated the effectiveness of our disclosure controls and procedures (as defined in Rules
13a-15(e) and 15d-15(e) promulgated under the Exchange Act) as of December 31, 2021. In designing and evaluating our disclosure controls and procedures, management recognized that any
controls and procedures, no matter how well designed and operated, can provide only reasonable assurance of achieving their objectives and our management necessarily applied its judgment in
evaluating the cost-benefit relationship of possible controls and procedures. Based on this evaluation, our Chief Executive Officer and Chief Financial Officer concluded that our disclosure controls
and procedures were (1) designed to ensure that material information relating to us is made known to our management including our principal executive officer and principal financial officer by
others, particularly during the period in which this report was prepared and (2) effective, in that they provide reasonable assurance that information required to be disclosed by us in the reports the
Company files or submit under the Exchange Act is recorded, processed, summarized and reported within the time periods specified in the SEC’s rules and forms.
Management’s report on the Company’s internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) appears below.
Internal Control Over Financial Reporting
(a) Management’s Report on Internal Control Over Financial Reporting
141

Our management is responsible for establishing and maintaining adequate internal control over our financial reporting. Internal control over financial reporting is defined in Rules 13a-15(f)
and 15d-15(f) promulgated under the Exchange Act as a process designed by, or under the supervision of, our principal executive and principal financial officers and effected by our board of
directors, management and other personnel, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in
accordance with generally accepted accounting principles and includes those policies and procedures that:
•
Pertain to the maintenance of records that in reasonable detail accurately and fairly reflect the transactions and dispositions of our assets;
•
Provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in accordance with generally accepted accounting principles,
and that receipts and our expenditures are being made only in accordance with authorizations of our management and directors; and
•
Provide reasonable assurance regarding prevention or timely detection of unauthorized acquisition, use or disposition of our assets that could have a material effect on the financial
statements.
Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Therefore, even those systems determined to be effective can provide only
reasonable assurance with respect to financial statement preparation and presentation. Projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become
inadequate because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.
Our management assessed the effectiveness of our internal control over financial reporting as of December 31, 2021. In making this assessment, management used the criteria set forth by the
Committee of Sponsoring Organizations of the Treadway Commission (COSO) in Internal Control—Integrated Framework (2013 framework). Based on its assessment, management believes that, as
of December 31, 2021, our internal control over financial reporting was effective based on those criteria.
Our independent registered public accounting firm has issued an attestation report of our internal control over financial reporting. This report appears below.
(b) Report of Independent Registered Public Accounting Firm
Report of Independent Registered Public Accounting Firm
To the Stockholders and the Board of Directors of AVEO Pharmaceuticals, Inc.
Opinion on Internal Control Over Financial Reporting
We have audited AVEO Pharmaceuticals, Inc.’s internal control over financial reporting as of December 31, 2021, based on criteria established in Internal Control—Integrated Framework issued by
the Committee of Sponsoring Organizations of the Treadway Commission (2013 framework) (the COSO criteria). In our opinion, AVEO Pharmaceuticals, Inc. (the Company) maintained, in all
material respects, effective internal control over financial reporting as of December 31, 2021, based on the COSO criteria.
We also have audited, in accordance with the standards of the Public Company Accounting Oversight Board (United States) (PCAOB), the consolidated balance sheets of the Company as of
December 31, 2021 and 2020, the related consolidated statements of operations, comprehensive income (loss), stockholders’ equity and cash flows for each of the three years in the period ended
December 31, 2021, and the related notes and our report dated March 14, 2022 expressed an unqualified opinion thereon.
Basis for Opinion
The Company’s management is responsible for maintaining effective internal control over financial reporting and for its
assessment of the effectiveness of internal control over financial reporting included in the accompanying Management’s Report on Internal Control Over Financial Reporting. Our responsibility is to
express an opinion on the Company’s internal control over financial reporting based on our audit. We are a public accounting firm registered with the PCAOB and are required to be independent with
respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and regulations of the Securities and Exchange Commission and the PCAOB.
142

We conducted our audit in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable assurance about whether effective internal
control over financial reporting was maintained in all material respects.
Our audit included obtaining an understanding of internal control over financial reporting, assessing the risk that a material
weakness exists, testing and evaluating the design and operating effectiveness of internal control based on the assessed risk, and performing such other procedures as we considered necessary in the
circumstances. We believe that our audit provides a reasonable basis for our opinion.
Definition and Limitations of Internal Control Over Financial Reporting
A company’s internal control over financial reporting is a process designed to provide reasonable assurance regarding the
reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally accepted accounting principles. A company’s internal control over
financial reporting includes those policies and procedures that (1) pertain to the maintenance of records that, in reasonable detail, accurately and fairly reflect the transactions and dispositions of the
assets of the company; (2) provide reasonable assurance that transactions are recorded as necessary to permit preparation of financial statements in accordance with generally accepted accounting
principles, and that receipts and expenditures of the company are being made only in accordance with authorizations of management and directors of the company; and (3) provide reasonable
assurance regarding prevention or timely detection of unauthorized acquisition, use, or disposition of the company’s assets that could have a material effect on the financial statements.
Because of its inherent limitations, internal control over financial reporting may not prevent or detect misstatements. Also,
projections of any evaluation of effectiveness to future periods are subject to the risk that controls may become inadequate
because of changes in conditions, or that the degree of compliance with the policies or procedures may deteriorate.
/s/ Ernst & Young LLP
Boston, Massachusetts
March 14, 2022
Changes in Internal Control Over Financial Reporting
During the year ended December 31, 2021, we implemented certain internal controls in connection with our product sales of FOTIVDA upon the commercial launch in the United States on
March 22, 2021. There were no other changes in our internal control over financial reporting (as defined in Rules 13a-15(f) and 15d-15(f) under the Exchange Act) during the years ended
December 31, 2021, which have materially affected, or are reasonably likely to materially affect, our internal control over financial reporting.
ITEM 9B.
Other Information
Executive Severance and Change in Control Benefits Plan
On March 8, 2021, our board of directors approved the adoption of an Executive Severance and Change in Control Benefits Plan, or the severance benefits plan, for certain of our employees,
including each of our executive officers. The severance benefits plan supersedes any and all prior arrangements for the provision of severance benefits to covered employees that may have been in
effect prior to March 8, 2021 with respect to any termination of employment that would result in the payment of benefits under the severance benefits plan, including the separation benefits provided
under the terms of any covered employee’s severance and change in control agreement and our Key Employee Change in Control Benefits Plan.
Under the terms of the severance benefits plan, if the employment of any of our executive officers is terminated by us without cause, by reason of such executive officer’s disability, or by the
executive officer for good reason, in any case prior to or more than 18 months following a change in control, each as defined in the plan, provided that the executive officer is not otherwise ineligible
to receive severance benefits under the severance benefits plan and subject to the executive officer’s execution and nonrevocation of a general release of claims in our favor, we will (i) continue to
pay the executive officer’s then-current base salary for a period of 12 months, (ii) make contributions to the cost of COBRA coverage on behalf of the officer and his or her applicable dependents for
a period of up to 12 months and, (iii) in the case
143

of our chief executive officer, pay, in a single lump-sum, an amount equal to our chief executive officer’s target bonus for the year in which our chief executive officer’s date of termination occurs,
pro-rated to reflect the portion of the year during which our chief executive officer provided services to us.
Further, under the terms of the severance benefits plan, if any covered employee’s employment is terminated by us without cause or by the employee for good reason on the date of or within
18 months following a change in control, provided that the covered employee is not otherwise ineligible to receive severance benefits under the severance benefits plan and subject to the employee’s
execution and nonrevocation of a general release of potential claims in our favor, we will (i) pay, in the case of our chief executive officer, an amount equal to the sum of 24 months’ of our chief
executive officer’s then-current base salary (or his or her base salary in effective prior to the change in control, if greater), plus an amount equal to 150% of our chief executive officer’s target annual
bonus for the year in which such termination occurs (or, if greater, his or her target annual bonus for the year in which the change in control occurs), plus a pro rata portion of our chief executive
officer’s target annual bonus for the year in which such termination occurs (or, if greater, his or her target annual bonus for the year in which the change in control occurs), such amount to be paid in
substantially equal installments over the course of 18 months, (ii) in the case of our other executive officers, an amount equal to the sum of 12 months’ of such executive officer’s then-current base
salary, plus an amount equal to 100% of such executive officer’s target annual bonus for the year in which such termination occurs (or, if greater, his or her target annual bonus for the year in which
the change in control occurs), and a pro rata portion of such executive officer’s target annual bonus for the year in which such termination occurs (or, if greater, his or her target annual bonus for the
year in which the change in control occurs), such amount to be paid, in substantially equal installments over the course of 12 months, (iii) in the case any covered employee with the title of senior vice
president or above (other than our chief executive officer and other executive officers), an amount equal to the sum of 12 months’ of such employee’s then-current base salary (or his or her base
salary in effective prior to the change in control, if greater), plus an amount equal to 100% of such employee’s target annual bonus for the year in which such termination occurs (or, if greater, his or
her target annual bonus for the year in which the change in control occurs), plus a pro rata portion of such employee’s target annual bonus for the year in which such termination occurs (or, if greater,
his or her target annual bonus for the year in which the change in control occurs), such amount to be paid, in substantially equal installments over the course of 12 months and (iv) in the case of our
other covered employees, an amount equal to the sum of nine months’ of such employee’s then-current base salary (or his or her base salary in effective prior to the change in control, if greater), plus
an amount equal to 75% of such employee’s target annual bonus for the year in which such termination occurs (or, if greater, his or her target annual bonus for the year in which the change in control
occurs), and a pro rata portion of such employee’s target annual bonus for the year in which such termination occurs (or, if greater, his or her target annual bonus for the year in which the change in
control occurs), such amount to be paid in substantially equal installments over the course of nine months. Each covered employee would also be entitled to receive (x) any earned but unpaid annual
bonus for the most recently completed fiscal year, (y) contributions to the cost of COBRA coverage on behalf of the covered employee and his or her applicable dependents for a period of up to 18
months, in the case of our chief executive officer, 12 months in the case of any of our other executive officers and six months in the case of our other covered employees and (z) full vesting
acceleration of any then-outstanding equity awards granted to the covered employee by us that vest based solely on the passage of time.
All contributions to the cost of COBRA coverage on behalf of a covered employee and his or her applicable dependents under the severance benefits plan shall be determined on the same
basis as our contribution to company-provided health and dental insurance coverage in effect for an active employee with the same coverage elections, provided that if such contributions to the cost
of COBRA coverage violate the nondiscrimination requirements of applicable law, the contributions shall not be made.
If the plan administrator of the severance benefits plan reasonably determines in good faith that a covered employee receiving benefits under the plan has failed to comply with the terms of
the plan, including his continuing obligations under the release, we may require payment to us of any benefits described above that the covered employee has already received to the extent permitted
by applicable law and any payments or benefits not yet received shall immediately be forfeited.
Our board of directors may amend, modify, or terminate the severance benefits plan at any time in its sole discretion. However, any amendment, modification or termination prior to a chance
in control that adversely affects the rights of a covered employee must be unanimously approved by our board, including any independent directors and our chief executive officer. In addition, no
amendment, modification or termination may affect the rights of a covered employee then receiving payments or benefits under the severance benefits plan without the consent of such person and no
amendment, modification or termination made after a change in control may be effective for 18 months
2022 Amendment to 2020 Credit Facility
144

On March 8, 2022, we entered into the a Loan Amendment with Hercules (the “2022 Loan Amendment”). The 2022 Loan Amendment makes the $5.0 million Tranche Four funding
available upon achieving $30.0 million in trailing three-month net product revenues from sales of FOTIVDA by no later than December 15, 2022, instead of being available at the discretion of the
lenders by no later than June 30, 2022. The 2022 Loan Amendment makes certain other changes to the Loan Agreement, including, among other things, (i) increasing the minimum unrestricted cash
position financial covenant from $10.0 million to $15.0 million, effective upon the earlier to occur of January 1, 2023 or such date on which the Tranche Four funding is received and continuing
through the maturity of the Loan Agreement, (ii) decreasing the monthly forecasted net product revenues operating covenant from achievement of greater than or equal to 75% of our forecasted net
product revenues from our sales of tivozanib over a 6-month trailing period, to achievement of greater than or equal to 65% of our forecasted net product revenues from our sales of tivozanib over a
6-month trailing period, effective beginning on the period ended June 2022, and (iii) waiving such monthly forecasted net product revenues operating covenant entirely if our unrestricted minimum
cash position equals or exceed the total outstanding obligations under the Loan Agreement.
ITEM 9C.
Disclosure Regarding Foreign Jurisdictions that Prevent Inspections
Not applicable.
PART III
ITEM 10.
Directors, Executive Officers and Corporate Governance
The information required by this Item 10 will be contained in the sections entitled “Election of Directors,” “Corporate Governance” and “Delinquent Section 16(a) Reports,” if applicable,
appearing in the definitive proxy statement we will file in connection with our 2022 Annual Meeting of Stockholders and is incorporated by reference herein. The information required by this item
relating to executive officers may be found below.
We post our Code of Business Conduct and Ethics, which applies to all of our directors, officers and employees, including our principal executive officer, principal financial officer, principal
accounting officer or controller, or persons performing similar functions, in the “Corporate Governance” sub-section of the “Investors” section of our website at www.aveooncology.com. We intend to
disclose on our website any amendments to, or waivers from, the Code of Business Conduct and Ethics that are required to be disclosed pursuant to the disclosure requirements of Item 5.05 of Form
8-K.
The following table lists the positions, names and ages of our executive officers as of March 11, 2022:
Executive Officers
Michael P. Bailey
 
 
56
 
 
Chief Executive Officer, President and Director
Michael J. Ferraresso
 
 
48
 
 
Chief Commercial Officer
Erick J. Lucera
 
 
54
 
 
Chief Financial Officer
Jebediah Ledell
 
 
46
 
 
Chief Operating Officer
Michael P. Bailey was appointed President and Chief Executive Officer and a member of our board of directors in January 2015. Mr. Bailey joined our company in September 2010 as Chief
Commercial Officer and was named Chief Business Officer in June 2013. Prior to joining our company, Mr. Bailey served as Senior Vice President, Business Development and Chief Commercial
Officer at Synta Pharmaceuticals Corp., a biopharmaceutical company focused on research, development and commercialization of oncology medicines, from 2008 to September 2010. From 1999 to
2008, Mr. Bailey worked at ImClone Systems Incorporated, a biopharmaceutical company focused on the development and commercialization of treatments for cancer patients. During his nine-year
tenure at ImClone, he was responsible for commercial aspects of the planning and launch of ERBITUX  (cetuximab) across multiple oncology indications, as well as new product planning for the
ImClone development portfolio, which included CYRAMZA  (ramucirumab) and PORTRAZZA  (necitumumab). In addition, Mr. Bailey was a key member of the strategic leadership committees
for ImClone and its North American and worldwide partnerships and led their commercial organization, most recently as Senior Vice President of Commercial Operations. Prior to his role at
ImClone, Mr. Bailey managed the cardiovascular development portfolio at Genentech, Inc., a biotechnology company, from 1997 to 1999. Mr. Bailey started his career in the pharmaceutical industry
as part of SmithKline Beecham’s Executive Marketing Development Program, where he held a variety of commercial roles from 1992 to 1997, including sales, strategic planning, and product
management. Since July 2020, Mr. Bailey currently serves as a member of the board of directors and chair of the Governance Committee and serves
®
®
®
145

on the audit and clinical committees of IMV Inc. Mr. Bailey received a B.S. in psychology from St. Lawrence University and an M.B.A. in international marketing from the Mendoza College of
Business at University of Notre Dame.
Michael J. Ferraresso was appointed Chief Commercial Officer in March 2021. Mr. Ferraresso joined our company in December 2017 as Senior Vice President, Business Analytics and
Commercial Operations. Prior to joining our company, Mr. Ferraresso served as Vice President, Commercial Operations at Verastem, Inc., a biopharmaceutical company, from January 2017 to
November 2017. From August 2013 to January 2017, Mr. Ferraresso served as Vice President, Commercial at Infinity Pharmaceuticals, Inc., a biopharmaceutical company. Prior to his role at Infinity
Pharmaceuticals, Inc., Mr. Ferraresso served in sales and commercial operations roles of increasing responsibility at several biotechnology and pharmaceutical companies, including at AMAG
Pharmaceuticals, Inc., Critical Therapeutics, Inc., Praecis Inc., Ascent Pediatrics Inc. and Muro Pharmaceutical Inc. Mr. Ferraresso has extensive experience in commercial strategy including
partnerships, development, pricing and field deployment models and has launched Oprapred™, Plenaxis™, Zyflo™ and Feraheme™. Mr. Ferraresso holds a B.A. in economics from Assumption
College.
Erick J. Lucera was appointed Chief Financial Officer in January 2020. From August 2016 to December 2019, Mr. Lucera served as Chief Financial Officer of Valeritas Holdings, Inc., a
commercial-stage medical technology company. From May 2015 to August 2016, Mr. Lucera served as the Chief Financial Officer, Treasurer and Secretary of Viventia Bio Inc., a biotechnology
company focused on developing targeted protein therapeutics for the treatment of cancer. From December 2012 to April 2015, Mr. Lucera served as Vice President, Corporate Development at Aratana
Therapeutics, Inc., a veterinary biopharmaceutical company. Mr. Lucera also previously served as Vice President, Corporate Development at Sunshine Heart, Inc., a medical device manufacturer,
from March 2012 to December 2012. Prior to his role at Sunshine Heart, Mr. Lucera also served as Vice President, Healthcare Analyst at Eaton Vance Management, a global asset management
company from 2008 to 2011 and held various positions at Intrepid Capital Partners, Independence Investment Associates, LLC and Price Waterhouse & Co. from 1990 to 2008. Since October 2021,
Mr. Lucera has served as a member of the board of directors, chairman of the audit committee and member of the compensation committee and nominating and corporate governance committee of
Bone Biologics Corporation. Since August 2017, Mr. Lucera has served as a member of the board of directors and chairman of the audit committee of Beyond Air, Inc. Mr. Lucera holds a C.P.H.
from Harvard University, an M.S. in finance from Boston College, an MBA from Indiana University, Bloomington, and a B.S. in accounting from the University of Delaware. Mr. Lucera currently
holds a CFA designation.
Jebediah Ledell was appointed Chief Operating Officer in December 2021. From September 2019 to November 2021, Mr. Ledell served as Chief Operating Officer at Enzyvant Therapeutics,
Inc., a biotechnology company. From April 2017 to April 2019, Mr. Ledell served as the Chief Operating Officer of Compass Therapeutics, Inc., a clinical-stage, oncology-focused biopharmaceutical
company developing proprietary antibody-based therapeutics to treat multiple human diseases. Mr. Ledell also previously served as Chief Operating Officer at Horizon Discovery Group plc, a gene-
editing company, from June 2014 to December 2017. Prior to his role at Horizon, Mr. Ledell held multiple technology, operations and development roles at Zalicus Inc. Mr. Ledell holds a B.S. in
Chemical Engineering from Worcester Polytechnic Institute.
ITEM 11.
Executive Compensation
The information required by this Item 11 will be contained in the sections entitled “Executive and Director Compensation,” “Executive and Director Compensation—Compensation Committee
Interlocks and Insider Participation” and “Executive and Director Compensation—Compensation Committee Report” appearing in the definitive proxy statement we will file in connection with our
2022 Annual Meeting of Stockholders and is incorporated by reference herein.
ITEM 12.
Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters
The information required by this Item 12 will be contained in the sections entitled “Ownership of Our Common Stock” and “Executive and Director Compensation—Equity Compensation
Plan Information” appearing in the definitive proxy statement we will file in connection with our 2022 Annual Meeting of Stockholders and is incorporated by reference herein.
146

ITEM 13.
Certain Relationships and Related Person Transactions, and Director Independence
The information required by this Item 13 will be contained in the sections entitled “Certain Relationships and Related Person Transactions” appearing in the definitive proxy statement we will
file in connection with our 2022 Annual Meeting of Stockholders and is incorporated by reference herein.
ITEM 14.
Principal Accountant Fees and Services
The information required by this Item 14 will be contained in the section entitled “Corporate Governance—Principal Accountant Fees and Services” appearing in the definitive proxy statement
we will file in connection with our 2022 Annual Meeting of Stockholders and is incorporated by reference herein.
PART IV
ITEM 15.
Exhibits, Financial Statement Schedules
(a)
Documents filed as part of Form 10-K.
 
(1)
Financial Statements
Report of Independent Registered Public Accounting Firm
Consolidated Balance Sheets
Consolidated Statements of Operations
Consolidated Statements of Comprehensive Income (Loss)
Consolidated Statements of Stockholders’ Equity (Deficit)
Consolidated Statements of Cash Flows
Notes to Consolidated Financial Statements
 
(2)
Schedules
Schedules have been omitted as all required information has been disclosed in the financial statements and related footnotes.
 
(3)
Exhibits
The Exhibits listed in the Exhibit Index are filed as a part of this Form 10-K.
ITEM 16.
Form 10-K Summary
None.
147

Exhibit Index
Incorporated by Reference
 
Filed
Herewith
xhibit
Number
Description of Exhibit
Form
File Number
Date of
Filing
Exhibit
Number 
 
 
 
 
 
 
Articles of Incorporation and Bylaws
 
 
 
 
 
Restated Certificate of Incorporation of the Registrant, as amended
 
 
 
 
 X
Second Amended and Restated Bylaws of the Registrant
S-1/A
333-163778
02/08/2010
3.5
 
 
 
 
 
 
 
Instruments Defining the Rights of Security Holders, Including Indentures
 
 
 
 
 
Specimen Stock Certificate evidencing the shares of common stock
10-K
001-34655
03/16/2020
4.1
 
Registration Rights Agreement, dated May 13, 2016, by and among the Company and the Investors named therein
8-K
001-34655
05/13/2016
10.3
 
Warrant Agreement, dated July 16, 2018, by and among the Company and Computershare Inc. and Computershare Trust
Company, N.A., acting jointly as Warrant Agent
8-K
001-34655
07/16/2018
4.1
 
Form of Offering Warrant
8-K
001-34655
04/04/2019
4.1
 
Description of Registered Securities
10-K
001-34655
03/16/2020
4.5
 
 
 
 
 
 
 
Material Contracts—Management Contracts and Compensatory Plans
 
 
 
 
 
Second Amended and Restated 2010 Stock Incentive Plan
8-K
001-34655
06/27/2017
99.1
 
Form of Incentive Stock Option Agreement under 2010 Stock Incentive Plan
S-1/A
333-163778
02/08/2010
10.6
 
Form of Nonqualified Stock Option Agreement under 2010 Stock Incentive Plan
S-1/A
333-163778
02/08/2010
10.7
 
Form of Restricted Stock Agreement under 2010 Stock Incentive Plan
10-K
001-34655
03/30/2012
10.8
 
2019 Equity Incentive Plan
DEF-14A
001-34655
04/30/2019
Appendix A
 
Amendment No.1 to 2019 Equity Incentive Plan
DEF-14A
001-34655
04/28/2020
Appendix A
 
Key Employee Change in Control Severance Benefits Plan
S-1
333-163778
12/16/2009
10.8
 
2010 Employee Stock Purchase Plan, as amended
S-1/A
333-163778
02/23/2010
10.17
 
Amendment No. 1 to 2010 Employee Stock Purchase Plan
8-K
001-34655
06/04/2013
99.2
 
Offer Letter by Registrant to Michael Bailey, dated as of January 6, 2015
10-Q
001-34655
05/07/2015
10.1
 
Severance Agreement, dated September 13, 2010, by and between the Registrant and Michael Bailey
10-Q
001-34655
11/05/2010
10.1
 
Letter Agreement regarding Retention Bonus Award and Severance Agreement, dated February 3, 2014, by and between the
Company and Michael Bailey
10-K
001-34655
3/13/2014
10.22
 
Offer Letter by the Registrant to Michael Needle, dated January 8, 2015
10-Q
001-34655
05/07/2015
10.4
 
Severance and Change in Control Agreement, dated as of January 9, 2015, by and between the Registrant and Michael Needle 10-Q
001-34655
05/07/2015
10.2
 
Offer Letter by and between the Registrant and Erick Lucera, dated December 12, 2019
10-K
001-34655
03/16/2020
10.16
 
Severance and Change in Control Agreement, dated January 6, 2020, by and between the Registrant and Erick Lucera
10-K
001-34655
03/16/2020
10.17
 
Separation and Release of Claims Agreement, dated January 25, 2021, by and between the Registrant and Karuna Rubin
8-K
001-34655
01/29/2021
10.1
 
Termination, Separation and Release of Claims Agreement, dated August 27, 2021 by and between the Registrant and Michael
Needle, M.D.
8-K
001-34655
08/27/2021
10.1
 
Offer Letter by the Registrant to Michael Ferraresso, dated April 8, 2021
X
Severance and Change in Control Agreement, dated March 10, 2021, by and between the Registrant and Michael Ferraresso
X
Offer Letter by the Registrant to Jebediah Ledell, dated November 12, 2021
X
Severance and Change in Control Agreement, dated December 1, 2021, by and between the Registrant and Jebediah Ledell
X
Executive Severance and Change in Control Plan
X
148

Form of Non-Competition and Non-Solicitation Agreement, dated March 8, 2022, by and between the Registrant and Each
Executive Officer
X
Material Contracts—Financing Agreements
 
 
 
 
 
Securities Purchase Agreement, dated May 13, 2016, by and among the Company and the Investors named therein
8-K
001-34655
05/13/2016
10.1
 
Form of Warrant to Purchase Common Stock
8-K
001-34655
05/13/2016
10.2
 
Amended and Restated Loan and Security Agreement, dated December 28, 2017, by and among the Registrant and the parties
named therein.
8-K
001-34655
01/02/2018
10.1
 
First Amendment to Amended and Restated Loan and Security Agreement, dated as of August 7, 2020, by and among the
Registrant, Hercules Capital, Inc. and the other lenders named therein
10-Q
001-34655
08/10/2020
10.1
 
Second Amendment to Amended and Restated Loan and Security Agreement, dated February 1, 2021, by and among the
Registrant, the several banks and other financial institutions or entities from time to time parties thereto and
Hercules Capital, Inc.
8-K
001-34655
02/02/2021
10.1
 
Sales Agreement dated February 16, 2018, by and between the Company and Leerink Partners LLC
8-K
001-34655
02/16/2018
1.1
 
Amendment No.1 to the Sales Agreement dated November 9, 2020, by and between the Registrant and SVB Leerink LLC
S-3
333-249982
11/09/2020
1.3
 
Third Amendment to Amended and Restated Loan and Security Agreement, dated March 8, 2022, by and among the
Registrant, the several banks and other financial institutions or entities from time to time parties thereto and
Hercules Capital, Inc.
X
Material Contracts—License and Strategic Partnership Agreements
License Agreement, dated as of December 21, 2006, by and between the Registrant and Kirin Brewery Co. Ltd.
S-1
333-163778
12/16/2009
10.22
 
Amendment to License Agreement, dated as of August 1, 2019, by and between the Registrant and Kyowa Kirin Co., Ltd.
8-K
001-34655
8/01/2019
10.1
 
Option and License Agreement, dated as of March 18, 2009, by and between the Registrant and Biogen Idec International
GmbH
 10-K
 001-34655
03/16/2021
10.27
Amendment No. 1 to Option and License Agreement, dated as of March 18, 2014 by and between the Registrant and Biogen
Idec MA Inc.
10-K
001-34655
03/16/2021
10.28
Co-Development and Collaboration Agreement, dated as of April 9, 2014 by and between the Registrant and Biodesix Inc.
10-Q
001-34655
05/07/2014
10.2
 
Amended and Restated License Agreement, dated August 13, 2015, by and between the Registrant and St. Vincent’s Hospital
Sydney Limited
10-Q
001-34655
11/08/2021
10.2
 
License Agreement, dated December 18, 2015, by and between the Registrant and EUSA Pharma (UK) Limited
X
Collaboration and License Agreement, dated March 17, 2016, by and between the Registrant and CANbridge Life Sciences
Ltd.
10-Q
001-34655
05/10/2016
10.1
 
First Amendment, dated October 14, 2016, to Co-Development and Collaboration Agreement, dated April 9, 2014, by and
between the Company and Biodesix, Inc.
10-Q
001-34655
11/04/2016
10.1
 
Clinical Trial Collaboration and Supply Agreement, dated January 26, 2021, by and between the Registrant and Bristol-Myers
Squibb Company
10-Q
001-34655
05/10/2021
10.2
Amendment No. 1 to Clinical Trial Collaboration and Supply Agreement, dated March 23, 2021, by and between the
Registrant and Bristol-Myers Squibb Company
10-Q
001-34655
05/10/2021
10.3
 
 
 
 
 
 
Additional Exhibits
 
 
 
 
 
Memorandum of Understanding, dated December 26, 2017, by and among the Company and the parties named therein
8-K
001-34655
12/26/2017
10.1
 
Stipulation of Settlement, dated January 29, 2018, by and among the Company and the parties named therein
10-Q
001-34655
5/8/2018
10.2
 
Sublease, dated March 5, 2020, by and between the Registrant and Commonwealth Care Alliance, Inc.
10-Q
001-34655
4/30/2020
10.2
 
First Amendment to Sublease Agreement, dated November 17, 2021, by and between the Registrant and Commonwealth Care
Alliance, Inc.
X
Revocable Temporary License Agreement, dated November 17, 2021, by and between the Registrant and Commonwealth Care
Alliance, Inc.
X
149

Subsidiaries of the Registrant
 
 
 
 
X
Consent of Ernst & Young LLP
 
 
 
 
X
Certification of principal executive officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as
amended.
 
 
 
 
X
Certification of principal financial officer pursuant to Rule 13a-14(a)/15d-14(a) of the Securities Exchange Act of 1934, as
amended.
 
 
 
 
X
Certification of principal executive officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-
Oxley Act of 2002.
 
 
 
 
X
Certification of principal financial officer pursuant to 18 U.S.C. §1350, as adopted pursuant to Section 906 of the Sarbanes-
Oxley Act of 2002.
 
 
 
 
X
XBRL Instance Document.
 
 
 
 
X
XBRL Taxonomy Extension Schema Document.
 
 
 
 
X
XBRL Taxonomy Calculation Linkbase Document.
 
 
 
 
X
XBRL Taxonomy Extension Definition Linkbase Document.
 
 
 
 
X
XBRL Taxonomy Label Linkbase Document.
 
 
 
 
X
XBRL Taxonomy Presentation Linkbase Document.
 
 
 
 
X
Cover Page Interactive Data File (embedded within the Inline XBRL document).
 
 
 
 
 
†     Confidential treatment has been granted as to certain portions, which portions have been omitted and separately     filed with the U.S. Securities and Exchange Commission.
††     Portions of this exhibit have been omitted pursuant to Item 601(b)(10)(iv) of Regulation S-K.
150

SIGNATURES
Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned, thereunto
duly authorized.
 
AVEO PHARMACEUTICALS, INC.
 
 
 
Date: March 14, 2022
By:
/s/ MICHAEL BAILEY
 
 
Michael Bailey
 
 
President & Chief Executive Officer
 
 
(Principal Executive Officer)
Pursuant to the requirements of the Securities Exchange Act of 1934, this report has been signed below by the following persons on behalf of the registrant and in the capacities and on the
dates indicated.
Signature
Title
Date
/s/ MICHAEL BAILEY
 President, Chief Executive Officer and Director
March 14, 2022
Michael Bailey
 Principal Executive Officer
/s/ ERICK LUCERA
 Chief Financial Officer
March 14, 2022
Erick Lucera
 Principal Financial and Accounting Officer
/s/ KENNETH M. BATE
 Director
March 14, 2022
Kenneth M. Bate
/s/ KEVIN J. CULLEN
 Director
March 14, 2022
Kevin J. Cullen
/s/ CORINNE EPPERLY
 Director
March 14, 2022
Corinne Epperly
/s/ ANTHONY B. EVNIN
 Director
March 14, 2022
Anthony B. Evnin
/s/ GREGORY T. MAYES
 Director
March 14, 2022
Gregory T. Mayes
/s/ SCARLETT SPRING
 Director
March 14, 2022
Scarlett Spring
151

Delaware The First State Page 1 3444819 8100X Authentication: 202854145 SR# 20220916489 Date: 03-08-22 You may verify this certificate online at corp.delaware.gov/authver.shtml I, JEFFREY W. BULLOCK, SECRETARY OF STATE OF THE STATE OF DELAWARE, DO HEREBY CERTIFY THE ATTACHED ARE TRUE AND CORRECT COPIES OF ALL DOCUMENTS FILED FROM AND INCLUDING THE RESTATED CERTIFICATE OR A MERGER WITH A RESTATED CERTIFICATE ATTACHED OF “AVEO PHARMACEUTICALS, INC.” AS RECEIVED AND FILED IN THIS OFFICE. THE FOLLOWING DOCUMENTS HAVE BEEN CERTIFIED: RESTATED CERTIFICATE, FILED THE SEVENTEENTH DAY OF MARCH, A.D. 2010, AT 8 O`CLOCK A.M. CERTIFICATE OF AMENDMENT, FILED THE TWENTY-EIGHTH DAY OF MAY, A.D. 2015, AT 5 O`CLOCK P.M. CERTIFICATE OF AMENDMENT, FILED THE TWENTY-SIXTH DAY OF JUNE, A.D. 2017, AT 8:33 O`CLOCK A.M. CERTIFICATE OF AMENDMENT, FILED THE THIRTEENTH DAY OF JUNE, A.D. 2019, AT 11:47 O`CLOCK A.M. CERTIFICATE OF AMENDMENT, FILED THE NINETEENTH DAY OF FEBRUARY, A.D. 2020, AT 8:20 O`CLOCK A.M.

 
Delaware The First State Page 2 3444819 8100X Authentication: 202854145 SR# 20220916489 Date: 03-08-22 You may verify this certificate online at corp.delaware.gov/authver.shtml

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

AVEO Pharmaceuticals, Inc.
30 Winter Street
Boston, MA 02108
p. 857.400.0101
April 8, 2021
Michael Ferraresso
84 Naugus Road
Marblehead, MA 01945
Dear Mike:
It is with great pleasure that we present to you a promotion from your current position of SVP, Commercial Analytics & Business Development to Chief Commercial
Officer.
Position. Your new position will be Chief Commercial Officer, and you will be designated a “Section 16 officer” (with the meaning of Rule 16a-1(f) under the
Securities Exchange Act of 1934).
Compensation:
•
Base Salary. Your annual salary will be at the annualized rate of $370,369 paid semi-monthly retroactive to January 1, 2021.
•
Incentive Bonus.  You will be eligible to participate in AVEO’s performance-based incentive bonus program. Your bonus target is 40% of your base annual
salary and is subject to corporate and individual performance assessments. Payment of the annual bonus requires approval by the AVEO Board of Directors and is
pro-rated based on your effective date of employment.
•
Stock Options. Subject to approval of the Company’s Compensation Committee, the Company shall grant you stock options to purchase 500,000 shares of
common stock pursuant to the Company’s 2010 Equity Incentive Plan. The options will vest over 4 years from your hire date with 25% of the options vesting
after 12 months and the remainder on a monthly basis thereafter.
You will be also eligible to participate in the Company’s annual renewal equity program. Subject to the Company’s Option Committee approval, your renewal
incentive stock options will be based on your performance and pro-rated to your effective date of employment. The renewal options will vest on a monthly basis
over 4 years from the grant date.
All options shall be subject to all terms, vesting schedules and other provisions set forth in the respective option plan and in a separate option agreement.
Benefits. Company benefits plans in which you are already enrolled will remain unchanged.
Severance and Change in Control. Please refer to the document included with this offer of employment entitled Severance and Change in Control Agreement
which is attached hereto with Exhibit A outlining specific Change in Control policies and incorporated herein by reference.

AVEO Pharmaceuticals, Inc.
30 Winter Street
Boston, MA 02108
p. 857.400.0101
Contingencies. Your offer of employment is contingent upon approval of your appointment by the AVEO Board of Directors.
Other. As a full-time employee we expect that you will devote your full-time professional efforts to the business and affairs of AVEO and, accordingly, will not
pursue any other employment or business opportunities outside of the Company unless approved by your management and Human Resources.
Miscellaneous. This offer of employment is intended to outline the terms of compensation and benefits available to you should you choose to accept this position. It
is not intended to imply any contract or contractual rights. Your employment will be at-will. Accordingly, you or the Company may end the employment relationship
for any reason, at any time.
This letter, together with the Severance and Change in Control Agreement and the Invention and Non-Disclosure Agreement to be executed by you and the Company,
constitutes our entire promotion regarding the terms and conditions of your employment by the Company. It supersedes any prior agreements, or other promises or
statements (whether oral or written) regarding the offered terms of employment.
If you decide to accept the terms of this promotion letter, please sign one of the enclosed copies and return it to our office (attn: Human Resources.)
.
Very truly yours,
/s/ Michael P. Bailey
Michael Bailey
President and Chief Executive Officer
The foregoing correctly sets forth the terms and conditions of my employment by AVEO. I am not relying on any other oral or written representations other than as
set forth above in this letter.
/s/ Michael Ferraresso                    April 29, 2021            
By: Michael Ferraresso                Date

SEVERANCE AND CHANGE IN CONTROL AGREEMENT
THIS SEVERANCE AND CHANGE IN CONTROL AGREEMENT (the “Agreement”), made this 10  day of March 2021 (the “Effective Date”), is entered into by AVEO
Pharmaceuticals, Inc., a Delaware corporation with its principal place of business at 30 Winter Street Boston, MA 02108 (the “Company”), and Michael Ferraresso (the
“Employee”).
WHEREAS, the Company has determined that appropriate steps should be taken to reinforce and encourage the employment and dedication of the Employee and the
Employee’s efforts to maximize the Company’s value.
NOW, THEREFORE, as an inducement for and in consideration of the Employee’s continued employment with the Company and as consideration for the Employee’s
agreement to enter into and be bound by the provisions of Section 4 hereof, the Company agrees that the Employee shall receive the severance benefits set forth in this Agreement in
the event the Employee’s employment with the Company is terminated under the circumstances described below.
1. Key Definitions.
As used herein, the following terms shall have the following respective meanings:
1.1 “Cause” means conduct involving one or more of the following: (i) the conviction of the Employee of, or, plea of guilty or nolo contendere to, any crime involving
dishonesty or any felony; (ii) the willful misconduct by the Employee resulting in material harm to the Company; (iii) fraud, embezzlement, theft or dishonesty by the Employee
against the Company resulting in material harm to the Company; (iv) the repeated and continuing failure of the Employee to follow the proper and lawful directions of the
Company’s Chief Executive Officer or the Board after a written demand is delivered to the Employee that specifically identifies the manner in which the Chief Executive Officer or
the Board believes that the Employee has failed to follow such instructions; (v) the Employee’s current alcohol or prescription drug abuse affecting work performance, or current
illegal use of drugs regardless of the effect on work performance; (vi) material violation of the Company’s code of conduct by the Employee that causes harm to the Company; or
(vii) the Employee’s material breach of any term of the Agreement, or any other applicable confidentiality and/or non-competition agreements with the Company.
1.2 “Good Reason” means the occurrence, without the Employee’s written consent, of any of the following events: (A)  any material diminution in the Employee’s duties,
responsibilities or authority, or (B) a material reduction in the Employee’s base salary (unless such reduction is effected in connection with a general and proportionate reduction of
compensation for all employees of his or her level), provided, however, that Good Reason can only occur if (i) the Employee has given the Company a written notice of termination
indicating the existence of a condition giving rise to Good Reason and the Company has not cured the condition giving rise to Good Reason within thirty (30) days after receipt of
such notice of termination, and (ii) such notice of termination is given within ninety (90) days after the initial occurrence of the condition giving rise to Good Reason and further
provided that a termination for Good Reason shall occur no more than one hundred eighty (180) days after the initial occurrence of the condition giving rise to Good Reason.
1.3 “Disability” means (i) the Employee is unable to engage in any substantial gainful activity by reason of any medically determinable physical or mental impairment that can
be expected to result in death or can be expected to last for a continuous period of not less than twelve (12) months or (ii) the Employee is, by reason of any medically determinable
physical or mental impairment that can be expected to result in death or can be expected to last for a continuous period of not less than twelve (12) months, receiving income
replacement benefits for a period of not less than three (3) months under an accident and health plan covering employees of the Company; provided that in each case, the
Employee’s physical or mental impairment shall be determined by an independent qualified physician mutually acceptable to the Company and the Employee (or his personal
representative) or, if the Company and the Employee (or such representative) are unable to agree on an independent qualified physician, as determined by a panel of three
physicians, one designated by the Company, one designated by the Employee (or his personal representative) and one designated by the two physicians so designated.
2. Termination Without Cause or for Good Reason.
th
    

2.1 Other than as set forth in Section 3 below, if the Employee’s employment with the Company is terminated by the Company without Cause or due to the Employee’s
Disability, or by the Employee for Good Reason, then the Company shall:
(a) continue to pay the Employee his base salary in effect on the date of termination, to be paid in accordance with the Company’s customary payroll practices as are
established or modified from time to time for the period of time (the “Severance Period”)
until the earlier of (x) the date twelve (12) months following the date of termination, or (y) the date on which the Employee commences employment or a consulting
relationship with substantially equivalent compensation;
(b) pay to the Employee (i) on the date of termination, any base salary earned but not paid and any vacation accrued but not used through the date of termination, and
(ii) within thirty (30) days after the date of termination, any reimbursable business expenses incurred by the Employee through the date of termination pursuant to any expense
reimbursement policies of the Company then in effect; and
 
(c) to the extent the Employee and any qualified beneficiary with respect to such Employee elects continuation of health benefit coverage under Section 4980B
(“COBRA”) of the Internal Revenue Code of 1986, as amended (the “Code”), and continues to be eligible for such benefits, the Company shall provide payments to the
Employee for such benefits equal to the amount contributed for active employees with similar benefits and similar participating beneficiaries until the earlier of (x) the
Severance Period, or (y) the date the Employee becomes eligible for group health coverage through another employer.
2.2 Except for the payments under Section 2(b) (which are not contingent upon the Employee’s execution of a release of claims), the payments and benefits to the Employee
under this Section 2 shall (i) be contingent upon the execution and non-revocation by the Employee of a general release of claims in favor of the Company, in the form provided by
the Company at the time of the Employee’s termination (the “Release”) within sixty (60) days following the date of termination (the “Release Period”); provided that if the Release
does not become effective during the Release Period, the payments and benefits described in Sections 2.1(a) and 2.1(c) of this Agreement that commenced following the date of
termination shall cease following the Release Period and (ii) constitute the sole remedy of the Employee in the event of a termination of the Employee’s employment in the
circumstances set forth in this Section 2.
2.3 Notwithstanding anything herein to the contrary, all benefits under this Section 2 shall terminate immediately if the Employee, at any time, violates any proprietary
information, assignment of inventions agreement, confidentiality, non-competition or non-solicitation obligation to the Company, or any other continuing obligation to the Company.
3. Termination upon a Change in Control.
If the Employee is an “Eligible Employee” as defined in the Key Employee Change in Control Benefits Plan adopted by the Company in December 2007, as amended and as
may be amended in the future (the current terms of which are attached hereto as Exhibit A) (the “Change in Control Plan”) at the time of a Change in Control, as defined in said
Change in Control Plan, then any termination of the Employee’s employment following such Change in Control shall be governed by the terms of the Change in Control Plan and no
benefits shall be provided under the terms of this Agreement.
 
4. Non-Competition and Non-Solicitation.
4.1 Restricted Activities. While the Employee is employed by the Company and for a period of one (1) year after the termination or cessation of such employment for any
reason, the Employee will not:
(a) directly engage in the development or commercialization of a Competitive Product for another business or enterprise. For purposes of this provision, a “Competitive
Product” means any therapeutic or diagnostic product that competes with any product that the Company (i) has, as of the date of cessation of the Employee’s employment with
the Company, developed to the stage of readiness for a phase 2 clinical trial or later; or (ii) has sold at any time during the Employee’s
    

employment with the Company or plans to commence selling during the one year period after the cessation of the Employee’s employment;
(b) directly or indirectly either alone or in association with others (i) solicit, or permit any organization directly or indirectly controlled by the Employee to solicit, any
employee of the Company to leave the employ of the Company, or (ii) solicit for employment, hire as an employee or engage as an independent contractor, or permit any
organization directly or indirectly controlled by the Employee to solicit for employment, hire as an employee or engage as an independent contractor, any person who was
employed or engaged by the Company at the time of the termination or cessation of the Employee’s employment with the Company or within six months preceding such
termination or cessation; provided, that this clause (ii) shall not apply to the solicitation, hiring or engagement of any individual whose employment with the Company has
been terminated for a period of six months or longer; or
(c) directly or indirectly make any statements that are professionally or personally disparaging about, or adverse to, the interests of the Company (including its officers,
directors, employees and consultants) including, but not limited to, any statements that disparage any person, product, service, finances, financial condition, capability or any
other aspect of the Company’s business, or engage in any conduct which could reasonably be expected to harm professionally or personally the Company’s business or
reputation (including its officers, directors, employees and consultants); provided that these obligations in Section 4.1(c) will not prevent the Employee from engaging in
ordinary business competition with the Company after the provisions of Section 4.1(a) have expired, providing truthful information to any regulatory agency or providing
truthful testimony in any litigation involving the Company or its officers, directors, employees and consultants.
 
If the Employee violates or breaches any of the provisions of this Section 4.1, then the provisions of this Section 4 shall be applicable to the Employee until a period of one
year has expired without any violation or breach of such provisions.
4.2 Interpretation. If any restriction set forth in Section 4.1 is found by any court of competent jurisdiction to be unenforceable because it extends for too long a period of time
or over too great a range of activities or in too broad a geographic area, it shall be interpreted to extend only over the maximum period of time, range of activities or geographic area
as to which it may be enforceable.
4.3 Equitable Remedies. The restrictions contained in this Section 4 are necessary for the protection of the business and goodwill of the Company and are considered by the
Employee to be reasonable for such purpose. The Employee agrees that any breach of this Section 4 is likely to cause the Company substantial and irrevocable damage which is
difficult to measure. Therefore, in the event of any such breach or threatened breach, the Employee agrees that the Company, in addition to such other remedies which may be
available, shall have the right to obtain an injunction from a court restraining such a breach or threatened breach and the right to specific performance of the provisions of this
Section 4 and the Employee hereby waives the adequacy of a remedy at law as a defense to such relief.
5. Taxes.
5.1 The payments set forth in Sections 2 and 3 above shall be subject to the withholding of such amounts, if any, relating to tax and other payroll deductions as the Company
determines are reasonably required pursuant to any applicable law or regulation. Neither the Employee nor the Company shall have the right to accelerate or to defer the delivery of
the payments to be made under Sections 2 and 3 of this Agreement.
 
5.2 Subject to this Section 5.2, payments or benefits under this Agreement shall begin only upon the date of a “separation from service” of the Employee (determined as set
forth below) which occurs on or after the termination of the Employee’s employment. The following rules shall apply with respect to distribution of the payments and benefits, if
any, to be provided to the Employee under this Agreement:
(a) It is intended that each installment of the payments and benefits provided under this Agreement shall be treated as a separate “payment” for purposes of Section 409A
of the Code and the guidance issued thereunder (“Section 409A”). Neither the Company nor the Employee shall
    

have the right to accelerate or defer the delivery of any such payments or benefits except to the extent specifically permitted or required by Section 409A;
(b) If, as of the date of the “separation from service” of the Employee from the Company, the Employee is not a “specified employee” (each within the meaning of
Section 409A), then each installment of the payments and benefits shall be made on the dates and terms set forth in this Agreement;
(c) If, as of the date of the “separation from service” of the Employee from the Company, the Employee is a “specified employee” (each, for purposes of this Agreement,
within the meaning of Section 409A), then:
(x) Each installment of the payments and benefits due under this Agreement that, in accordance with the dates and terms set forth herein, will in all circumstances,
regardless of when the separation from service occurs, be paid within the short-term deferral period (as defined in Section 409A) shall be treated as a short-term deferral
within the meaning of Treasury Regulation Section 1.409A-1(b)(4) to the maximum extent permissible under Section 409A; and
(y) Each installment of the payments and benefits due under this Agreement that is not described in Section 5(c)(x) and that would, absent this subsection, be paid
within the six-month period following the “separation from service” of the Employee of the Company shall not be paid until the date that is six months and one day after
such separation from service (or, if earlier, the death of the Employee), with any such installments that are required to be delayed being accumulated during the six-month
period and paid in a lump sum on the date that is six months and one day following the Employee’s separation from service and any subsequent installments, if any, being
paid in accordance with the dates and terms set forth herein; provided, however, that the preceding provisions of this sentence shall not apply to any installment of
payments and benefits if and to the maximum extent that that such installment is deemed to be paid under a separation pay plan that does not provide for a deferral of
compensation by reason of the application of Treasury Regulation 1.409A-1(b)(9)(iii) (relating to separation pay upon an involuntary separation from service). Such
payments shall bear interest at an annual rate equal to the prime rate as set forth in the Eastern edition of the Wall Street Journal on the Date of Termination, from the
Date of Termination to the date of payment. Any installments that qualify for the exception under Treasury Regulation Section 1.409A-1(b)(9)(iii) must be paid no later
than the last day of the second taxable year of the Employee following the taxable year of the Employee in which the separation from service occurs.
(d) The determination of whether and when a separation from service of the Employee from the Company has occurred shall be made and in a manner consistent with,
and based on the presumptions set forth in, Treasury Regulation Section 1.409A-1(h). Solely for purposes of this Section 5(d), “Company” shall include all persons with whom
the Company would be considered a single employer as determined under Treasury Regulation Section 1.409A-1(h)(3).
(e) All reimbursements and in-kind benefits provided under this Agreement shall be made or provided in accordance with the requirements of Section 409A to the extent
that such reimbursements or in-kind benefits are subject to Section 409A, including, where applicable, the requirements that (i) any reimbursement is for expenses incurred
during the Executive’s lifetime (or during a shorter period of time specified in this Agreement), (ii) the amount of expenses eligible for reimbursement during a calendar year
may not affect the expenses eligible for reimbursement in any other calendar year, (iii) the reimbursement of an eligible expense will be made on or before the last day of the
calendar year following the year in which the expense is incurred and (iv) the right to reimbursement is not subject to set off or liquidation or exchange for any other benefit.
(f) Notwithstanding anything herein to the contrary, the Company shall have no liability to the Employee or to any other person if the payments and benefits provided in
this Agreement that are intended to be exempt from or compliant with Section 409A are not so exempt or compliant.
6. Other Employment Termination. If the Employee’s employment terminates for any reason other than as described in Sections 2 and 3, the Employee shall only receive any
compensation owed to such Employee as of the termination date and any other post-termination benefits which the Employee is eligible to receive under any plan or program of the
Company.
    

7. Successors.
7.1 Successor to Company. The Company shall require any successor (whether direct or indirect, by purchase, merger, consolidation or otherwise) to all or substantially all of
the business or assets of the Company expressly to assume and agree to perform this Agreement to the same extent that the Company would be required to perform it if no such
succession had taken place. All covenants and agreements hereunder shall inure to the benefit of and be enforceable by such successors or assigns without the necessity that this
Agreement be re-signed at the time of such assignment. As used in this Agreement, “Company” shall mean the Company as defined above and any successor to its business or assets
as aforesaid which assumes and agrees to perform this Agreement, by operation of law or otherwise.
 
7.2 Successor to Employee. This Agreement shall inure to the benefit of and be enforceable by the Employee’s personal or legal representatives, executors, administrators,
successors, heirs, distributees, devisees and legatees. If the Employee should die while any amount would still be payable to the Employee or the Employee’s family hereunder if the
Employee had continued to live, all such amounts, unless otherwise provided herein, shall be paid in accordance with the terms of this Agreement to the executors, personal
representatives or administrators of the Employee’s estate.
8. Notices. All notices, instructions and other communications given hereunder or in connection herewith shall be in writing. Any such notice, instruction or communication
shall be sent either (i) by registered or certified mail, return receipt requested, postage prepaid, or (ii) prepaid via a reputable nationwide overnight courier service, in each case
addressed to the Company, at 1 Broadway 14  Floor, Cambridge, MA 02142, ATTN: Michael Bailey, Chief Executive Officer, and to the Employee at the Employee’s address
indicated in the introduction to this Agreement (or to such other address as either the Company or the Employee may have furnished to the other in writing in accordance herewith).
Any such notice, instruction or communication shall be deemed to have been delivered five business days after it is sent by registered or certified mail, return receipt requested,
postage prepaid, or one business day after it is sent via a reputable nationwide overnight courier service. Either party may give any notice, instruction or other communication
hereunder using any other means, but no such notice, instruction or other communication shall be deemed to have been duly delivered unless and until it actually is received by the
party for whom it is intended.
9. Miscellaneous.
9.1 Employment by Subsidiary. For purposes of this Agreement, the Employee’s employment with the Company shall not be deemed to have terminated solely as a result of
the Employee continuing to be employed by a wholly-owned subsidiary of the Company.
9.2 Severability. The invalidity or unenforceability of any provision of this Agreement shall not affect the validity or enforceability of any other provision of this Agreement,
which shall remain in full force and effect.
9.3 Governing Law. The validity, interpretation, construction and performance of this Agreement shall be governed by the internal laws of the Commonwealth of
Massachusetts, without regard to conflicts of law principles. The Employee hereby irrevocably submits to and acknowledges and recognizes the jurisdiction of the courts of
the Commonwealth of Massachusetts, or if appropriate, a federal court located in Massachusetts (which courts, for purposes of this Agreement, are the only courts of competent
jurisdiction), over any suit, action or other proceeding arising out of, under or in connection with this Agreement or the subject matter hereof.
 
9.4 Waiver of Right to Jury Trial. Both the Company and the Employee expressly waive any right that any party either has or may have to a jury trial of any dispute arising out
of or in any way related to the matters covered by this Agreement.
9.5 Waivers. No waiver by the Employee at any time of any breach of, or compliance with, any provision of this Agreement to be performed by the Company shall be deemed
a waiver of that or any other provision at any subsequent time.
9.6 Counterparts. This Agreement may be executed in counterparts, each of which shall be deemed to be an original but both of which together shall constitute one and the
same instrument.
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9.7 Entire Agreement. Except to the extent provided herein, this Agreement, together with the Offer Letter dated May 5, 2017 (except for Exhibit A to the Offer Letter, entitled
“Key Employee Change in Control Severance Benefits Plan,” which is superseded by this Agreement) and the Invention and Non-Disclosure Agreement, sets forth the entire
agreement of the parties hereto in respect of the subject matter contained herein and supersedes all prior agreements, promises, covenants, arrangements, communications,
representations or warranties, whether oral or written, by any officer, employee or representative of any party hereto in respect of the subject matter contained herein.
9.8 Not an Employment Contract. The Employee acknowledges that this Agreement does not constitute a contract of employment or impose on the Company any obligation to
retain the Employee as an employee and that this Agreement does not prevent the Employee from terminating employment at any time.
9.9 Amendments. This Agreement may be amended or modified only by a written instrument executed by both the Company and the Employee, and, notwithstanding the
provisions of the Change in Control Plan, the language of such Change in Control Plan may not be amended as it applies to the Employee except to the extent subject to a written
instrument executed by both parties.
9.10 Employee’s Acknowledgements. The Employee acknowledges that he: (a) has read this Agreement; (b) has been represented in the preparation, negotiation and execution
of this Agreement by legal counsel of the Employee’s own choice or has voluntarily declined to seek such counsel; and (c) understands the terms and consequences of this
Agreement.
9.11 Representations Regarding Prior Work. You represent that you have no agreement or other legal obligation with any prior employer or any other person or entity that
restricts your ability to engage in employment discussion with, employment with or to perform function for, the Company. You represent that you have been advised by the
Company that at no time should you divulge to or use for the benefit of the Company, any trade secret or proprietary information of any previous employer. You acknowledge that
you have not divulged or used any such information for the benefit of the Company. You acknowledge that the Company is basing important business decision on these
representations, affirm that all of the statements included herein are true and that any breach of this Section 9.11 would be considered a material breach of this Agreement.
 
[Remainder of page intentionally left blank]
 
    

IN WITNESS WHEREOF, the parties hereto have executed this Agreement as of the day and year set forth above.
 
AVEO Pharmaceuticals, Inc.
 
 
 
By:
 
/s/ Michael Bailey
 
 
/s/ Mike Ferraresso
Michael Bailey
Mike Ferraresso
Title:
 President & CEO
 
 
 
 
    

EXHIBIT A
AVEO PHARMACEUTICALS, INC.
KEY EMPLOYEE CHANGE IN CONTROL BENEFITS PLAN
SECTION 1. INTRODUCTION
The Key Employee Change in Control Benefits Plan (the “Plan”) is designed to provide separation pay and benefits to certain eligible employees of AVEO Pharmaceuticals,
Inc. (“the “Company”) whose employment is involuntarily terminated without cause or voluntarily terminated for good reason as set forth in this Plan.
SECTION 2. DEFINITIONS
For purposes of this Plan, the following terms shall have the meanings set forth below:
(a) “BASE SALARY” means the annual base salary for an Eligible Employee as in effect on the Change in Control Date, or as increased thereafter.
(b) “BOARD” means the Board of Directors of the Company.
(c) “CAUSE” means conduct involving one or more of the following: (i) the conviction of the Eligible Employee of, or, plea of guilty or nolo contendere to, any crime
involving dishonesty or any felony; (ii) the willful misconduct by the Eligible Employee resulting in material harm to the Company; (iii) fraud, embezzlement, theft or dishonesty by
the Eligible Employee against the Company resulting in material harm to the Company; (iv) the repeated and continuing failure of the Eligible Employee to follow the proper and
lawful directions of the Company’s Chief Executive Officer or the Board after a written demand is delivered to the Eligible Employee that specifically identifies the manner in
which the Chief Executive Officer or the Board believes that the Employee has failed to follow such instructions; (v) the Eligible Employee’s current alcohol or prescription drug
abuse affecting work performance, or current illegal use of drugs regardless of the effect on work performance; (vi) material violation of the Company’s code of conduct by the
Eligible Employee that causes harm to the Company; or (vii) the Eligible Employee’s material breach of any term of the Plan or any applicable written proprietary information,
confidentiality, non-competition and/or non-solicitation agreements with the Company.
(d) “CHANGE IN CONTROL” means the occurrence of any of the events set forth in subsections (A) or (B) below, provided that such event(s) constitute (i) a change in the
ownership of the Company (as defined in Treasury Regulation Section 1.409A-3(i)(5)(v)), (ii) a change in effective control of the Company (as defined in Treasury Regulation
Section 1.409A-3(i)(5)(vi)), or (iii) a change in the ownership of a substantial portion of the assets of the Company (as defined in Treasury Regulation Section 1.409A-3(i)(5)(vii)):
(A) when a person, entity or group (within the meaning of Section 13(d)(3) or 14(d)(2) of the Securities Exchange Act of 1934, a amended) acquires beneficial ownership
of the Company’s capital stock equal to 50% or more of either: (X) the then-outstanding shares of the Company’s common stock (the “Outstanding Company Common Stock”)
or (Y) the combined voting power of the Company’s then-outstanding securities entitled to vote generally in the election of directors (the “Outstanding Company Voting
Securities”) provided, however, that for purposes of this subsection (A), the following acquisitions of securities shall not constitute a Change in Control: (1) any acquisition of
securities directly from the Company (excluding an acquisition of securities pursuant to the exercise, conversion or exchange of any security exercisable for, convertible into or
exchangeable for common stock or voting securities of the Company, unless the Person exercising, converting or exchanging such security acquired such security directly from
the Company or an underwriter or agent of the Company) or (2) any acquisition of securities by the Company; or
 
(B) upon the consummation by the Company of a reorganization, merger, consolidation, statutory share exchange or a sale or other disposition of all or substantially all of
the assets of the Company in one or a series of transactions (a “Business Combination”), provided that, in each case, the persons who were the Company’s beneficial owners of
the Outstanding Company Common
    

Stock and Outstanding Company Voting Securities immediately prior to such Business Combination do not beneficially own, directly or indirectly, more than 50% of the then-
outstanding shares of common stock and the combined voting power of the then-outstanding securities entitled to vote generally in the election of directors, respectively, of the
resulting or acquiring corporation in such Business Combination (which shall include, without limitation, a corporation which as a result of such transaction owns the
Company or substantially all of the Company’s assets either directly or through one or more subsidiaries) in substantially the same proportions as their ownership, immediately
prior to such Business Combination, of the Outstanding Company Common Stock and Outstanding Company Voting Securities, respectively; or
(C) such time as the Continuing Directors (as defined below) do not constitute a majority of the Board (or, if applicable, the Board of Directors of a successor corporation
to the Company), where the term “Continuing Director” means at any date a member of the Board (i) who was a member of the Board on the effective date of this Plan, or
(ii) who was nominated or elected subsequent to such date by at least a majority of the directors who were Continuing Directors at the time of such nomination or election or
whose election to the Board was recommended or endorsed by at least a majority of the directors who were Continuing Directors at the time of such nomination or election;
provided, however, that there shall be excluded from this clause (ii) any individual whose initial assumption of office occurred as a result of an actual or threatened election
contest with respect to the election or removal of directors or other actual or threatened solicitation of proxies or consents, by or on behalf of a person other than the Board.
(e) “CHANGE IN CONTROL DATE” means the first date on which a Change in Control occurs.
(f) “DISABILITY” means (i) the Eligible Employee is unable to engage in any substantial gainful activity by reason of any medically determinable physical or mental
impairment that can be expected to result in death or can be expected to last for a continuous period of not less than twelve (12) months or (ii) the Eligible Employee is, by reason of
any medically determinable physical or mental impairment that can be expected to result in death or can be expected to last for a continuous period of not less than twelve
(12) months, receiving income replacement benefits for a period of not less than three (3) months under an accident and health plan covering employees of the Company; provided
that in each case, the Eligible Employee’s physical or mental impairment shall be determined by an independent qualified physician mutually acceptable to the Company and the
Eligible Employee (or his personal representative) or, if the Company and the Eligible Employee (or such representative) are unable to agree on an independent qualified physician,
as determined by a panel of three physicians, one designated by the Company, one designated by the Eligible Employee (or his personal representative) and one designated by the
two physicians so designated.
(g) “INVOLUNTARY TERMINATION WITHOUT CAUSE” means an Eligible Employee’s dismissal or discharge by the Company (or, if applicable, by any successor
entity) for a reason other than Cause. The termination of employment will not be deemed to be an “Involuntary Termination Without Cause” if such termination occurs as a result of
the Eligible Employee’s voluntary resignation without Good Reason, death or Disability.
(i) “MANAGEMENT TEAM” shall include any executive officer, senior vice-president and vice-president of the Company and other employees of the Company nominated
by the Chief Executive Officer and ratified by the Compensation Committee.
(j) “QUALIFYING TERMINATION” means that an Eligible Employee’s employment terminates due to an Involuntary Termination Without Cause or a Voluntary
Termination for Good Reason, in either case, within eighteen (18) months following a Change in Control Date.
 
(k) “SECTION 16 OFFICER” means an executive officer of the Company, other than the Chief Executive Officer, Chief Financial Officer, Chief Business Officer and Chief
Medical Officer, who is considered to be an “officer” of the Company within the meaning of Rule 16a-1(f) under the Securities Exchange Act of 1934, as amended and “executive
Officer” of the Company within the meaning of Rule 3b-7 under the Securities Exchange Act of 1934, as amended.
(l) “VOLUNTARY TERMINATION FOR GOOD REASON” means any action by the Company without the Eligible Employee’s prior consent which results in he or she
voluntarily terminating his or her
    

employment with the Company (or, if applicable, with any successor entity) after any of the following are undertaken by the Company (or, if applicable, by any successor entity)
without such Eligible Employee’s express consent, provided, however, that a termination for Good Reason can only occur if (i) the Eligible Employee has given the Company a
written notice of termination indicating the existence of a condition giving rise to Good Reason and the Company has not cured the condition giving rise to Good Reason within
thirty (30) days after receipt of such notice of termination, and (ii) such notice of termination is given within ninety (90) days after the initial occurrence of the condition giving rise
to Good Reason and further provided that a termination for Good Reason shall occur no more than one hundred eighty (180) days after the initial occurrence of the condition giving
rise to Good Reason: (A) any requirement by the Company that the Eligible Employee perform his or her principal duties outside a radius of 50 miles from the Company’s
Cambridge, Massachusetts location, (B) any material diminution in the Eligible duties, responsibilities or authority; or (C) a material reduction in the Eligible Employee’s base
salary (unless such reduction is effected in connection with a general and proportionate reduction of compensation for all employees of his or her level).
SECTION 3. ELIGIBILITY AND PARTICIPATION
An individual is deemed an “Eligible Employee” and, therefore, eligible to participate in the Plan if he or she is a member of the Company’s Management Team at the time of
such individual’s termination of employment with the Company, and such employment terminates due to an event which constitutes a Qualifying Termination.
SECTION 4. BENEFITS
Eligible Employees are eligible to receive the following benefits on the following conditions:
(a) SALARY AND BONUS PAYOUT. Commencing in the first month following the month of a Qualifying Termination and the Release set forth in Section (f) below
becoming binding on the Eligible Employee, Eligible Employee will be paid in periodic installments consistent with the Company’s payroll procedures as then in effect and
continuing for a number of months equal to the product of the Eligible Employee’s “Severance Multiple” (as set forth below) times twelve (12), a total sum equal to: (i) Severance
Multiple times the Eligible Employee’s Base Salary; (ii) the Eligible Employee’s Severance Multiple times his/her target bonus on the date of the Qualifying Termination; and
(iii) the Eligible Employee’s target bonus on the date of termination multiplied by a fraction, the numerator of which shall equal the number of days the Eligible Employee was
employed by the Company during the Company fiscal year in which the termination occurs and the denominator of which shall equal 365.
Severance Multiple shall be based on the following:
 
Chief Executive Officer
  
—    
1.5
Chief Financial Officer, Chief Business Officer, Chief Medical Officer, Section 16 Officer, and any other Eligible Employee
nominated by the CEO and ratified by the Compensation Committee
  
—    
1.0
Senior Vice Presidents, Vice Presidents and other Eligible Employees nominated by CEO and ratified by Compensation
Committee, other than those considered Section 16 Officers
  
—    
0.5
 
(b) HEALTH BENEFITS. Provided the Eligible Employee timely elects continued coverage under federal COBRA law, the Company shall pay, on the Eligible Employee’s
behalf, the portion of premiums for the type of group health insurance coverage, including coverage for his or her eligible dependents, that the Company paid prior to his or her
termination of employment for a period following his or her Qualifying Termination based on the Eligible Employee’s level as follows:
 
    

Chief Executive Officer
  
—    
18 months
Chief Financial Officer, Chief Business Officer, Chief Medical Officer, Section 16 Officer, and any other Eligible
Employee nominated by the CEO and ratified by the Compensation Committee
  
—    
12 months
Senior Vice Presidents, Vice Presidents and other Eligible Employees nominated by CEO and ratified by
Compensation Committee, other than those considered Section 16 Officers
  
—    
6 months
provided, however, that the Company will pay such premiums for the Eligible Employee and his/her eligible dependents only for coverage for which such individual and those
dependents were enrolled immediately prior to the Qualifying Termination. The Eligible Employee shall continue to be required to pay that portion of the premium of such group
health insurance coverage, including coverage for his/her eligible dependents that he/she had been required to pay as an active employee immediately prior to the Qualifying
Termination of employment (subject to change). For the balance of the period that an Eligible Employee is eligible to receive coverage under federal COBRA law, the Eligible
Employee shall be eligible to maintain coverage for himself/herself and his/her eligible dependents at the Eligible Employee’s own expense in accordance with applicable law.
(c) EQUITY ACCELERATION. In addition to any other rights that Eligible Employees may have with respect to the acceleration of the vesting of any stock options or
restricted stock awards (“Awards”) granted to such Eligible Employees pursuant to the Company’s 2002 Stock Incentive Plan, as amended (the “2002 Stock Incentive Plan”), or any
successor plan, including without limitation those certain change in control related acceleration rights (upon a termination without cause) approved by the Board on December 11,
2007, and notwithstanding any provision to the contrary contained in the 2002 Stock Incentive Plan, the instrument evidencing any Award or any other agreement between an
Eligible Employee and the Company, each such Award shall be immediately exercisable in full and/or free of all restrictions on repurchase, as the case may be, if the Eligible
Employee’s employment with the Company or the acquiring or succeeding corporation is terminated as a result of a Qualifying Termination.
(d) EARNED BUT UNPAID BENEFITS. As of the Qualifying Termination date an Eligible Employee will also be eligible to receive any earned but unpaid benefits including
salary earned but unpaid, the annual bonus for the most recently completed financial year and payment for unused accrued vacation.
(e) RELEASE. To receive benefits under this Plan, an Eligible Employee must execute a general release of claims in favor of the Company within thirty (30) days following
the Eligible Employee’s Qualifying Termination, in a form provided by the Company at the time of the Employee’s Qualifying Termination, and such release must become effective
in accordance with its terms (the “Release”). Notwithstanding the foregoing, if the 30  day following the Eligible Employee’s Qualifying Termination occurs in the calendar year
following the Eligible Employee’s Qualifying Termination, then the payments and benefits will commence no earlier than January 1 of such subsequent calendar year.
 
(f) TERMINATION OF BENEFITS. Benefits under this Plan shall terminate immediately if an Eligible Employee, at any time, violates any proprietary information,
confidentiality, non-competition or non-solicitation obligation to the Company, or any other continuing obligation to the Company.
(g) NON-DUPLICATION OF BENEFITS. Eligible Employees are not eligible to receive benefits under this Plan more than one time and are not eligible to receive benefits
under any other Company change in control severance plan, arrangement or agreement.
(h) TAX WITHHOLDING. Any payments that an Eligible Employee receives under this Plan shall be subject to all required tax withholding.
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(i) DISTRIBUTIONS. The following rules shall apply with respect to distribution of the payments and benefits, if any, to be provided to the Eligible Employee under this
Section 4:
(A) It is intended that each installment of the payments and benefits provided under Section 4 shall be treated as a separate “payment” for purposes of Section 409A of
the U.S. Internal Revenue Code of 1986, as amended, and the guidance issued thereunder (“Section 409A”). Neither the Company nor the Eligible Employee shall have the
right to accelerate or defer the delivery of any such payments or benefits except to the extent specifically permitted or required by Section 409A;
(B) If, as of the date of the “separation from service” of the Eligible Employee from the Company, the Eligible Employee is not a “specified employee” (each within the
meaning of Section 409A), then each installment of the payments and benefits shall be made on the dates and terms set forth in Section 4; and
(C) If, as of the date of the “separation from service” of the Eligible Employee from the Company, the Eligible Employee is a “specified employee” (each, for purposes of
this Agreement, within the meaning of Section 409A), then:
(x) Each installment of the payments and benefits due under Section 4 that, in accordance with the dates and terms set forth herein, will in all circumstances,
regardless of when the separation from service occurs, be paid within the Short-Term Deferral Period (as hereinafter defined) shall be treated as a short-term deferral
within the meaning of Treasury Regulation Section 1.409A-1(b)(4) to the maximum extent permissible under Section 409A. For purposes of this Agreement, the “Short-
Term Deferral Period” means the period ending on the later of the 15th day of the third month following the end of the Eligible Employee’s tax year in which the Eligible
Employee’s separation from service occurs and the 15th day of the third month following the end of the Company’s tax year in which the Eligible Employee’s separation
from service occurs; and
(y) Each installment of the payments and benefits due under Section 4 that is not paid within the Short-Term Deferral Period and that would, absent this subsection,
be paid within the six-month period following the “separation from service” of the Eligible Employee of the Company shall not be paid until the date that is six months
and one day after such separation from service (or, if earlier, the death of the Eligible Employee), with any such installments that are required to be delayed being
accumulated during the six-month period and paid in a lump sum on the date that is six months and one day following the Eligible Employee’s separation from service
and any subsequent installments, if any, being paid in accordance with the dates and terms set forth herein; provided, however, that the preceding provisions of this
sentence shall not apply to any installment of payments and benefits if and to the maximum extent that that such installment is deemed to be paid under a separation pay
plan that does not provide for a deferral of compensation by reason of the application of Treasury Regulation 1.409A-1(b)(9)(iii) (relating to separation pay upon an
involuntary separation from service) or Treasury Regulation 1.409A-1(b)(9)(v) (relating to reimbursements and certain other separation payments). Such payments shall
bear interest at an annual rate equal to the prime rate as set forth in the Eastern edition of the Wall Street Journal on the Date of Termination, from the Date of
Termination to the date of payment. Any installments that qualify for the exception under Treasury Regulation Section 1.409A-1(b)(9)(iii) must be paid no later than the
last day of the second taxable year of the Eligible Employee following the taxable year of the Eligible Employee in which the separation from service occurs.
SECTION 5. OTHER TERMINATIONS
An otherwise Eligible Employee shall NOT be eligible to receive benefits under this Plan if (i) the Eligible Employee’s employment terminates due to death, Disability or any
other reason other than a Qualifying Termination; or (ii) an Eligible Employee’s employment is terminated within thirty (30) days of his or her refusal to accept an offer of
comparable employment by any successor to the Company (provided that “comparable employment” shall mean employment at a business office the location of which is not
violative of Section 2(g)(i), with duties and responsibilities not violative of Section 2(g)(ii) and with a reduction in such Eligible Employee’s base salary not violative of 2(g)(iii)).
SECTION 6. CLAIMS PROCEDURE
    

Ordinarily, severance benefits will be paid to an Eligible Employee without to having to file a claim or take any action other than signing the Release as provided in
Section 4(f) of this Plan and, where applicable, not revoking the Release during the applicable revocation period. If an Eligible Employee believes that he or she is entitled to
severance benefits under the Plan that are not being paid, he or she may submit a written claim for payment to the Company. Any claim for benefits shall be in writing, addressed to
the Company and must be sufficient to notify the Company of the benefit claimed. If such claim is denied, the Company shall within a reasonable period of time provide a written
notice of denial. The notice will include the specific reasons for denial, the provisions of the Plan on which the denial is based, and the procedure for a review of the denied claim.
Where appropriate, it will also include a description of any additional material or information necessary to complete or perfect the claim and an explanation of why that material or
information is necessary. Eligible Employees may request in writing a review of a claim denied by the Company and may review pertinent documents and submit issues and
comments in writing to the Company. The Company shall provide a written decision upon such request for review of a denied claim. The decision of the Company upon such review
shall be final.
SECTION 7. MISCELLANEOUS
The Company reserves the right to amend or terminate this Plan at any time; provided however, that this Plan may not be amended or terminated following the Change in
Control Date; and further provided that Section 4(c) of this Plan shall not be amended without the Eligible Employee’s consent unless the Board determines that the amendment,
taking into account any other related action, would not materially adversely affect the Eligible Employee. This Plan shall be binding upon any surviving entity resulting from a
Change in Control and upon any other person who is a successor by merger, acquisition, consolidation or otherwise to the business formerly carried on by the Company without
regard to whether or not such person actively adopts or formally continues the Plan. The Plan shall be interpreted in accordance with the laws of the Commonwealth of
Massachusetts. The Eligible Employee hereby irrevocably submits to and acknowledges and recognizes the jurisdiction of the courts of the Commonwealth of Massachusetts, or if
appropriate, a federal court located in Massachusetts (which courts, for purposes of the Plan, are the only courts of competent jurisdiction), over any suit, action or other proceeding
arising out of, under or in connection with the Plan or the subject matter hereof.
 
    

November 12, 2021
Jebediah Ledell
36 Village View Rd Westford, MA, 01886
Dear Jeb:
It is with great pleasure that we extend you this offer of employment to join AVEO Pharmaceuticals, Inc. (the "Company" or "AVEO"). The following letter sets
forth the proposed terms and conditions of your offer of employment.
Position. Your position, conditioned on approval by the Company's Board of Directors (the "Board"), will be Chief Operating Officer reporting to me as Chief
Executive Officer. If you accept this offer, your employment with the Company shall commence on a mutually agreed upon date (the "Start Date"). You will be
employed to serve on a full-time basis. You will work out of our Boston office (or remotely depending on circumstances related to the pandemic). You will be
responsible for the duties customarily associated with this position, plus such other duties as may from time to time be assigned to you by the Company.
Compensation:
•
Base Salary. Your base salary will be at the annualized rate of $450,000 paid semi-monthly in accordance with the Company's standard payroll practices.
•
Discretionary Incentive Bonus. Beginning in 2022, you will be eligible to participate in AVEO's performance-based incentive bonus program. Your bonus
target is 40% of your annualized base salary and is subject to corporate and individual performance assessments, both as determined by the Board and/or the
Compensation Committee of the Board in its sole discretion. Payment of the annual bonus requires approval by the Board and/or the Compensation Committee
and is pro-rated based on your Start Date. You must be an active employee of the Company on the date any bonus is distributed in order to be eligible for and
to earn any bonus award. No bonus shall be considered earned until it is paid, as it also serves as an incentive to remain employed by the Company. Any such
bonus will be paid on or before March 15  of the calendar year following the applicable performance year to which it relates.
•
One Time Bonus. You will receive a one time bonus of $50,000 (the "One Time Bonus") to be paid during the 2021 compensation review cycle and paid on or
before March 15, 2022. In the event that you are no longer employed by the Company, or a successor or affiliate of the Company due to a change in control of
the Company, on or before December 31, 2022, the Company may recover the One Time Bonus up and until December 31, 2023. The Board will determine, in
its discretion, the method for recouping the One Time Bonus, which may include,: (a) requiring reimbursement of cash incentive compensation previously
paid; (b) seeking recovery of any gain realized on the vesting, exercise, settlement, sale, transfer or
other disposition of any equity-based awards; (c) offsetting the recouped amount from any compensation otherwise owed by the Company to you; (d)
cancelling outstanding vested or unvested equity awards; and/or (e) taking any other remedial and recovery action permitted by law, as determined by the
Board.
•
Stock Options. Subject to approval of the Company's Compensation Committee, the Company shall grant you stock options to purchase 170,000 shares of
common stock of the Company (the "Option"), pursuant to the Company's 2019 Equity Incentive Plan. The Options will vest over 4
th

years from your hire date with 25% of the options vesting after 12 months and the remainder on a monthly basis thereafter.
You will be also eligible to participate in the Company's annual renewal equity program. Subject to the Company's Option Committee approval, your renewal
incentive stock options will be based on your performance and pro-rated to your effective date of employment. The renewal options will vest on a monthly
basis over 4 years from the grant date.
All options shall be subject to all terms, vesting schedules and other provisions set forth in the respective option plan and in a separate option agreement. Any
compensation paid to you will be less all applicable deductions, taxes, and other amounts required to be withheld in accordance with applicable law.
Benefits. You may participate in any and all benefit programs that the Company establishes and makes available to its employees from time to time, provided that
you are eligible under (and subject to all provisions of) the plan documents that govern those programs. The Company currently offers family health, dental,
individual life, and disability insurance, a 401(k) savings plan, 15 days of paid vacation per year accrued on per pay period basis (vacation may be taken at such
times as may be approved by the Company and is subject to all terms of the Company's vacation policy), paid holidays, flexible spending accounts for eligible
medical and dependent care expenses, and a commuter assistance program. For more details, please refer to the enclosed Benefits Summary.
The benefits made available by the Company, and the rules, terms and conditions for participation in such plans and programs, may be changed by the Company at
any time without advance notice and in the Company's sole discretion.
Severance and Change in Control. Please refer to the document included with this offer of employment entitled Severance and Change in Control Agreement
which is attached hereto with Exhibit A outlining specific Change in Control policies and incorporated herein by reference.
Contingencies. Your offer of employment is contingent upon AVEO's review and determination of a successful completion of a background investigation, which
may include an evaluation of both your credit and criminal history. You will be required to execute authorizations for the Company to obtain consumer reports
and/or investigative consumer reports and use them in conducting background checks as a condition to your employment. The Company may obtain background
check reports both pre-employment and from time to time during your employment with the Company, as it deems necessary.
As a condition of your employment and prior to your Start Date, you will be required to sign the Invention and Non-Disclosure Agreement attached hereto as
Exhibit B.
Further, the Federal government requires you to provide proper identification verifying your eligibility to work in the United States. Please bring documents
necessary to complete the Employment Eligibility Verification Form I-9 on your first date of employment. Refer to the enclosed Form I-9 for a list of acceptable
documents.
Other. As a full-time employee we expect that you will devote your full-:time professional efforts to the business and affairs of AVEO and, accordingly, will not
pursue any other employment or business opportunities outside of the Company unless approved by your management and Human Resources.
As an employee of the Company, you agree to abide by the rules, regulations, instructions, personnel practices and policies of the Company, and any changes
therein that may be adopted from time to

time by the Company. Violations of such policies may lead to immediate termination of your employment. Further, the Company's premises, including all
documents and other tangible materials therein, and all information technology resources of the Company (including computers, electronic files, and all internet
and email), are subject to oversight and inspection by the Company at any time. Company employees should have no expectation of privacy with regard to any
Company premises, documents, materials, information or technology resources.
Miscellaneous. This letter shall not be construed as an agreement, either express or implied, to employ you for any stated term, and shall in no way alter the
Company's policy of employment at-will, under which both the Company and you remain free to end the employment relationship for any reason, at any time, with
or without cause or notice. Although your job duties, title, compensation and benefits, as well as the Company's personnel policies and procedures, may change
from time to time, the "at-will" nature of your employment may only be changed by a written agreement signed by you and the Chief Executive Officer, or a
member of the Board, which expressly states the intention to modify the at-will nature of your employment. Similarly, nothing in this letter, except to the extent set
forth in the Severance and Change in Control Agreement, which is incorporated herein by reference, shall be construed as an agreement, either express or implied,
to pay you any compensation or grant you any benefit beyond the end of your employment with the Company.
Please be advised that AVEO is hiring you because of your general skills and abilities, and not because of your possession or knowledge of protectable,
confidential, or trade secret information belonging to a previous employer. In fact, the Company prohibits you from directly or indirectly using or disclosing such
information in connection with your employment at the Company. You agree that while performing your responsibilities for the Company, you will not breach any
obligations owed to previous employers involving such information, including any
confidentiality, non-competition or non-solicitation agreement. You represent that you are not bound by any employment contract, restrictive covenant or other
restriction preventing you from entering into employment with or carrying out your responsibilities for the Company, or which is in any way inconsistent with the
terms of this offer letter.
This letter, together with the Severance and Change in Control Agreement and the Invention and Non-Disclosure Agreement to be executed by you and the
Company, constitutes our entire offer regarding the terms and conditions of your prospective employment by the Company. It supersedes any prior agreements, or
other promises or statements (whether oral or written) regarding the offered terms of employment.
If you decide to accept the terms of this letter, please sign and scan the fully executed documents to cgallagher@aveooncology.com. This offer of employment is
valid until Monday, November 15, 2021.
Jeb, we are very excited about having you join AVEO and have every expectation of a productive and rewarding relationship together. If you have any questions
regarding this offer, please call Colleen Gallagher at 617-803-4780.
Very truly yours,
/s/ Michael Bailey
Michael Bailey
President and Chief Executive Officer

The foregoing correctly sets forth the terms and conditions of my employment by AVEO. I am not relying on any other oral or written representations other than
as set forth above in this letter.
     /s/ Jebediah Ledell                11/15/2021
     By: Jebediah Ledell                Date

SEVERANCE AND CHANGE IN CONTROL AGREEMENT
.    THIS SEVERANCE AND CHANGE IN CONTROL AGREEMENT (the "Agreement"), made this
15 day of November 2021 (the "Effective Date"), is entered into by AYEO Pharmaceuticals, Inc., a Delaware corporation with its principal place of business at 30 Winter Street
Boston, MA 02108 (the "Company"), and Jebediah Ledell (the "Employee") with a address at 36 Village View Rd., Westford, MA, 01886.
WHEREAS, the Company has determined that appropriate steps should be taken to reinforce and encourage the employment and dedication of the Employee and the
Employee's efforts to maximize the Company's value.
NOW, THEREFORE, as an inducement for and in consideration of the Employee's continued employment with the Company and as consideration for the Employee's
agreement to enter into and be bound by the provisions of Section 4 hereof, the Company agrees that the Employee shall receive the severance benefits set forth in this Agreement
in the event the Employee's employment with the Company is terminated under the circumstances described below.
1. Key Definitions.
As used herein, the following terms shall have the following respective meanings:
1.1
"Cause" means conduct involving one or more of the following: (i) the conviction of the Employee of, or, plea of guilty or nolo contendere to, any crime
involving dishonesty or any felony;
(ii) the willful misconduct by the Employee resulting in material hann to the Company; (iii) fraud, embezzlement, theft or dishonesty by the Employee against the Company
resulting in material harm to the Company; (iv) the repeated and continuing failure of the Employee to follow the proper and lawful directions of the Company's Chief Executive
Officer or the Board after a written demand is delivered to the Employee that specifically identifies the manner in which the Chief Executive Officer or the Board believes that the
Employee has failed to follow such instructions; (v) the Employee's current alcohol or prescription drug abuse affecting work performance, or current illegal use of drugs regardless
of the effect on work performance; (vi) material violation of the Company's code of conduct by the Employee that causes harm to the Company; or (vii) the Employee's material
breach of any term of the Agreement, or any other applicable confidentiality and/or non-competition agreements with the Company.
1.2
"Good Reason" means the occurrence, without the Employee's written consent, of any of the following events: (A) any material diminution in the Employee's
duties, responsibilities or authority, or
(B) a material reduction in the Employee's base salary (unless such reduction is effected in connection with a general and proportionate reduction of compensation for all
employees of his or her level), provided, however, that Good Reason can only occur if (i) the Employee has given the Company a written notice of termination indicating the
existence of a condition giving rise to Good Reason and the Company has not cured the condition giving rise to Good Reason within thirty (30) days after receipt of such notice of
termination, and (ii) such notice of termination is given within ninety (90) days after the initial occurrence of the condition giving rise to Good Reason and further provided that a
termination for Good Reason shall occur no more than one hundred eighty (180) days after the initial occurrence of the condition giving rise to Good Reason.
1.3
"Disability" means (i) the Employee is unable to engage in any substantial gainful activity by reason of any medically determinable physical or mental
impairment that can be expected to result in death or can be expected to last for a continuous period of not less than twelve (12) months or (ii) the Employee is, by reason of any
medically determinable physical or mental impairment that can be

expected to result in death or can be expected to last for a continuous period of not less than twelve
(12) months, receiving income replacement benefits for a period of not less than three (3) months under an accident and health plan covering employees of the Company; provided
that in each case, the Employee's physical or mental impairment shall be determined by an independent qualified physician mutually acceptable to the Company and the Employee
(or his personal representative) or, if the Company and the Employee (or such representative) are unable to agree on an independent qualified physician, as determined by a panel
of three physicians, one designated by the Company, one designated by the Employee (or his personal representative) and one designated by the two physicians so designated.
2. Termination Without Cause or for Good Reason.
2.1
Other than as set forth in Section 3 below, if the Employee's employment with the Company is terminated by the Company without Cause or due to the
Employee's Disability, or by the Employee for Good Reason, then the Company shall:
(a) continue to pay the Employee his base salary in effect on the date of termination, to be paid in accordance with the Company's customary payroll practices as are
established or modified from time to time for the period of time (the "Severance Period")
until the earlier of (x) the date twelve (12) months following the date of termination, or
(y) the date on which the Employee commences employment or a consulting relationship with substantially equivalent compensation;
(b)pay to the Employee (i) on the date of termination, any base salary earned but not paid and any vacation accrued but not used through the date of termination, and
(ii) within thirty (30) days after the date of termination, any reimbursable business expenses incurred by the Employee through the date of termination pursuant to any
expense reimbursement policies of the Company then in effect; and
(c) to the extent the Employee and any qualified beneficiary with respect to such Employee elects continuation of health benefit coverage under Section 4980B
("COBRA") of the Internal Revenue Code of 1986, as amended (the "Code"), and continues to be eligible for such benefits, the Company shall provide payments to the
Employee for such benefits equal to the amount contributed for active employees with similar benefits and similar participating beneficiaries until the earlier of
(x) the Severance Period, or (y) the date the Employee becomes eligible for group health coverage through another employer.
2.2
Except for the payments under Section 2(b) (which are not contingent upon the Employee's execution of a release of claims), the payments and benefits to the
Employee under this Section 2 shall
(i)
be contingent upon the execution and non-revocation by the Employee of a general release of claims in favor of the Company, in the form provided by the Company at the
time of the Employee's termination (the "Release") within sixty (60) days following the date of termination (the "Release Period"); provided that if the Release does not become
effective during the Release Period, the payments and benefits described in Sections 2.l(a) and 2.l(c) of this Agreement that commenced following the date of termination shall
cease following the Release Period and (ii) constitute the sole remedy of the Employee in the event of a termination of the Employee's employment in the circumstances set forth in
this
Section 2.
2.3
Notwithstanding anything herein to the contrary, all benefits under this Section 2 shall terminate immediately if the Employee, at any time, violates any proprietary
information, assignment of inventions agreement, confidentiality, non-competition or non-solicitation obligation to the Company, or any other continuing obligation to the
Company.

3. Termination upon a Change in Control.
If the Employee is an "Eligible Employee" as defined in the Key Employee Change in Control Benefits Plan adopted by the Company in December 2007, as amended and as
may be amended in the future (the current terms of which are attached hereto as Exhibit A) (the "Change in Control Plan") at the time ofa Change in Control, as defined in said
Change in Control Plan, then any termination of the Employee's employment following such Change in Control shall be governed by the terms of the Change in Control Plan and
no benefits shall be provided under the terms of this Agreement.
4. Non-Competition and Non-Solicitation.
4.1 Restricted Activities. While the Employee is employed by the Company and for a period of one
(1) year after the termination or cessation of such employment for any reason, the Employee will not:
(a) directly engage in the development or commercialization of a Competitive Product for another business or enterprise. For purposes of this provision, a
"Competitive Product" means any therapeutic or diagnostic product that competes with any product that the Company (i) has, as of the date of cessation of the Employee's
employment with the Company, developed to the stage of readiness for a phase 2 clinical trial or later; or (ii) has sold at any time during the Employee's employment with the
Company or plans to commence selling during the one year period after the cessation of the Employee's employment;
(b) directly or indirectly either alone or in association with others (i) solicit, or permit any organization directly or indirectly controlled by the Employee to solicit, any
employee of the Company to leave the employ of the Company, or (ii) solicit for employment, hire as an employee or engage as an independent contractor, or permit any
organization directly or indirectly controlled by the Employee to solicit for employment, hire as an employee or engage as an independent contractor, any person who was
employed or engaged by the Company at the time of the termination or cessation of the Employee's employment with the Company or within six months preceding such
termination or cessation; provided, that this clause (ii) shall not apply to the solicitation, hiring or engagement of any individual whose employment with the Company has
been terminated for a period of six months or longer; or
(c) directly or indirectly make any statements that are professionally or personally disparaging about, or adverse to, the interests of the Company (including its officers,
directors, employees and consultants) including, but not limited to, any statements that disparage any person, product, service, finances, financial condition, capability or any
other aspect of the Company's business, or engage in any conduct which could reasonably be expected to harm professionally or personally the Company's business or
reputation (including its officers, directors, employees and consultants); provided that these obligations in Section 4.1(c) will not prevent the Employee from engaging in
ordinary business competition with the Company after the provisions of Section 4.1(a) have expired, providing truthful information to any regulatory agency or providing
truthful testimony in any litigation involving the Company or its officers, directors, employees and consultants.
If the Employee violates or breaches any of the provisions of this Section 4.1, then the provisions of this Section 4 shall be applicable to the Employee until a period of one
year has expired without any violation or breach of such provisions.
4.2
Interpretation. If any restriction set forth in Section 4.1 is found by any court of competent jurisdiction to be unenforceable because it extends for too long a period
of time or over too great a range of activities or in too broad a geographic area, it shall be interpreted to extend only over the maximum period of time, range of activities or
geographic area as to which it may be enforceable.

1.3
Equitable Remedies. The restrictions contained in this Section 4 are necessary for the protection of the business and goodwill of the Company and are considered
by the Employee to be reasonable for such purpose. The Employee agrees that any breach of this Section 4 is likely to cause the Company substantial and irrevocable damage
which is difficult to measure. Therefore, in the event of any such breach or threatened breach, the Employee agrees that the Company, in addition to such other remedies which
may be available, shall have the right to obtain an injunction from a court restraining such a breach or threatened breach and the right to specific performance of the provisions of
this Section '4 and the Employee hereby waives the adequacy of a remedy at law as a defense to such relief.
5. Taxes.
5.1
The payments set forth in Sections 2 and 3 above shall be subject to the withholding of such amounts, if any, relating to tax and other payroll deductions as the
Company determines are reasonably required pursuant to any applicable law or regulation. Neither the Employee nor the Company shall have the right to accelerate or to defer the
delivery of the payments to be made under Sections 2 and 3 of this Agreement.
5.2
Subject to this Section 5.2, payments or benefits under this Agreement shall begin only upon the date of a "separation from service" of the Employee (determined as
set forth below) which occurs on or after the termination of the Employee's employment. The following rules shall apply with respect to distribution of the payments and benefits,
if any, to be provided to the Employee under this Agreement:
(a) It is intended that each installment of the payments and benefits provided under this Agreement shall be treated as a separate "payment" for purposes of Section
409A of the Code and the guidance issued thereunder ("Section 409A"). Neither the Company nor the Employee shall have the right to accelerate or defer the delivery of
any such payments or benefits except to the extent specifically permitted or required by Section 409A;
(b) If, as of the date of the "separation from service" of the Employee from the Company, the Employee is not a "specified employee" (each within the meaning of
Section 409A), then each installment of the payments and benefits shall be made on the dates and tenns set forth in this Agreement;
(c) If, as of the date of the "separation from service" of the Employee from the Company, the Employee is a "specified employee" (each, for purposes of this
Agreement, within the meaning of Section 409A), then:
(x)
Each installment of the payments and benefits due under this Agreement that, in accordance with the dates and terms set forth herein, will in all
circumstances, regardless of when the separation from service occurs, be paid within the short-term deferral period (as defined in Section 409A) shall be treated as a
short-term deferral within the meaning of Treasury Regulation Section l.409A-l(b)(4) to the maximum extent permissible under Section 409A; and
(y)
Each installment of the payments and benefits due under this Agreement that is not described in Section 5(c)(x) and that would, absent this subsection, be
paid within the six month period following the "separation from service" of the Employee of the Company shall not be paid until the date that is six months and one day
after such separation from service (or, if earlier, the death of the Employee), with any such installments that are required to be delayed being accumulated during the six-
month period and paid in a lump sum on the date that is six months and one day following the Employee's separation from service and any subsequent installments, if
any, being paid in accordance with the dates and terms set forth herein; provided, however, that the preceding provisions of this sentence shall not apply to any
installment of payments and benefits if and to the maximum extent that that such installment is deemed to be paid under a separation pay plan that does not provide for a
deferral of

compensation by reason of the application of Treasury Regulation l.409A-l(b)(9)(iii) (relating to separation pay upon an involuntary separation from service). Such
payments shall bear interest at an annual rate equal to the prime rate as set forth in the Eastern edition of the Wall Street Journal on the Date of Termination, from the
Date of Termination to the date of payment. Any installments that qualify for the exception under Treasury Regulation
Section l.409A-l (b)(9)(iii) must be paid no later than the last day of the second taxable year of the Employee following the taxable year of the Employee in which the
separation from service occurs.
(d) The determination of whether and when a separation from service of the Employee from the Company has occurred shall be made and in a manner consistent with,
and based on the presumptions set forth in, Treasury Regulation Section l.409A-1(h). Solely for purposes of this Section S(d), "Company" shall include all persons with
whom the Company would be considered a single employer as determined under Treasury Regulation Section 1.409A-1(h)(3).
(e) All reimbursements and in-kind benefits provided under this Agreement shall be made or provided in accordance with the requirements of Section 409A to the
extent that such reimbursements or in-kind benefits are subject to Section 409A, including, where applicable, the requirements that (i) any reimbursement is for expenses
incurred during the Executive's lifetime (or during a shorter period of time specified in this Agreement), (ii) the amount of expenses eligible for reimbursement during a
calendar year may not affect the expenses eligible for reimbursement in any other calendar year, (iii) the reimbursement of an eligible expense will be made on or before the
last day of the calendar year following the year in which the expense is incurred and (iv) the right to reimbursement is not subject to set off or liquidation or exchange for any
other benefit.
(f) Notwithstanding anything herein to the contrary, the Company shall have no liability to the Employee or to any other person if the payments and benefits provided
in this Agreement that are intended to be exempt from or compliant with Section 409A are not so exempt or compliant.
6.
Other Employment Termination. If the Employee's employment terminates for any reason other than as described in Sections 2 and 3, the Employee shall only
receive any compensation owed to such Employee as of the termination date and any other post-termination benefits which the Employee is eligible to receive under any plan or
program of the Company.
7. Successors.
7.1 Successor to Company. The Company shall require any successor (whether direct or indirect, by purchase, merger, consolidation or otherwise) to all or substantially all of
the business or assets of the Company expressly to assume and agree to perform this Agreement to the same extent that the Company would be required to perform it if no such
succession had taken place. All covenants and agreements hereunder shall inure to the benefit of and be enforceable by such successors or assigns without the necessity that this
Agreement be re-signed at the time of such assignment. As used in this Agreement, "Company" shall mean the Company as defined above and any successor to its business or
assets as aforesaid which assumes and agrees to perform this Agreement, by operation of law or otherwise.
7.2 Successor to Employee. This Agreement shall inure to the benefit of and be enforceable by the Employee's personal or legal representatives, executors, administrators,
successors, heirs, distributees, devisees and legatees. If the Employee should die while any amount would still be payable to the Employee or the Employee's family hereunder if
the Employee had continued to live, all such amounts, unless otherwise provided herein, shall be paid in accordance with the terms of this Agreement to the executors, personal
representatives or administrators of the Employee's estate.
8.
Notices. All notices, instructions and other communications given hereunder or in connection herewith shall be in writing. Any such notice, instruction or
communication shall be sent either (i) by

registered or certified mail, return receipt requested, postage prepaid, or (ii) prepaid via a reputable nationwide overnight courier service, in each case addressed to the Company, at
l Broadway 14  Floor, Cambridge, MA 02142, ATIN: Michael Bailey, Chief Executive Officer, and to the Employee at the Employee's address indicated in the introduction to this
Agreement (or to such other address as either the Company or the Employee may have furnished to the other in writing in accordance herewith). Any such notice, instruction or
communication shall be deemed to have been delivered five business days after it is sent by registered or certified mail, return receipt requested, postage prepaid, or one business
day after it is sent via a reputable nationwide overnight courier service. Either party may give any notice, instruction or other communication hereunder using any other means, but
no such notice, instruction or other communication shall be deemed to have been duly delivered unless and until it actually is received by the party for whom it is intended.
9. Miscellaneous.
9.1
Employment by Subsidiary. For purposes of this Agreement, the Employee's employment with the Company shall not be deemed to have terminated solely as a
result of the Employee continuing to be employed by a wholly owned subsidiary of the Company.
9.2
Severability. The invalidity or unenforceability of any provision of this Agreement shall not affect the validity or enforceability of any other provision of this
Agreement, which shall remain in full force and effect.
9.3
Governing Law. The validity, interpretation, construction and performance of this Agreement shall be governed by the internal laws of the Commonwealth of
Massachusetts, without regard to conflicts of law principles. The Employee hereby irrevocably submits to and acknowledges and recognizes the jurisdiction of the courts of the
Commonwealth of Massachusetts, or if appropriate, a federal court located in Massachusetts (which courts, for purposes of this Agreement, are the only courts of competent
jurisdiction), over any suit, action or other proceeding arising out of, under or in connection with
this Agreement or the subject matter hereof.
9.4
Waiver of Right to Jury Trial. Both the Company and the Employee expressly waive any right that any party either has or may have to a jury trial of any dispute
arising out of or in any way related to the matters covered by this Agreement.
9.5
Waivers. No waiver by the Employee at any time of any breach of, or compliance with, any provision of this Agreement to be performed by the Company shall
be deemed a waiver of that or any other provision at any subsequent time.
9.6
Counterparts. This Agreement may be executed in counterparts, each of which shall be deemed to be an original but both of which together shall constitute one
and the same instrument.
9.7
Entire Agreement. Except to the extent provided herein, this Agreement, together with the Offer Letter dated November 12, 2021 and the Invention and Non-
Disclosure Agreement, sets forth the entire agreement of the parties hereto in respect of the subject matter contained herein and supersedes all prior agreements, promises,
covenants, arrangements, communications, representations or warranties, whether oral or written, by any officer, employee or representative of any party hereto in respect of the
subject matter contained herein.
9.8
Not an Employment Contract. The Employee acknowledges that this Agreement does not constitute a contract of employment or impose on the Company any
obligation to retain the Employee as an employee and that this Agreement does not prevent the Employee from terminating employment at any time.
th

9.9
Amendments. This Agreement may be amended or modified only by a written instrument executed by both the Company and the Employee, and,
notwithstanding the provisions of the Change in Control Plan, the language of such Change in Control Plan may not be amended as it applies to the Employee except to the
extent subject to a written instrument executed by both parties.
9.10
Employee's Acknowledgements. The Employee acknowledges that he: (a) has read this Agreement; (b) has been represented in the preparation, negotiation and
execution of this Agreement by legal counsel of the Employee's own choice or has voluntarily declined to seek such counsel; and
(c) understands the terms and consequences of this Agreement.
9.11
Representations Regarding Prior Work. You represent that you have no agreement or other legal obligation with any prior employer or any other person or entity
that restricts your ability to engage in employment discussion with, employment with or to perform function for, the Company. You represent that you have been advised by the
Company that at no time should you divulge to or use for the benefit of the Company, any trade secret or proprietary information of any previous employer. You acknowledge that
you have not divulged or used any such information for the benefit of the Company. You acknowledge that the Company is basing important business decision on these
representations, affirm that all of the statements included herein are true and that any breach of this Section 9.11 would be considered a material breach of this Agreement.
[Remainder of page intentionally left blank]

IN WITNESS WHEREOF, the parties hereto have executed this Agreement as of the day and year set forth above.
AVEO Pharmaceuticals, Inc.
By: /s/ Michael Bailey                     /s/ Jebediah Ledell        
Michael Bailey                    Jebediah Ledell
Title: President & CEO

EXHIBIT A
AVEO PHARMACEUTICALS, INC.
KEY EMPLOYEE CHANGE IN CONTROL BENEFITS PLAN
SECTION 1. INTRODUCTION
The Key Employee Change in Control Benefits Plan (the "Plan") is designed to provide separation pay and benefits to certain eligible employees of AYEO Pharmaceuticals,
Inc. ("the "Company") whose employment is involuntarily terminated without cause or voluntarily terminated for good reason as set forth in this Plan.
SECTION 2. DEFINITIONS
For purposes of this Plan, the following terms shall have the meanings set forth below:
(a)
"BASE SALARY" means the annual base salary for an Eligible Employee as in effect on the Change in Control Date, or as increased thereafter.
(b) "BOARD" means the Board of Directors of the Company.
(c)
"CAUSE" means conduct involving one or more of the following: (i) the conviction of the Eligible Employee of, or, plea of guilty or nolo contendere to, any
crime involving dishonesty or any felony; (ii) the willful misconduct by the Eligible Employee resulting in material harm to the Company;
(iii)
fraud, embezzlement, theft or dishonesty by the Eligible Employee against the Company resulting in material harm to the Company; (iv) the repeated and continuing failure
of the Eligible Employee to follow the proper and lawful directions of the Company's Chief Executive Officer or the Board after a written demand is delivered to the Eligible
Employee that specifically identifies the manner in which the Chief Executive Officer or the Board believes that the Employee has failed to follow such instructions; (v) the Eligible
Employee's current alcohol or prescription drug abuse affecting work performance, or current illegal use of drugs regardless of the effect on work performance; (vi) material
violation of the Company's code of conduct by the Eligible Employee that causes harm to the Company; or (vii) the Eligible Employee's material breach of any term of the Plan or
any applicable written proprietary information, confidentiality, non-competition and/or non-solicitation agreements with the Company.
(d) "CHANGE IN CONTROL" means the occurrence of any of the events set forth in subsections
(A)
or (B) below, provided that such event(s) constitute (i) a change in the ownership of the Company (as defined in Treasury Regulation Section l.409A-3(i)(5)(v)), (ii) a change
in effective control of the Company (as defined in Treasury Regulation Section l.409A-3(i)(5)(vi)), or (iii) a change in the ownership of a substantial portion of the assets of the
Company (as defined in Treasury Regulation Section l .409A-3(i)(5)(vii)):
(A)when a person, entity or group (within the meaning of Section 13(d)(3) or 14(d)(2) of the Securities Exchange Act ofl934, a amended) acquires beneficial
ownership of the Company's capital stock equal to 50% or more of either: (X) the then-outstanding shares of the Company's common stock (the "Outstanding Company
Common Stock") or (Y) the combined voting power of the Company's then-outstanding securities entitled to vote generally in the election of directors (the "Outstanding
Company Voting Securities") provided, however, that for purposes of this subsection (A), the following acquisitions of securities shall not constitute a Change in Control: (1)
any acquisition of securities directly from the Company (excluding an acquisition of securities pursuant to the exercise, conversion or exchange of any security exercisable
for, convertible into or

exchangeable for common stock or voting securities of the Company, unless the Person exercising, converting or exchanging such security acquired such security directly
from the Company or an underwriter or agent of the Company) or (2) any acquisition of securities by the Company; or
(B) upon the consummation by the Company of a reorganization, merger, consolidation, statutory share exchange or a sale or other disposition of all or substantially all
of the assets of the Company in one or a series of transactions (a "Business Combination"), provided that, in each case, the persons who were the Company's beneficial
owners of the Outstanding Company Common Stock and Outstanding Company Voting Securities immediately prior to such Business Combination do not beneficially own,
directly or indirectly, more than 50% of the then-outstanding shares of common stock and the combined voting power of the then-outstanding securities entitled to vote
generally in the election of directors, respectively, of the resulting or acquiring corporation in such Business Combination (which shall include, without limitation, a
corporation which as a result of such transaction owns the Company or substantially all of the Company's assets either directly or through one or more subsidiaries) in
substantially the same proportions as their ownership, immediately prior to such Business Combination, of the Outstanding Company Common Stock and Outstanding
Company Voting Securities, respectively; or
(C) such time as the Continuing Directors (as defined below) do not constitute a majority of the Board (or, if applicable, the Board of Directors of a successor
corporation to the Company), where the term "Continuing Director" means at any date a member of the Board (i) who was a member of the Board on the effective date of this
Plan, or (ii) who was nominated or elected subsequent to such date by at least a majority of the directors who were Continuing Directors at the time of such nomination or
election or whose election to the Board was recommended or endorsed by at least a majority of the directors who were Continuing Directors at the time of such nomination
or election; provided, however, that there shall be excluded from this clause (ii) any individual whose initial assumption of office occurred as a result of an actual or
threatened election contest with respect to the election or removal of directors or other actual or threatened solicitation of proxies or consents, by or on behalf of a person
other than the Board.
(e) "CHANGE IN CONTROL DATE" means the first date on which a Change in Control occurs.
(t) "DISABILITY" means (i) the Eligible Employee is unable to engage in any substantial gainful activity by reason of any medically determinable physical or mental
impairment that can be expected to result in death or can be expected to last for a continuous period of not less than twelve (12) months or
(ii) the Eligible Employee is, by reason of any medically determinable physical or mental impairment that can be expected to result in death or can be expected to last for a
continuous period of not less than twelve
(12) months, receiving income replacement benefits for a period of not less than three (3) months under an accident and health plan covering employees of the Company; provided
that in each case, the Eligible Employee's physical or mental impairment shall be determined by an independent qualified physician mutually acceptable to the Company and the
Eligible Employee (or his personal representative) or, if the Company and the Eligible Employee (or such representative) are unable to agree on an independent qualified
physician, as determined by a panel of three physicians, one designated by the Company, one designated by the Eligible Employee (or his personal representative) and one
designated by the two physicians so designated.
(g) "INVOLUNTARY TERMINATION WITHOUT CAUSE" means an Eligible Employee's dismissal or discharge by the Company (or, if applicable, by any successor
entity) for a reason other than Cause. The termination of employment will not be deemed to be an "Involuntary Termination Without Cause" if such termination occurs as a result of
the Eligible Employee's voluntary resignation without Good Reason, death or Disability.

(i) "MANAGEMENT TEAM" shall include any executive officer, senior vice-president and vice president of the Company and other employees of the Company nominated
by the Chief Executive Officer and ratified by the Compensation Committee.
G) "QUALIFYING TERMINATION" means that an Eligible Employee's employment terminates due to an Involuntary Termination Without Cause or a Voluntary
Termination for Good Reason, in either case, within eighteen (18) months following a Change in Control Date.
(k)
"SECTION 16 OFFICER" means an executive officer of the Company, other than the Chief Executive Officer, Chief Financial Officer, Chief Business Officer and
Chief Medical Officer, who is considered to be an "officer" of the Company within the meaning of Rule 16a-l(f) under the Securities Exchange Act of 1934, as amended and
"executive Officer" of the Company within the meaning of Rule 3b-7 under the Securities Exchange Act of 1934, as amended.
(I)
"VOLUNTARY TERMINATION FOR GOOD REASON" means any action by the Company without the Eligible Employee's prior consent which results in he or
she voluntarily terminating his or her employment with the Company (or, ifapplicable, with any successor entity) after any of the following are undertaken by the Company (or, if
applicable, by any successor entity) without such Eligible Employee's express consent, provided, however, that a termination for Good Reason can only occur if (i) the Eligible
Employee has given the Company a written notice of termination indicating the existence of a condition giving rise to Good Reason and the Company has not cured the condition
giving rise to Good Reason within thirty (30) days after receipt of such notice of termination, and (ii) such notice of termination is given within ninety (90) days after the initial
occurrence of the condition giving rise to Good Reason and further provided that a termination for Good Reason shall occur no more than one hundred eighty
(180) days after the initial occurrence of the condition giving rise to Good Reason: (A) any requirement by the Company that the Eligible Employee perform his or her principal
duties outside a radius of 50 miles from the Company's Cambridge, Massachusetts location, (B) any material diminution in the Eligible duties, responsibilities or authority; or (C)
a material reduction in the Eligible Employee's base salary (unless such reduction is effected in connection with a general and proportionate reduction of compensation for all
employees of his or her level).
SECTION 3. ELIGIBILITY AND PARTICIPATION
An individual is deemed an "Eligible Employee" and, therefore, eligible to participate in the Plan if he or she is a member of the Company's Management Team at the time
of such individual's termination of employment with the Company, and such employment terminates due to an event which constitutes a Qualifying Termination.
SECTION 4. BENEFITS
Eligible Employees are eligible to receive the following benefits on the following conditions:
(a)
SALARY AND BONUS PAYOUT. Commencing in the first month following the month ofa Qualifying Termination and the Release set forth in Section (f) below
becoming binding on the Eligible Employee, Eligible Employee will be paid in periodic installments consistent with the Company's payroll procedures as then in effect and
continuing for a number of months equal to the product of the Eligible Employee's "Severance Multiple" (as set forth below) times twelve (12), a total sum equal to:
(i)
Severance Multiple times the Eligible Employee's Base Salary; (ii) the Eligible Employee's Severance Multiple times his/her target bonus on the date of the Qualifying
Termination; and (iii) the Eligible Employee's target bonus on the date of termination multiplied by a fraction, the numerator of which shall equal the number of days the Eligible
Employee was employed by the Company during the Company fiscal year in which the termination occurs and the denominator of which shall equal 365.

Severance Multiple shall be based on the following:
Chief Executive Officer    1.5
Chief Financial Officer, Chief Business Officer, Chief Medical Officer,
Section 16 Officer, and any other Eligible Employee nominated by the CEO
and ratified by the Compensation Committee    1.0
Senior Vice Presidents, Vice Presidents and other Eligible Employees nominated by CEO and ratified by Compensation Committee, other than
those considered Section 16 Officers    0.5
(b)
HEALTH BENEFITS. Provided the Eligible Employee timely elects continued coverage under federal COBRA law, the Company shall pay, on the Eligible
Employee's behalf, the portion of premiums for the type of group health insurance coverage, including coverage for his or her eligible dependents, that the Company paid prior to
his or her termination of employment for a period following his or her Qualifying Termination based on the Eligible Employee's level as follows:
Chief Executive Officer
Chief Financial Officer, Chief Business Officer, Chief Medical Officer, Section 16
Officer, and any other Eligible Employee nominated by the CEO and ratified by the
Compensation Committee
Senior Vice Presidents, Vice Presidents and other Eligible Employees nominated by
CEO and ratified by Compensation Committee, other than those considered Section
16 Officers
18 months
12 months
6 months
provided, however, that the Company will pay such premiums for the Eligible Employee and his/her eligible dependents only for coverage for which such individual and those
dependents were enrolled immediately prior to the Qualifying Termination. The Eligible Employee shall continue to be required to pay that portion of the premium of such group
health insurance coverage, including coverage for his/her eligible dependents that he/she had been required to pay as an active employee immediately prior to the Qualifying
Termination of employment (subject to change). For the balance of the period that an Eligible Employee is eligible to receive coverage under federal COBRA law, the Eligible
Employee shall be eligible to maintain coverage for himself/herself and his/her eligible dependents at the Eligible Employee's own expense in accordance with applicable law.
(c)
EQUITY ACCELERATION. In addition to any other rights that Eligible Employees may have with respect to the acceleration of the vesting of any stock options or
restricted stock awards ("Awards") granted to such Eligible Employees pursuant to the Company's 2002 Stock Incentive Plan, as amended (the "2002 Stock Incentive Plan"), or any
successor plan, including without limitation those certain change in control related acceleration rights (upon a termination without cause) approved by the Board on December 11,
2007, and notwithstanding any provision to the contrary contained in the 2002 Stock Incentive Plan, the instrument evidencing any Award or any other agreement between an
Eligible Employee and the Company, each such Award shall be immediately exercisable in full and/or free of all restrictions on repurchase, as the case may be, if the Eligible
Employee's employment with the Company or the acquiring or succeeding corporation is terminated as a result of a Qualifying Termination.

(d)
EARNED BUT UNPAID BENEFITS. As of the Qualifying Termination date an Eligible Employee will also be eligible to receive any earned but unpaid benefits
including salary earned but unpaid, the annual bonus for the most recently completed financial year and payment for unused accrued vacation.
(e)
RELEASE. To receive benefits under this Plan, an Eligible Employee must execute a general release of claims in favor of the Company within thirty (30) days
following the Eligible Employee's Qualifying Termination, in a form provided by the Company at the time of the Employee's Qualifying Termination, and such release must
become effective in accordance with its tenns (the "Release"). Notwithstanding the foregoing, if the 30  day following the Eligible Employee's Qualifying Termination occurs in
the calendar year following the Eligible Employee's Qualifying Termination, then the payments and benefits will commence no earlier than January 1 of such subsequent calendar
year.
(f)
TERMINATION OF BENEFITS. Benefits under this Plan shall terminate immediately if an Eligible Employee, at any time, violates any proprietary information,
confidentiality, non-competition or non-solicitation obligation to the Company, or any other continuing obligation to the Company.
(g)
NON-DUPLICATION OF BENEFITS. Eligible Employees are not eligible to receive benefits under this Plan more than one time and are not eligible to receive
benefits under any other Company change in control severance plan, arrangement or agreement.
(h)
TAX WITHHOLDING. Any payments that an Eligible Employee receives under this Plan shall be subject to all required tax withholding.
(i)
DISTRIBUTIONS. The following rules shall apply with respect to distribution of the payments and benefits, if any, to be provided to the Eligible Employee under
this Section 4:
(A)It is intended that each installment of the payments and benefits provided under Section 4 shall be treated as a separate "payment" for purposes of Section 409A of
the U.S. Internal Revenue Code of 1986, as amended, and the guidance issued thereunder ("Section 409A"). Neither the Company nor the Eligible Employee shall have the
right to accelerate or defer the delivery of any such payments or benefits except to the extent specifically permitted or required by Section 409A;
(B)If, as of the date of the "separation from service" of the Eligible Employee from the Company, the Eligible Employee is not a "specified employee" (each within
the meaning of Section 409A), then each installment of the payments and benefits shall be made on the dates and tenns set forth in Section 4; and
(C)If, as of the date of the "separation from service" of the Eligible Employee from the Company, the Eligible Employee is a "specified employee" (each, for
purposes of this Agreement, within the meaning of Section 409A), then:
(x)
Each installment of the payments and benefits due under Section 4 that, in accordance with the dates and tenns set forth herein, will in all circumstances,
regardless of when the separation from service occurs, be paid within the Short-Tenn Deferral Period (as hereinafter defined) shall be treated as a short-tenn deferral
within the meaning of Treasury Regulation Section 1.409A-1(b)(4) to the maximum extent permissible under Section 409A. For purposes of this Agreement, the "Short-
Tenn Deferral Period" means the period ending on the later of the 15th day of the third month following the end of the Eligible Employee's tax year in which the
Eligible Employee's separation from service occurs and the 15th day of the third month following the end of the Company's tax year in which the Eligible Employee's
separation from service occurs; and
(y)
Each installment of the payments and benefits due under Section 4 that is not paid within the Short-Tenn Deferral Period and that would, absent this
subsection, be paid within
th

the six-month period following the "separation from service" of the Eligible Employee of the Company shall not be paid until the date that is six months and one day
after such separation from service (or, if earlier, the death of the Eligible Employee), with any such installments that are required to be delayed being accumulated during
the six-month period and paid in a lump sum on the date that is six months and one day following the Eligible Employee's separation from service and any subsequent
installments, if any, being paid in accordance with the dates and terms set forth herein; provided, however, that the preceding provisions of this sentence shall not apply
to any installment of payments and benefits if and to the maximum extent that that such installment is deemed to be paid under a separation pay plan that does not
provide for a deferral of compensation by reason of the application of Treasury Regulation 1.409A-
l (b)(9)(iii) (relating to separation pay upon an involuntary separation from service) or Treasury Regulation l.409A-l(b)(9)(v) (relating to reimbursements and certain
other separation payments). Such payments shall bear interest at an annual rate equal to the prime rate as set forth in the Eastern edition of the Wall Street Journal on
the Date of Termination, from the Date of Termination to the date of payment. Any installments that qualify for the exception under Treasury Regulation Section
l.409A-l(b)(9)(iii) must be paid no later than the last day of the second taxable year of the Eligible Employee following the taxable year of the Eligible Employee in
which the separation from service occurs.
SECTION 5. OTHER TERMINATIONS
An otherwise Eligible Employee shall NOT be eligible to receive benefits under this Plan if (i) the Eligible Employee's employment terminates due to death, Disability or
any other reason other than a Qualifying Termination; or (ii) an Eligible Employee's employment is terminated within thirty (30) days of his or her refusal to accept an offer of
comparable employment by any successor to the Company (provided that "comparable employment" shall mean employment at a business office the location of which is not
violative of Section 2(g)(i), with duties and responsibilities not violative of
Section 2(g)(ii) and with a reduction in such Eligible Employee's base salary not violative of 2(g)(iii)). SECTION 6. CLAIMS PROCEDURE
Ordinarily, severance benefits will be paid to an Eligible Employee without to having to file a claim or take any action other than signing the Release as provided in Section
4(f) of this Plan and, where applicable, not revoking the Release during the applicable revocation period. If an Eligible Employee believes that he or she is entitled to severance
benefits under the Plan that are not being paid, he or she may submit a written claim for payment to the Company. Any claim for benefits shall be in writing, addressed to the
Company and must be sufficient to notify the Company of the benefit claimed. If such claim is denied, the Company shall within a reasonable period of time provide a written
notice of denial. The notice will include the specific reasons for denial, the provisions of the Plan on which the denial is based, and the procedure for a review of the denied claim.
Where appropriate, it will also include a description of any additional material or information necessary to complete or perfect the claim and an explanation of why that material or
information is necessary. Eligible Employees may request in writing a review of a claim denied by the Company and may review pertinent documents and submit issues and
comments in writing to the Company. The Company shall provide a written decision upon such request for review of a denied claim. The decision of the Company upon such
review shall be final.
SECTION 7. MISCELLANEOUS
The Company reserves the right to amend or terminate this Plan at any time; provided however, that this Plan may not be amended or terminated following the Change in
Control Date; and further provided that Section 4(c) of this Plan shall not be amended without the Eligible Employee's consent unless the Board determines that the amendment,
taking into account any other related action, would not materially

adversely affect the Eligible Employee. This Plan shall be binding upon any surviving entity resulting from a Change in Control and upon any other person who is a successor by
merger, acquisition, consolidation or otherwise to the business formerly carried on by the Company without regard to whether or not such person actively adopts or formally
continues the Plan. The Plan shall be interpreted in accordance with the laws of the Commonwealth of Massachusetts. The Eligible Employee hereby irrevocably submits to and
acknowledges and recognizes the jurisdiction of the courts of
the Commonwealth of Massachusetts, or if appropriate, a federal court located in Massachusetts (which courts, for purposes of the Plan, are the only courts of competent
jurisdiction), over any suit, action or other proceeding arising out of, under or in connection with the Plan or the subject matter hereof.

    
AVEO Pharmaceuticals, Inc.
Executive Severance and Change in Control Benefits Plan 
1.
Establishment of Plan. AVEO Pharmaceuticals, Inc., a Delaware corporation, hereby establishes an unfunded severance benefits plan (the “Plan”) that is
intended to be a welfare benefit plan within the meaning of Section 3(1) of ERISA. The Plan is in effect for Covered Employees who experience a Covered
Termination occurring after the Effective Date and before the termination of the Plan. The Plan supersedes and terminates any and all prior arrangements, plans,
policies, promises, covenants, communications, representations or warranties for severance benefits applying to Covered Employees that may have been in effect
before the Effective Date with respect to any termination that would, under the terms of the Plan, constitute a Covered Termination, including, without limitation, the
Company’s Key Employee Change in Control Benefits Plan, any Severance and Change in Control Agreement between a Covered Employee and the Company, and
the severance benefit provisions of any offer letter or employment agreement between a Covered Employee and the Company (but for the avoidance of doubt, no
other provisions thereof) (collectively, the “Prior Arrangements”).
2.
Purpose. The purpose of the Plan is to establish the conditions under which Covered Employees will receive the severance benefits described herein if
employment with the Company (or its successor in a Change in Control) terminates under the circumstances specified herein. The severance benefits paid under the
Plan are intended to assist Covered Employees in making a transition to new employment and are not intended to be a reward for prior service with the Company.
3.
Definitions. For purposes of this Plan,
(a)
“Base Salary” shall mean, for any Covered Employee, such Covered Employee’s base rate of pay as in effect immediately before a Covered
Termination (or prior to the Change in Control, if greater) and exclusive of any bonuses, overtime pay, shift differentials, “adders,” any other form of
premium pay, or other forms of compensation.
(b)
“Benefits Continuation” shall have the meaning set forth in Section 8(a) hereof.
(c)
“Board” shall mean the Board of Directors of AVEO Pharmaceuticals, Inc.
(d)
“Bonus” shall mean, for any Covered Employee, the target annual bonus established by the compensation committee of the Board that the
employee was eligible to earn for the year in which the Covered Termination occurs (or for the year in which the Change in Control occurs, if greater),
without regard to whether the performance goals applicable to such bonus had been established or satisfied at the date of termination of employment.
(e)
“Cause” shall mean conduct involving one or more of the following: (i) the conviction of the employee of, or, plea of guilty or nolo contendere
to, any crime involving dishonesty or any felony; (ii) the willful misconduct by the employee resulting in material harm to the Company; (iii) fraud,
embezzlement, theft or dishonesty by the employee against the Company resulting in material harm to the Company; (iv) the repeated and continuing failure
of the employee to follow the proper and lawful

directions of the Company’s Chief Executive Officer or the Board after a written demand is delivered to the employee that specifically identifies the manner
in which the Chief Executive Officer or the Board believes that the employee has failed to follow such instructions; (v) the employee’s current alcohol or
prescription drug abuse affecting work performance, or current illegal use of drugs regardless of the effect on work performance; (vi) material violation of the
Company’s code of conduct by the employee that causes harm to the Company; or (vii) the employee’s material breach of any term of any employment
agreement or offer letter with the Company, or any applicable written proprietary information and inventions, nondisclosure, non-competition, non-
solicitation (or similar) agreement(s) with the Company.
(f)
“Change in Control” shall mean the occurrence of any of the events set forth in subsections (A), (B) or (C) below, provided that such event(s)
constitute (i) a change in the ownership of the Company (as defined in Treasury Regulation Section 1.409A-3(i)(5)(v)), (ii) a change in effective control of the
Company (as defined in Treasury Regulation Section 1.409A-3(i)(5)(vi)), or (iii) a change in the ownership of a substantial portion of the assets of the
Company (as defined in Treasury Regulation Section 1.409A-3(i)(5)(vii)): (A) when a person, entity or group (within the meaning of Section 13(d)(3) or
14(d)(2) of the Securities Exchange Act of 1934, as amended) acquires beneficial ownership of the Company’s capital stock equal to 50% or more of either:
(X) the then-outstanding shares of the Company’s common stock (the “Outstanding Company Common Stock”) or (Y) the combined voting power of the
Company’s then-outstanding securities entitled to vote generally in the election of directors (the “Outstanding Company Voting Securities”) provided,
however, that for purposes of this subsection (A), the following acquisitions of securities shall not constitute a Change in Control: (1) any acquisition of
securities directly from the Company (excluding an acquisition of securities pursuant to the exercise, conversion or exchange of any security exercisable for,
convertible into or exchangeable for common stock or voting securities of the Company, unless the Person exercising, converting or exchanging such security
acquired such security directly from the Company or an underwriter or agent of the Company) or (2) any acquisition of securities by the Company; or (B)
upon the consummation by the Company of a reorganization, merger, consolidation, statutory share exchange or a sale or other disposition of all or
substantially all of the assets of the Company in one or a series of transactions (a “Business Combination”), provided that, in each case, the persons who were
the Company’s beneficial owners of the Outstanding Company Common Stock and Outstanding Company Voting Securities immediately prior to such
Business Combination do not beneficially own, directly or indirectly, more than 50% of the then-outstanding shares of common stock and the combined
voting power of the then-outstanding securities entitled to vote generally in the election of directors, respectively, of the resulting or acquiring corporation in
such Business Combination (which shall include, without limitation, a corporation which as a result of such transaction owns the Company or substantially all
of the Company’s assets either directly or through one or more subsidiaries) in substantially the same proportions as their ownership, immediately prior to
such Business Combination, of the Outstanding Company Common Stock and Outstanding Company Voting Securities, respectively; or (C) such time as the
Continuing Directors (as defined below) do not constitute a majority of the Board (or, if applicable, the board of directors of a successor corporation to the
Company), where the term “Continuing Director” means at any date a member of the Board (i) who was a member of the Board on the Effective Date of this
Plan, or (ii) who was nominated or elected subsequent to such date by at least a majority of the directors who were Continuing Directors at the time of such
nomination or election or whose election to the Board was recommended or endorsed by at least a majority of the directors who were Continuing
2

Directors at the time of such nomination or election; provided, however, that there shall be excluded from this clause (ii) any individual whose initial
assumption of office occurred as a result of an actual or threatened election contest with respect to the election or removal of directors or other actual or
threatened solicitation of proxies or consents, by or on behalf of a person other than the Board.
(g)
“Change in Control Date” shall mean the first date on which a Change in Control occurs.
(h)
“Change in Control Termination” shall mean a termination of the Covered Employee’s employment by the Company without Cause or a
termination of the Covered Employee’s employment by the Covered Employee for Good Reason, in either case, on or within the eighteen (18)-month period
following the Change in Control Date.
(i)
“COBRA” shall mean the Consolidated Omnibus Budget Reconciliation Act.
(j)
“Code” shall mean the Internal Revenue Code of 1986, as amended.
(k)
“Committee” shall have the meaning set forth in Section 14(a) below
(l)
“Company” shall mean AVEO Pharmaceuticals, Inc. (or, following a Change in Control, any successor thereto) together with the wholly-
owned subsidiaries of AVEO Pharmaceuticals, Inc., provided, that, for purposes of the definition of Change in Control in Section 3(f) hereof, Company shall
mean solely AVEO Pharmaceuticals, Inc.
(m)
“Covered Employees” shall mean all Regular Full-Time Employees (both exempt and non-exempt) who are, or were immediately prior to a
Change in Control, Executives, who experience a Covered Termination, and who are not designated as ineligible to receive severance benefits under the Plan
as provided in Section 5 hereof. For the avoidance of doubt, neither Temporary Employees nor Part-Time Employees are eligible for severance benefits under
the Plan. An employee’s full-time, part-time or temporary status for the purpose of this Plan shall be determined in good faith by the Plan Administrator upon
review of the employee’s status immediately before termination. Any person who is classified by the Company as an independent contractor or third party
employee is not eligible for severance benefits even if such classification is modified retroactively.
(n)
“Covered Termination” shall mean a termination designated by the Plan Administrator as (i) in the case of a Covered Employee who is a Key
Leadership Team Executive, either (A) a Non-Change in Control Termination or (B) a Change in Control Termination or (ii) in the case of a Covered
Employee who is not a Key Leadership Team Executive, a Change in Control Termination. The Plan Administrator shall determine whether a particular
termination is a Change in Control Termination or a Non-Change in Control Termination, and may determine, based on the facts and circumstances, that a
termination does not qualify as a Covered Termination.
(o)
“Disability” shall mean (i) the employee is unable to engage in any substantial gainful activity by reason of any medically determinable
physical or mental impairment that can be expected to result in death or can be expected to last for a continuous period of not less than twelve (12) months or
(ii) the employee is, by reason of any medically determinable physical or mental impairment that can be expected to result in death or can be expected to last
for a continuous period of not less than twelve (12) months, receiving income replacement benefits for a period of not less than three
3

(3) months under an accident and health plan covering employees of the Company; provided that in each case, the employee’s physical or mental impairment
shall be determined by an independent qualified physician mutually acceptable to the Company and the employee (or his personal representative) or, if the
Company and the employee (or such representative) are unable to agree on an independent qualified physician, as determined by a panel of three physicians,
one designated by the Company, one designated by the employee (or his personal representative) and one designated by the two physicians so designated.
(p)
“Effective Date” shall mean the date of Board approval of this Plan.
(q)
“ERISA” shall mean the Employee Retirement Income Security Act of 1974, as amended.
(r)
“Executive” shall mean any executive officer, senior vice-president and vice-president of the Company and any other employee of the
Company designated by the Chief Executive Officer and ratified by the Board.
(s)
“Good Reason” shall mean the occurrence, without the employee’s written consent of any of the following events: (i) any material diminution
in the employee’s duties, responsibilities or authority; (ii) a material reduction in the employee’s base salary (unless such reduction is effected in connection
with a general and proportionate reduction of compensation for all employees of his or her level) or (iii) following a Change in Control, a change in the
principal location at which the employee provides services to the Company to a location more than 50 miles from such principal location; provided, however,
that a termination for Good Reason can only occur if (A) the employee has given the Company a written notice of termination indicating the existence of a
condition giving rise to Good Reason and the Company has not cured the condition giving rise to Good Reason within thirty (30) days after receipt of such
notice of termination, and (B) such notice of termination is given within ninety (90) days after the initial occurrence of the condition giving rise to Good
Reason and further provided that a termination for Good Reason shall occur no more than one hundred eighty (180) days after the initial occurrence of the
condition giving rise to Good Reason.
(t)
“Key Leadership Team Executive” shall mean each Section 16 Officer and any other Executive designated by the Chief Executive Officer and
ratified by the Board.
(u)
“Non-Change in Control Severance Period” shall have the meaning set forth in Section 7(a) hereof.
(v)
“Non-Change in Control Termination” shall mean a termination of the Covered Employee’s employment by the Company without Cause or by
reason of the Covered Employee’s Disability or a termination of the Covered Employee’s employment by the Covered Employee for Good Reason, in any
case, prior to or more than eighteen (18) months after a Change in Control Date.
(w)
“Part-Time Employees” shall mean employees who are not Regular Full-Time Employees or Temporary Employees and are treated as such by
the Company.
(x)
“Participants” shall mean Covered Employees receiving severance payments and benefits pursuant to the Plan.
4

(y)
“Plan Administrator” shall have the meaning set forth in Section 14 hereof.
(z)
“Prior Arrangements” shall have the meaning set forth in Section 1 hereof.
(aa)
“Release” shall have the meaning set forth in Section 6 hereof.
(ab)
“Release Effective Date” shall have the meaning set forth in Section 13(c)(1) hereof.
(ac)
“Regular Full-Time Employees” shall mean employees, other than Temporary Employees, normally scheduled to work at least thirty (30)
hours a week unless the Company’s local practices, as from time to time in force, whether or not in writing, establish a different hours threshold for regular
full-time employees.
(ad)
“Section 16 Officer” shall mean an Executive who is designated by the Board to be an “officer” of the Company within the meaning of Rule
16a-1(f) under the Securities Exchange Act of 1934, as amended (the “Exchange Act”).
(ae)
“Severance Multiple” shall have the meaning set forth in Section 7(b) hereof.
(af)
“Temporary Employees” are employees treated as such by the Company, whether or not in writing.
4.
Coverage.    Subject to satisfaction of the eligibility and other requirements set forth in Sections 5 and 6 of this Plan, a Covered Employee will be entitled to
receive severance benefits under the Plan if such employee experiences a Covered Termination.
5.
Eligibility for Severance Benefits. The following employees will not be eligible for severance benefits, except to the extent specifically determined
otherwise by the Plan Administrator or as provided herein: (a) an employee who is terminated for Cause; (b) an employee who voluntarily retires or otherwise
voluntarily terminates his employment, except for a resignation for Good Reason in accordance with the terms of this Plan, or dies or becomes Disabled; (c) an
employee who is employed for a specific period of time in accordance with the terms of a written offer letter or employment agreement; (d) an employee whose
employment is terminated within thirty (30) days of his or her refusal to accept an offer of comparable employment by the Company following a Change in Control
(provided that “comparable employment” shall mean employment on terms that would not give rise to Good Reason), (e) an employee whose consent to the
amendment or termination of the Prior Arrangements is required but who has not so consented; and (f) an employee who is asked to enter into proprietary
information and inventions, nondisclosure, non-competition, non-solicitation (or similar) agreement(s) with the Company, in such form(s) as the Company may
require from time to time prior to the date of a Change in Control, but who is not a party to such agreement(s) with the Company into which they have been asked to
enter.
6.
Release; Timing of Severance Benefits. Receipt of any severance payments or benefits under the Plan requires that the Covered Employee execute and
deliver a severance and release of claims agreement in favor of the Company in the form to be provided by the Company at the time of the Covered Employee’s
termination (which shall include, at a minimum, a release of all releasable claims, non-disparagement and cooperation obligations, reaffirmation of the Covered
Employee’s continuing obligations under any applicable proprietary information and inventions, nondisclosure, non-competition, non-solicitation (or similar)
agreement(s) with the Company,
5

and an agreement, to the extent permitted by law, not to compete with the Company for one (1) year following the Covered Employee’s separation from employment
with the Company) (the “Release”), which Release becomes binding within sixty (60) days following the Covered Employee’s termination of employment (or such
shorter period as may be directed by the Company). The severance payments described herein will be paid in accordance with the terms of the Plan and otherwise on
the Company’s regularly scheduled payroll dates in effect from time to time and the Benefits Continuation will be paid in the amount and at the time premium
payments are made by other participants in the Company’s health benefit plans with the same coverage. The payments, which at all times are subject to the Covered
Employee’s compliance with the Covered Employee’s continuing obligations under the Release, shall be made or commence on the first payroll date after the Release
Effective Date in accordance with the terms of Section 13(c) hereof.
7.
Cash Severance.
(a)
Non-Change in Control Termination. A Covered Employee who experiences a Covered Termination that is a Non-Change in Control
Termination shall be entitled to receive continuation of such employee’s monthly Base Salary for twelve (12) months following the date of termination. In the
event the Chief Executive Officer experiences a Non-Change in Control Termination, the Chief Executive Officer shall, in addition to the severance benefits
described in the immediately preceding sentence, also be entitled to receive, in a single lump-sum, an amount equal to the Chief Executive’s Bonus multiplied
by a fraction, the numerator of which shall equal the number of days the Chief Executive Officer was employed by the Company during the year in which the
Non-Change in Control Termination occurs and the denominator of which shall equal 365.
(b)
Change in Control Termination. A Covered Employee who experiences a Change in Control Termination shall be entitled to receive periodic
and substantially equal installment payments for a number of months equal to the product of the Covered Employee’s “Severance Multiple” (as set forth
below) and twelve (12), of a total sum equal to: (i) the Covered Employee’s Severance Multiple multiplied by the Covered Employee’s Base Salary; (ii) the
Covered Employee’s Severance Multiple multiplied by his/her Bonus; and (iii) the Covered Employee’s Bonus multiplied by a fraction, the numerator of
which shall equal the number of days the Covered Employee was employed by the Company during the Company fiscal year in which the termination occurs
and the denominator of which shall equal 365.
The Covered Employee’s Severance Multiple shall be as set forth in the table below:
 
Chief Executive Officer
  
—    
2.0
Key Leadership Team Executives other than the Chief Executive Officer
  
—    
1.5
Executives with the title of SVP or above (other than Key Leadership Team Executives)
  
—    
1.0
Executives with the title of VP or above (other than Key Leadership Team Executives and Executives with the title of
SVP or above)
—
0.75
6

For purposes of this Section 7, a Covered Employee’s title shall be such employee’s title immediately prior to the Covered Termination or, if such employee’s
title was changed in connection with the Change in Control, immediately prior to such change in connection with the Change in Control.
8.
Other Severance Benefits.
(a)
Continued Benefits. In the event of a Covered Termination, a Covered Employee entitled to severance benefits under this Plan shall be entitled to Company
contributions to the cost of COBRA coverage on behalf of the Covered Employee and any applicable dependents for the period set forth in the table below (unless
such period is shortened in accordance with the terms of this Plan) if the Covered Employee timely elects COBRA coverage or substantially similar coverage, as
applicable, and only so long as such coverage continues in force (the “Benefits Continuation”). Such costs shall be determined on the same basis as the Company’s
contribution to Company-provided health and dental insurance coverage in effect for an active employee with the same coverage elections; provided that the Benefits
Continuation shall be only for coverage in which the Covered Employee and any applicable dependents were enrolled immediately prior to the Covered Termination
and shall end when the Covered Employee becomes eligible for group health coverage through another employer; and provided further, that if such Benefits
Continuation will violate the nondiscrimination requirements of applicable law, this benefit will not apply.
Non-Change in Control Termination
Covered Employee
—
12 months
Change in Control Termination
Chief Executive Officer
  
—    
18 months
Key Leadership Team Executives other than the Chief Executive Officer
  
—    
12 months
Executives other than Key Leadership Team Executives
  
—    
6 months
During the Benefits Continuation period, the Covered Employee shall continue to be required to pay that portion of the premium of such group health
insurance coverage, including coverage for his/her eligible dependents that is not paid by the Company. For the balance of the period that the Covered
Employee is eligible to receive coverage under COBRA, the Covered Employee shall be eligible to maintain coverage for himself/herself and his/her eligible
dependents at the Covered Employee’s own expense in accordance with applicable law.
7

(b)
Earned but Unpaid Bonus. In the event of a Change in Control Termination, the Covered Employee will be eligible to receive any earned but unpaid annual
bonus for the most recently completed fiscal year.
9.
Equity Awards. In the event of a Change in Control Termination, all of a Covered Employee’s equity awards granted by the Company that vest solely based
on the passage of time and that are outstanding and unvested as of such termination, will vest and become fully exercisable or non-forfeitable on the date of such
termination, and otherwise will continue to be dictated by the terms of the applicable award agreements. The vesting of performance-based equity awards in the event
of a Change in Control Termination shall be dictated by the terms of the applicable award agreements.
10.
Recoupment. If the Plan Administrator reasonably determines in good faith that the Covered Employee has failed to comply with the terms of the Plan,
including the provisions of Section 6 above, the Company may require payment to the Company of any benefits described in Sections 7, 8 and 9 above that the
Covered Employee has already received to the extent permitted by applicable law and with the “value” determined in the sole discretion of the Plan Administrator. 
Payment is due in cash or by check within thirty (30) days, or such earlier date as may be required by law or by any clawback policy that the Company adopts, after
the Company provides notice to a Covered Employee that it is enforcing this provision.  Any benefits described in Sections 7, 8 and 9 above not yet received by such
Covered Employee will be immediately forfeited.
11.
Death; Permanent Disability. If a Participant dies or is permanently Disabled after the date of his or her Covered Termination but before all payments or
benefits to which such Participant is entitled pursuant to the Plan have been paid or provided, payments will be made to any beneficiary or legal representative
designated by the Participant prior to or in connection with such Participant’s Covered Termination or, if no such beneficiary or legal representative has been
designated, to the Participant’s estate. For the avoidance of doubt, if a Participant dies or is permanently Disabled during the Benefits Continuation period provided
for the Participant in Section 8, Benefits Continuation will continue for the Participant’s applicable dependents for the remainder of the Benefits Continuation period
provided for such Participant in Section 8.
12.
Withholding. The Company may withhold from any payment or benefit under the Plan: (a) any federal, state, or local income or payroll taxes required by
law to be withheld with respect to such payment; (b) such sum as the Company may reasonably estimate is necessary to cover any taxes for which the Company may
be liable and which may be assessed with regard to such payment; and (c) such other amounts as appropriately may be withheld under the Company’s payroll policies
and procedures from time to time in effect.
13.
Section 409A. It is expected that the payments and benefits provided under this Plan will be exempt from or compliant with Section 409A of the Code, and
the guidance issued thereunder (“Section 409A”). The Plan shall be interpreted consistent with this intent to the maximum extent permitted and generally, with the
provisions of Section 409A. A termination of employment shall not be deemed to have occurred for purposes of any provision of this Plan providing for the payment
of any amounts or benefits upon or following a termination of employment (which amounts or benefits constitute nonqualified deferred compensation within the
meaning of Section 409A) unless such termination is also a “separation from service” within the meaning of Section 409A and, for purposes of any such provision of
this Plan, references to a “termination,” “termination of employment” or like terms shall mean “separation from service”. Neither the Participant nor the Company
shall have the right to accelerate or defer the delivery of any payment or benefit except to the extent specifically permitted or required by Section 409A.
8

To the extent the severance payments or benefits under this Plan are subject to Section 409A, the following rules shall apply with respect to distribution of the
payments and benefits, if any, to be provided to Participants under this Plan:
(a)
Each installment of the payments and benefits provided under this Plan will be treated as a separate “payment” for purposes of Section 409A.
Whenever a payment under this Plan specifies a payment period with reference to a number of days (e.g., “payment shall be made within ten (10) days
following the date of termination”), the actual date of payment within the specified period shall be in the Company’s sole discretion. Notwithstanding any
other provision of this Plan to the contrary, in no event shall any payment under this Plan that constitutes “non-qualified deferred compensation” for purposes
of Section 409A be subject to transfer, offset, counterclaim or recoupment by any other amount unless otherwise permitted by Section 409A.
(b)
Notwithstanding any other payment provision herein to the contrary, if the Company or appropriately-related affiliates become publicly-traded
and a Covered Employee is deemed on the date of termination to be a “specified employee” within the meaning of that term under Code Section 409A(a)(2)
(B) with respect to such entity, then each of the following shall apply:
(i)
With regard to any payment that is considered “non-qualified deferred compensation” under Section 409A payable on account of a “separation
from service,” such payment shall be made on the date which is the earlier of (A) the day following the expiration of the six (6) month period
measured from the date of such “separation from service” of the Covered Employee, and (B) the date of the Covered Employee’s death (the “Delay
Period”) to the extent required under Section 409A. Upon the expiration of the Delay Period, all payments delayed pursuant to this provision (whether
otherwise payable in a single sum or in installments in the absence of such delay) shall be paid to or for the Covered Employee in a lump sum, and all
remaining payments due under this Plan shall be paid or provided for in accordance with the normal payment dates specified herein; and
(ii)
To the extent that any benefits to be provided during the Delay Period are considered “non-qualified deferred compensation” under Section
409A payable on account of a “separation from service,” and such benefits are not otherwise exempt from Section 409A, the Covered Employee shall
pay the cost of such benefits during the Delay Period, and the Company shall reimburse the Covered Employee, to the extent that such costs would
otherwise have been paid by the Company or to the extent that such benefits would otherwise have been provided by the Company at no cost to the
Covered Employee, the Company’s share of the cost of such benefits upon expiration of the Delay Period. Any remaining benefits shall be reimbursed
or provided by the Company in accordance with the procedures specified in this Plan.
(c)
To the extent that severance benefits pursuant to this Plan are conditioned upon a Release, the Covered Employee shall forfeit all rights to such
payments and benefits unless such release is signed and delivered (and no longer subject to revocation, if applicable) within sixty (60) days following the date
of the termination of the Covered Employee’s employment with the Company (or such shorter period as may be directed by the Company). If the Release is
no longer subject to revocation as provided in the preceding sentence, then the following shall apply:
9

(i)
To the extent any severance benefits to be provided are not “non-qualified deferred compensation” for purposes of Section 409A, then such
benefits shall commence upon the first scheduled payment date immediately after the date the Release is executed and no longer subject to revocation
(the “Release Effective Date”). The first such cash payment shall include all amounts that otherwise would have been due prior thereto under the terms
of this Plan applied as though such payments commenced immediately upon the termination of Covered Employee’s employment with the Company,
and any payments made after the Release Effective Date shall continue as provided herein. The delayed benefits shall in any event expire at the time
such benefits would have expired had such benefits commenced immediately following the termination of Covered Employee’s employment with the
Company.
(ii)
To the extent any such severance benefits to be provided are “non-qualified deferred compensation” for purposes of Section 409A, then the
Release must become irrevocable within sixty (60) days of the date of termination and benefits shall be made or commence upon the date provided in
Section 6, provided that if the sixtieth day following the termination of the Covered Employee’s employment with the Company falls in the calendar
year following the calendar year containing the date of termination, the benefits will be made no earlier than the first business day of that following
calendar year (subject to Section 13(b), above). The first such cash payment shall include all amounts that otherwise would have been due prior
thereto under the terms of this Plan had such payments commenced immediately upon the termination of the Covered Employee’s employment with
the Company, and any payments made after the first such payment shall continue as provided herein. The delayed benefits shall in any event expire at
the time such benefits would have expired had such benefits commenced immediately following the termination of the Covered Employee’s
employment with the Company.
(d)
The Company makes no representations or warranties and shall have no liability to any Participant or any other person if any provisions of or
payments under this Plan are determined to constitute deferred compensation subject to Section 409A of the Code but not to satisfy the conditions of that
section.
14.
Plan Administration.
(a)
Plan Administrator. The Plan Administrator shall be the Board or a committee thereof designated by the Board (the “Committee”); provided,
however, that the Board or such Committee may in its sole discretion appoint a new Plan Administrator to administer the Plan following a Change in Control. The
Plan Administrator shall also serve as the Named Fiduciary of the Plan under ERISA. The Plan Administrator shall be the “administrator” within the meaning of
Section 3(16) of ERISA and shall have all the responsibilities and duties contained therein.
The Plan Administrator can be contacted at the following address:
    
        30 Winter Street
        Boston, MA 02108        
(b)
Decisions, Powers and Duties. The general administration of the Plan and the responsibility for carrying out its provisions shall be vested in the Plan
Administrator. The Plan Administrator shall have such powers and authority as are necessary to discharge such duties and
10

responsibilities which also include, but are not limited to, interpretation and construction of the Plan, the determination of all questions of fact, including, without
limit, eligibility, participation and benefits, the resolution of any ambiguities and all other related or incidental matters, and such duties and powers of the plan
administration which are not assumed from time to time by any other appropriate entity, individual or institution. The Plan Administrator may adopt rules and
regulations of uniform applicability in its interpretation and implementation of the Plan.
The Plan Administrator shall discharge its duties and responsibilities and exercise its powers and authority in its sole discretion and in accordance with the
terms of the controlling legal documents and applicable law, and its actions and decisions that are not arbitrary and capricious shall be binding on any
employee, employee’s spouse or other dependent or beneficiary and any other interested parties whether or not in being or under a disability.
15.
Indemnification. To the extent permitted by law, all employees, officers, directors, agents and representatives of the Company shall be indemnified by the
Company and held harmless against any claims and the expenses of defending against such claims, resulting from any action or conduct relating to the administration
of the Plan, whether as a member of the Committee or otherwise, except to the extent that such claims arise from gross negligence, willful neglect, or willful
misconduct.
16.
Plan Not an Employment Contract. The Plan is not a contract between the Company and any employee, nor is it a condition of employment of any
employee. Nothing contained in the Plan gives, or is intended to give, any employee the right to be retained in the service of the Company, or to interfere with the
right of the Company to discharge or terminate the employment of any employee at any time and for any reason. No employee shall have the right or claim to
benefits beyond those expressly provided in this Plan, if any. All rights and claims are limited as set forth in the Plan.
17.
Severability. In case any one (1) or more of the provisions of this Plan (or part thereof) shall be held to be invalid, illegal or unenforceable in any respect,
such invalidity, illegality or unenforceability shall not affect the other provisions hereof, and this Plan shall be construed as if such invalid, illegal or unenforceable
provisions (or part thereof) never had been contained herein.
18.
Non-Assignability. No right or interest of any Covered Employee in the Plan shall be assignable or transferable in whole or in part either directly or by
operation of law or otherwise, including, but not limited to, execution, levy, garnishment, attachment, pledge or bankruptcy.
19.
Integration With Other Pay or Benefits Requirements. The severance payments and benefits provided for in the Plan are the maximum benefits that the
Company will pay to Covered Employees on a Covered Termination. To the extent that the Company owes any amounts in the nature of severance benefits under any
other program, policy or plan of the Company that is not otherwise superseded by this Plan, or to the extent that any federal, state or local law, including, without
limitation, so-called “plant closing” laws, requires the Company to give advance notice or make a payment of any kind to an employee because of that employee’s
involuntary termination due to a layoff, reduction in force, plant or facility closing, sale of business, or similar event, the benefits provided under this Plan or the
other arrangement shall either be reduced or eliminated to avoid any duplication of payment. The Company intends for the benefits provided under this Plan to
partially or fully satisfy any and all statutory obligations that may arise out of an employee’s involuntary termination for the foregoing reasons and the Company shall
so construe and implement the terms of the Plan.
11

20.
Amendment or Termination. The Board may amend, modify, or terminate the Plan at any time in its sole discretion; provided, however, that (a) any such
amendment, modification or termination made prior to a Change in Control that adversely affects the rights of any Covered Employee shall be unanimously approved
by the Company’s Board of Directors, including any independent director(s) and the Chief Executive Officer, (b) no such amendment, modification or termination
may affect the rights of a Covered Employee then receiving payments or benefits under the Plan without the consent of such person, and (c) no such amendment,
modification or termination made after a Change in Control shall be effective for eighteen months.
21.
Governing Law. The Plan and the rights of all persons under the Plan shall be construed in accordance with and under applicable provisions of ERISA, and
the regulations thereunder, and the laws of the Commonwealth of Massachusetts (without regard to conflict of laws provisions) to the extent not preempted by federal
law.
12

NON-COMPETITION AND NON-SOLICITATION AGREEMENT
This Non-Competition and Non-Solicitation Agreement (the “Agreement”) is made between AVEO Pharmaceuticals, Inc. a Delaware corporation (hereinafter
referred to collectively with its subsidiaries as the “Company”), and the undersigned employee (the “Employee”).
For good consideration, including, without limitation, the continued employment of the Employee by the Company and, with respect to the non-competition
restrictions, the additional consideration set forth in Section 1(c), the Employee and the Company agree as follows:
1.
Non-Competition.
(a)
During the Restricted Period (as defined below), the Employee will not, in the Applicable Territory (as defined below), directly or indirectly, whether as an
owner, partner, officer, director, employee, consultant, investor, lender or otherwise, except as the passive holder of not more than 1% of the outstanding stock of a
publicly-held company, engage or assist others in engaging in any business or enterprise that is competitive with the Company’s business, including but not limited to
any business or enterprise that researches, develops, manufactures, markets, licenses, sells or provides any product or service that competes with any product or
service researched, developed, manufactured, marketed, licensed, sold or provided, or planned to be researched, developed, manufactured, marketed, licensed, sold or
provided by the Company (a “Competitive Company”), if the Employee would be performing job duties or services for the Competitive Company that are of a
similar type that the Employee performed for the Company at any time during the last two (2) years of the Employee’s employment.
(b)
Certain Definitions. Solely for purposes of this Section 1:
i.
the “Restricted Period” shall include the duration of the Employee’s employment with the Company and the twelve (12) month period
thereafter; provided, however, that the Restricted Period shall automatically be extended to two (2) years following the cessation of the Employee’s
employment if the Employee breaches a fiduciary duty to the Company or the Employee unlawfully takes, physically or electronically, any property
belonging to the Company. Notwithstanding the foregoing, the Restricted Period shall end immediately upon the Employee’s last day of employment with the
Company if: (x) the Company terminates the Employee’s employment other than for Cause (as defined below); or (y) the Company notifies the Employee in
writing that it is waiving the post-employment restrictions set forth in this Section 1 (such notice to be provided no later than the Employee’s last day of
employment or by the seventh (7 ) business day following an Employee’s notice of resignation, if later).
ii.
 “Applicable Territory” shall mean the geographic areas in which the Employee provided services or had a material presence or
influence at any time during his/her last two (2) years of employment.
iii.
“Cause” shall mean any of: (a) the Employee’s conviction of, or plea of guilty or nolo contendere to, any crime involving dishonesty or
moral turpitude, or any felony; or (b) a good faith finding by the Company in its sole discretion that the Employee has (i) engaged in dishonesty, misconduct
or gross negligence; (ii) committed an act that injures or would reasonably be expected to injure the reputation, business or business relationships of the
Company; (iii) breached the terms of this Agreement or any other restrictive covenant or confidentiality agreement with or policy of the Company; (iv) failed
or refused to comply with any of the Company’s policies or procedures; or (v)
th

failed to perform the Employee’s duties and/or responsibilities to the Company’s satisfaction.
(c)
Additional Consideration for Non-Competition Restrictions. In exchange for the Employee’s compliance with the restrictions set forth in this Section 1, the
Employee will be eligible to receive cash severance and other severance benefits pursuant to the terms and conditions of the Company’s Executive Severance and
Change in Control Benefits Plan. The Employee understands and agrees that the above-stated consideration has been mutually agreed upon by the Company and the
Employee, is fair and reasonable, and is sufficient consideration in exchange for the restrictions set forth in this Section 1.
2.
Non-Solicitation.
(a)
While the Employee is employed by the Company and for a period of twelve (12) months after the termination or cessation of such employment for any
reason, the Employee will not directly or indirectly:
(i)    Either alone or in association with others, solicit, divert or take away, or attempt to divert or take away, the business or patronage of any of
the actual or prospective clients, customers, accounts or business partners of the Company which were contacted, solicited, or served by the Company during the
Employee’s employment with the Company; or
(ii)    Either alone or in association with others (I) solicit, induce or attempt to induce, any employee or independent contractor of the Company
to terminate his or her employment or other engagement with the Company, or (II) hire or recruit, or attempt to hire or recruit, or engage or attempt to engage as an
independent contractor, any person who was employed or otherwise engaged by the Company at any time during the term of the Employee’s employment with the
Company; provided, that this clause (II) shall not apply to the recruitment or hiring or other engagement of any individual whose employment or other engagement
with the Company ended at least six (6) months before the recruitment, hiring, or other engagement.
(b)
If the Employee violates the provisions of any of the preceding paragraphs of this Section 2, the Employee shall continue to be bound by the restrictions set
forth in such paragraph until a period of twelve (12) months has expired without any violation of such provisions. Further, the twelve (12) month post-employment
restrictions set forth in this Section 2 shall be extended to two (2) years if the Employee breaches a fiduciary duty to the Company or the Employee unlawfully takes,
physically or electronically, any property belonging to the Company.
3.
Notice of New Business Activities. The Employee agrees that during any period of time when the Employee is subject to restrictions pursuant to either
Section 1 or Section 2, the Employee will notify any prospective employer or business associate of the terms and existence of this Agreement and the Employee’s
continuing obligations to the Company hereunder. The Employee further agrees, during such period, to give notice to the Company of each new business activity the
Employee plans to undertake, at least (10) business days prior to beginning any such activity. The notice shall state the name and address of the individual,
corporation, association or other entity or organization (“Entity”) for whom such activity is undertaken and the name of the Employee’s business relationship or
position with the Entity. The Employee also agrees to provide the Company with other pertinent information concerning such business activity as the Company may
reasonably request in order to determine the Employee’s continued compliance with his/her obligations under this Agreement. The Employee hereby authorizes the
Company to notify others, including but not limited to customers of the Company and any of the
    - 2 -

Employee’s future employers or prospective business associates, of the terms and existence of this Agreement and the Employee’s continuing obligations to the
Company hereunder.
4.
Miscellaneous.
(a)
Equitable Remedies. The Employee acknowledges that the restrictions contained in this Agreement are necessary for the protection of the business and
goodwill of the Company and are considered by the Employee to be reasonable for such purpose. The Employee agrees that any breach or threatened breach of this
Agreement is likely to cause the Company substantial and irrevocable damage which is difficult to measure. Therefore, in the event of any such breach or threatened
breach, the Employee agrees that the Company, in addition to such other remedies which may be available, shall have the right to obtain an injunction from a court
restraining such a breach or threatened breach without posting a bond and the right to specific performance of the provisions of this Agreement and the Employee
hereby waives the adequacy of a remedy at law as a defense to such relief. Additionally, the Employee acknowledges and agrees that, while the non-solicitation
obligations herein are essential to the protection of the Company’s legitimate business interests, such interests cannot be adequately protected without the non-
competition obligations set forth in Section 1.
(b)
Obligations to Third Parties. The Employee represents that, except as the Employee has disclosed in writing to the Company, the Employee is not bound by
the terms of any agreement with any previous employer or other party to refrain from using or disclosing any trade secret or confidential or proprietary information in
the course of his/her employment with the Company, to refrain from competing, directly or indirectly, with the business of such previous employer or any other party,
or to refrain from soliciting employees, customers or suppliers of such previous employer or other party. The Employee further represents that his/her performance of
all the terms of this Agreement and the performance of his/her duties as an employee of the Company does not and will not conflict with or breach any agreement
with any prior employer or other party (including, without limitation, any nondisclosure or non-competition agreement), and that the Employee will not disclose to
the Company or induce the Company to use any confidential or proprietary information or material belonging to any previous employer or others.
(c)
Not Employment Contract. The Employee acknowledges that this Agreement does not constitute a contract of employment, does not imply that the Company
will continue his/her employment for any period of time, and does not change the at-will nature of his/her employment.
(d)
Acknowledgments.
The Employee acknowledges that he or she has the right to consult with counsel prior to signing this Agreement. The Employee further acknowledges that this
Agreement is supported by fair and reasonable consideration independent from the Employee’s continued employment, and that this Agreement shall not take effect
until the eleventh (11th) business day following the date on which the Company provided it to the Employee for review and execution.
(e)
Successors and Assigns. The Employee’s obligations under this Agreement are personal and shall not be assigned by the Employee. This Agreement shall,
however, be binding upon and inure to the benefit of the Company and its successors and assigns, including any corporation or entity with which or into which the
Company may be merged or that may succeed to all or substantially all of its assets or business. The Employee expressly consents to be bound by the provisions of
this Agreement for the benefit of any successor or assign of the Company without the necessity that this Agreement be re-signed, in which event “Company” shall be
interpreted to include any successor or assign of the Company.
    - 3 -

(f)
Interpretation. If any restriction or definition set forth in Section 1 or Section 2 is found by any court of competent jurisdiction to be unenforceable because it
extends for too long a period of time or over too great a range of conduct, activities, or geographic area, it shall be interpreted to extend only over the maximum
period of time, range of conduct, activities or geographic area as to which it may be enforceable.
(g)
Severability. In case any provision of this Agreement shall be invalid, illegal or otherwise unenforceable, the validity, legality and enforceability of the
remaining provisions shall in no way be affected or impaired thereby.
(h)
Waivers. No delay or omission by the Company in exercising any right under this Agreement will operate as a waiver of that or any other right. A waiver or
consent given by the Company on any one occasion is effective only in that instance and will not be construed as a bar to or waiver of any right on any other
occasion.
(i)
Governing Law and Consent To Jurisdiction. This Agreement shall be governed by and construed in accordance with the laws of the Commonwealth of
Massachusetts (without reference to the conflicts of laws provisions thereof). Any action, suit, or other legal proceeding which is commenced to resolve any matter
arising under or relating to any provision of this Agreement shall be commenced only in a court in Suffolk County, Massachusetts (or, if appropriate, a federal court
located within Massachusetts), and the Company and the Employee each consents to the jurisdiction of such courts. The Company and the Employee each hereby
irrevocably waives any right to a trial by jury in any action, suit or other legal proceeding arising under or relating to any provision of this Agreement.
(j)
Entire Agreement; Amendment. This Agreement supersedes all prior agreements, written or oral, between the Employee and the Company relating to the
subject matter of this Agreement. This Agreement may not be modified, changed or discharged in whole or in part, except by an agreement in writing signed by the
Employee and the Company. The Employee agrees that any change or changes in his/her duties, authority, title, reporting relationship, territory, salary or
compensation after the signing of this Agreement shall not affect the validity or scope of this Agreement.
(k)
Captions. The captions of the sections of this Agreement are for convenience of reference only and in no way define, limit or affect the scope or substance of
any section of this Agreement.
[Remainder of Page Intentionally Left Blank]
    - 4 -

    THE EMPLOYEE ACKNOWLEDGES THAT HE/SHE HAS CAREFULLY READ THIS AGREEMENT AND UNDERSTANDS AND AGREES TO ALL OF
THE PROVISIONS IN THIS AGREEMENT.
EMPLOYEE
Date:_______________________
_______________________________
Name:
AVEO PHARMACEUTICALS, INC.
Date: ______________________
By:____________________________
Name: 
Title:
Signature Page to Non-Competition and Non-Solicitation Agreement

Execution Version
Conformed – 3  Amendment
AMENDED AND RESTATED LOAN AND SECURITY AGREEMENT
THIS AMENDED AND RESTATED LOAN AND SECURITY AGREEMENT (as amended by that certain (i) First Amendment to Amended and Restated
Loan and Security Agreement dated as of August 7, 2020 (the “First Amendment”), (ii) Second Amendment to Amended and Restated Loan and Security Agreement
dated as of February 1, 2021 (the “Second Amendment”) and (iii) Third Amendment to Amended and Restated Loan and Security Agreement dated as of March 8,
2022 (the “Third Amendment”)) is made and dated as of December 28, 2017 and is entered into by and between AVEO PHARMACEUTICALS, INC., a Delaware
corporation, and each of its Qualified Subsidiaries (hereinafter collectively referred to as “Borrower”), the several banks and other financial institutions or entities
from time to time parties to this Agreement (collectively, referred to as “Lender”) and HERCULES CAPITAL, INC., a Maryland corporation, in its capacity as
administrative agent and collateral agent for itself and Lender (in such capacity, “Agent”).
RECITALS
A.    Immediately prior to the effectiveness of the First Amendment, the aggregate outstanding principal amount of the Advances hereunder is Nine Million,
Six Hundred Seventy One Thousand and Thirteen Dollars and 48/100 ($9,671,013.48) (the “Existing Term Loan Advances”);
B.     Borrower has requested that Lender make available to Borrower 2020 Term Loan Advances (as defined below) in an aggregate principal amount of up to
Forty Five Million Dollars ($45,000,000) in order to, among other things, refinance the Existing Term Loan Advances; and
C.    Lender is willing to make the 2020 Term Loan Advances on the terms and conditions set forth in this Agreement.
AGREEMENT
NOW, THEREFORE, Borrower, Agent and Lender hereby agree as follows:
Section 1. 
DEFINITIONS AND RULES OF CONSTRUCTION
1.1
Unless otherwise defined herein, the following capitalized terms shall have the following meanings:
“2020 End of Term Charge” has the meaning assigned to such term in Section 2.5.
“2020 Term A Commitment” means as to any Lender, the obligation of such Lender, if any, to make 2020 Term A Loan Advances to Borrower in a principal
amount not to exceed the amount set forth under the heading “2020 Term A Commitment” opposite such Lender’s name on Schedule 1.1.
“2020 Term A Loan Advance” has the meaning assigned to such term in Section 2.1(a)(i).
“2020 Term B Commitment” means as to any Lender, the obligation of such Lender, if any, to make 2020 Term B Loan Advances to Borrower in a principal
amount not to exceed the amount set forth under the heading “2020 Term B Commitment” opposite such Lender’s name on Schedule 1.1.
rd

“2020 Term B Loan Advance” has the meaning assigned to such term in Section 2.1(a)(ii).
“2020 Term C Commitment” means as to any Lender, the obligation of such Lender, if any, to make 2020 Term C Loan Advances to Borrower in a principal
amount not to exceed the amount set forth under the heading “2020 Term C Commitment” opposite such Lender’s name on Schedule 1.1.
“2020 Term C Loan Advance” has the meaning assigned to such term in Section 2.1(a)(iii).
“2020 Term Commitment” means as to any Lender, collectively, its 2020 Term A Commitment, 2020 Term B Commitment and 2020 Term C Commitment.
“2020 Term D Loan Advance” has the meaning assigned to such term in Section 2.1(a)(iv).
“2020 Term D Share” means as to any Lender, the principal amount set forth under the heading “2020 Term D Share” opposite such Lender’s name on
Schedule 1.1.
“2020 Term Loan Advance” and “2020 Term Loan Advances” has the meaning assigned to such terms in Section 2.1(a)(v).
“Account Control Agreement(s)” means any agreement entered into by and among Agent, Borrower and a third-party Bank or other institution (including a
Securities Intermediary) in which Borrower maintains a Deposit Account or an account holding Investment Property and which grants Agent a perfected first priority
security interest in the subject account or accounts.
“ACH Authorization” means the ACH Debit Authorization Agreement in substantially the form of Exhibit H.
“Advance(s)” means an Existing Term Loan Advance or a 2020 Term Loan Advance.
“Advance Date” means the funding date of any Advance.
“Advance Request” means a request for an Advance submitted by Borrower to Agent in substantially the form of Exhibit A.
“Affiliate” means (a) any Person that directly or indirectly controls, is controlled by, or is under common control with the Person in question, (b) any Person
directly or indirectly owning, controlling or holding with power to vote twenty percent (20%) or more of the outstanding voting securities of another Person, (c) any
Person twenty percent (20%) or more of whose outstanding voting securities are directly or indirectly owned, controlled or held by another Person with power to vote
such securities, or (d) any Person related by blood or marriage to any Person described in subsection (a), (b) or (c) of this paragraph. As used in the definition of
“Affiliate,” the term “control” means the possession, directly or indirectly, of the power to direct or cause the direction of the management and policies of a Person,
whether through ownership of voting securities, by contract or otherwise.
“Agent” has the meaning given to it in the preamble to this Agreement.
“Agreement” means this Amended and Restated Loan and Security Agreement, as amended by the First Amendment, the Second Amendment, the Third
Amendment and as may

be further amended, modified, supplemented or restated from time to time in accordance with the terms hereof.
“Anti-Corruption Laws” shall mean all laws, rules, and regulations of any jurisdiction applicable to Borrower or any of its Affiliates from time to time
concerning or relating to bribery or corruption, including without limitation the United States Foreign Corrupt Practices Act of 1977, as amended, the UK Bribery
Act 2010 and other similar legislation in any other jurisdictions.
“Anti-Terrorism Laws” means any laws, rules, regulations or orders relating to terrorism or money laundering, including without limitation Executive Order
No. 13224 (effective September 24, 2001), the USA PATRIOT Act, the laws comprising or implementing the Bank Secrecy Act, and the laws administered by
OFAC.
“Assignee” has the meaning given to it in Section 11.13.
“Blocked Person” means any Person: (a) listed in the annex to, or is otherwise subject to the provisions of, Executive Order No. 13224, (b) a Person owned or
controlled by, or acting for or on behalf of, any Person that is listed in the annex to, or is otherwise subject to the provisions of, Executive Order No. 13224, (c) a
Person with which any Lender is prohibited from dealing or otherwise engaging in any transaction by any Anti-Terrorism Law, (d) a Person that commits, threatens
or conspires to commit or supports “terrorism” as defined in Executive Order No. 13224, or (e) a Person that is named a “specially designated national” or “blocked
person” on the most current list published by OFAC or other similar list.
“Borrower Products” means all products, drugs, drug compounds, software, service offerings, technical data or technology currently being designed,
manufactured or sold by Borrower or which Borrower intends to sell, license, or distribute in the future including any products or service offerings under
development, collectively, together with all products, software, service offerings, technical data or technology that have been sold, licensed or distributed by
Borrower since its incorporation.
“Business Day” means any day other than Saturday, Sunday and any other day on which banking institutions in the State of California are closed for business.
“Cash” means all cash and liquid funds.
“Cash Equivalents” shall mean (a) securities issued, or directly and fully guaranteed or insured, by the United States or any agency or instrumentality thereof
(provided that the full faith and credit of the United States is pledged in support thereof) having maturities of not more than twenty four months from the date of
acquisition, (b) U.S. dollar denominated time deposits, certificates of deposit and bankers' acceptances of (i) any domestic commercial bank of recognized standing
having capital and surplus in excess of $500,000,000, or (ii) any bank (or the parent company of such bank) whose short-term commercial paper rating from Standard
& Poor’s Ratings Services (“S&P”) is at least A-2 or the equivalent thereof or from Moody’s Investors Service, Inc. (“Moody’s”) is at least P-2 or the equivalent
thereof in each case with maturities of not more than twenty four months from the date of acquisition (any bank meeting the qualifications specified in clauses (b)(i)
or (ii), an “Approved Bank”), (c) repurchase obligations with a term of not more than seven days for underlying securities of the types described in clause (a), above,
entered into with any Approved Bank, (d) commercial paper or corporate notes issued by any Approved Bank or by the parent company of any Approved Bank and
commercial paper or corporate notes issued by, or guaranteed by, any industrial or financial company with a short-term commercial paper rating of at least A-2 or the
equivalent thereof by S&P or at least P-2 or the equivalent thereof by Moody’s, or guaranteed by any industrial

company with a long term unsecured debt rating of at least A or A2, or the equivalent of each thereof, from S&P or Moody’s, as the case may be, and in each case
maturing within twenty four months after the date of acquisition, (e) debt issued by government-sponsored enterprises with maturities of not more than twenty four
months from the date of acquisition, (f) municipal obligations having a long term rating of at least A2 or equivalent by Moody’s and A or equivalent by S&P or short
term ratings of P-1 or equivalent by Moody’s and A-1 or equivalent by S&P, in each case with maturities or put dates of not more than twenty four months from the
date of acquisition and (g) investments in money market funds substantially all of whose assets are comprised of securities of the type described in clauses (a)
through (f) above.
“Change in Control” means any reorganization, recapitalization, consolidation or merger (or similar transaction or series of related transactions) of Borrower,
or sale or exchange of outstanding shares (or similar transaction or series of related transactions) of Borrower, in each case in which the holders of Borrower’s
outstanding voting securities, or affiliates of such holders, immediately before consummation of such transaction or series of related transactions do not, immediately
after consummation of such transaction or series of related transactions, hold voting securities representing more than fifty percent (50%) of the voting power of the
outstanding voting securities of the surviving or resulting entity in such transaction or series of related transactions (or of the parent of such surviving or resulting
entity if such surviving or resulting entity is wholly owned by such parent), in each case without regard to whether Borrower or Subsidiary is the surviving or
resulting entity.
“Claims” has the meaning given to it in Section 11.10.
“Closing Date” means the date of this Agreement.
“Collateral” means the property described in Section 3.
“Compliance Certificate” means a certificate in the form attached hereto as Exhibit F.
“Confidential Information” has the meaning given to it in Section 11.12.
“Contingent Obligation” means, as applied to any Person, any direct or indirect liability, contingent or otherwise, of that Person with respect to (i) any
indebtedness, lease, dividend, letter of credit or other obligation of another, including any such obligation directly or indirectly guaranteed, endorsed, co-made or
discounted or sold with recourse by that Person, or in respect of which that Person is otherwise directly or indirectly liable; (ii) any obligations with respect to
undrawn letters of credit, corporate credit cards or merchant services issued for the account of that Person; and (iii) all obligations arising under any interest rate,
currency or commodity swap agreement, interest rate cap agreement, interest rate collar agreement, or other agreement or arrangement designated to protect a Person
against fluctuation in interest rates, currency exchange rates or commodity prices; provided, however, that the term “Contingent Obligation” shall not include
endorsements for collection or deposit in the Ordinary Course of Business. The amount of any Contingent Obligation shall be deemed to be an amount equal to the
stated or determined amount of the primary obligation in respect of which such Contingent Obligation is made or, if not stated or determinable, the maximum
reasonably anticipated liability in respect thereof as determined by such Person in good faith; provided, however, that such amount shall not in any event exceed the
maximum amount of the obligations under the guarantee or other support arrangement.
“Copyrights” means all copyrights, whether registered or unregistered, held pursuant to the laws of the United States, any State thereof, or of any other
country.

“Copyright License” means any written agreement granting any right to use any Copyright or Copyright registration, now owned or hereafter acquired by
Borrower or in which Borrower now holds or hereafter acquires any interest.
“Default” means any fact or condition exists that would (or would, with the passage of time, the giving of notice, or both) constitute an Event of Default.
“Deposit Accounts” means any “deposit accounts,” as such term is defined in the UCC, and includes any checking account, savings account, or certificate of
deposit.
“Domestic Subsidiary” means any Subsidiary that is not a Foreign Subsidiary.
“End of Term Charge” has the meaning given to it in Section 2.5 hereof.
“ERISA” is the Employee Retirement Income Security Act of 1974, as amended from time to time and its regulations.
“Event of Default” has the meaning given to it in Section 9.
“Excluded Agreements” means (i) any stock purchase agreement, options, or warrants to acquire, or agreements governing the rights of, any capital stock or
other equity security, or any common stock, preferred stock, or equity security issued to or purchased by Lender or its nominee or assignee; and (ii) any other warrant
agreement by and among Lender or Agent and Borrower.
“Existing Term Commitment” means as to any Lender, such obligation of such Lender, if any, to make an Existing Term Loan Advance to Borrower under
this Agreement immediately prior to the effectiveness of the First Amendment and the refinancing of the Existing Term Loan Advances as contemplated herein, but
excluding, for the avoidance of doubt, any such obligation to make 2020 Term Loan Advances.
“Existing Term Loan Advance” has the meaning assigned to such term in the preamble to this Agreement.
“Financial Statements” has the meaning given to it in Section 7.1.
“First Amendment” has the meaning given to it in the preamble to this Agreement.
“First Amendment Closing Date” means August 7, 2020.
“Forecast” means, with respect to the calculation of Section 7.22, for measurement periods (i) ending on or between January 1, 2022, and December 31, 2022,
that certain FY 2022 Net Product Revenue Forecast provided to Agent by Borrower and attached hereto as Schedule 1E and (ii) ending after December 31, 2022, a
subsequent Forecast approved by Borrower’s board of directors that is reasonably acceptable to Lender and provided (at Borrower’s option) to Agent by Borrower
and identified as a “Forecast” delivered pursuant to this definition.
“Foreign Subsidiary” means any Subsidiary other than a Subsidiary organized under the laws of any state within the United States of America.
“GAAP” means generally accepted accounting principles in the United States of America, as in effect from time to time.

“Indebtedness” means (a) all indebtedness for borrowed money or the deferred purchase price of property or services (excluding trade credit entered into in
the Ordinary Course of Business), including reimbursement and other obligations with respect to surety bonds and letters of credit, (b) all obligations evidenced by
notes, bonds, debentures or similar instruments, (c) all capital lease obligations, and (d) all Contingent Obligations.
“Intellectual Property” means all of Borrower’s Copyrights; Trademarks; Patents; Licenses; trade secrets and inventions; mask works; Borrower’s
applications therefor and reissues, extensions, or renewals thereof; and Borrower’s goodwill associated with any of the foregoing, together with Borrower’s rights to
sue for past, present and future infringement of Intellectual Property and the goodwill associated therewith.
“Investment” means any beneficial ownership (including stock, partnership or limited liability company interests) of or in any Person, or any loan, advance or
capital contribution to any Person or the acquisition of all, or substantially all, of the assets or stock of another Person.
“Joinder Agreements” means for each Qualified Subsidiary, a completed and executed Joinder Agreement in substantially the form attached hereto as Exhibit
G.
“JV Restrictions” has the meaning given to it in Section 7.6.
“Lender” has the meaning given to it in the preamble to this Agreement.
“License” means any Copyright License, Patent License, Trademark License or other license of rights or interests.
“Liquidity” means, as of any date, Borrower’s Cash, and/or Cash Equivalents maintained in Deposit Accounts and/or accounts holding Investment Property
that are subject to an Account Control Agreement.
“Lien” means any mortgage, deed of trust, pledge, hypothecation, assignment for security; security interest, encumbrance, levy, lien or charge of any kind,
whether voluntarily incurred or arising by operation of law or otherwise, against any property, any conditional sale or other title retention agreement, and any lease in
the nature of a security interest.
“Loan” means the Advances made under this Agreement.
“Loan Documents” means this Agreement, the Notes, the ACH Authorization, the Account Control Agreements, the Joinder Agreements, all UCC Financing
Statements, and any other documents executed in connection with the Secured Obligations or the transactions contemplated hereby, as the same may from time to
time be amended, modified, supplemented or restated; provided, that the term “Loan Document” shall not include any Excluded Agreements.
“Material Adverse Effect” means a material adverse effect upon: (i) the business, operations, properties, assets or condition (financial or otherwise) of
Borrower, provided, however, the failure of an FDA clinical trial, in and of itself, shall not constitute a Material Adverse Effect or (ii) the ability of Borrower to
perform the Secured Obligations in accordance with the terms of the Loan Documents, or the ability of Agent or Lender to enforce any of their rights or remedies
with respect to the Secured Obligations; or (iii) the Collateral or Agent’s Liens on the Collateral or the priority of such Liens.
“Maximum Term Loan Amount” means an aggregate amount up to Forty Million Dollars ($40,000,000); provided, however, after giving effect to the funding
of the 2020 Term D Loan Advance, Maximum Term Loan Amount shall mean Forty Five Million Dollars ($45,000,000).

“Maximum Rate” shall have the meaning assigned to such term in Section 2.2.
“Milestone A Event” means the satisfaction of each of the following: (a) no Default or Event of Default shall have occurred and is continuing and (b) the
approval by the Food and Drug Administration of the new drug application for Tivozanib as a treatment for relapsed or refractory renal cell carcinoma, for patients in
at least the third-line and fourth-line setting, no later than June 30, 2021 and with a label claim generally consistent with that sought in Borrower’s new drug
application filing, as determined by Agent in its reasonable discretion.
“Milestone B Event” means receipt by Agent of evidence in form and substance reasonably satisfactory to it that Borrower has achieved $35,000,000 in Net
Product Revenue no later than April 1, 2022.
“Milestone C Event” means receipt by Agent of evidence in form and substance reasonably satisfactory to it that Borrower has achieved $30,000,000 in Net
Product Revenue for the trailing three- (3) month period ended on such date no later than December 15, 2022.
“MSC Subsidiary” means AVEO Securities Corporation, a Massachusetts corporation, which is a Subsidiary of Borrower that has applied or is in the process
of applying to be classified as a “security corporation” under Massachusetts General Laws Ch. 63, Section 38B(a), as amended, supplemented and/or modified.
“Net Product Revenue” means, as of any date of determination or applicable period, net product revenue (as determined in accordance with GAAP) from the
sale of Tivozanib (which for the avoidance of doubt shall not include any royalty, profit sharing, or milestone revenue) in the United States. For the further avoidance
of doubt, when calculating “Net Products Revenue” the tiered royalties Aveo would owe to KKC on annual net sales of Tivozanib, which are classified as “cost of
goods sold” in accordance with GAAP, shall not be deducted.
“Note(s)” means a Term Note.
“OFAC” is the U.S. Department of Treasury Office of Foreign Assets Control.
“OFAC Lists” are, collectively, the Specially Designated Nationals and Blocked Persons List maintained by OFAC pursuant to Executive Order No. 13224,
66 Fed. Reg. 49079 (Sept. 25, 2001) and/or any other list of terrorists or other restricted Persons maintained pursuant to any of the rules and regulations of OFAC or
pursuant to any other applicable Executive Orders.
“Ordinary Course of Business” means the normal and customary operations of Borrower and/or its Subsidiaries, as applicable, and their business, including
activities relating to the identification, acquisition through license or otherwise, development or commercialization of a biologic or drug.
“Original End of Term Charge” has the meaning given to it in Section 2.5 hereof.
“Original Facility Charge” means one-half of one percent (0.50%) of the Maximum Term Loan Amount as of the Closing Date, which was One Hundred
Thousand Dollars ($100,000.00).
“Original Loan and Security Agreement” means that certain Loan and Security Agreement dated as of May 28, 2010 (as amended by that certain Amendment
No.1 to Loan and Security Agreement dated as of December 21, 2011, that certain Amendment No.2 to Loan and Security Agreement dated as of March 31, 2012,
that certain Amendment No. 3 to Loan and Security Agreement dated as of September 24, 2014, and that certain Amendment No.4 to Loan

and Security Agreement dated as of May 13, 2016, and as further amended, restated, supplemented, or otherwise modified from time to time prior to December 28,
2017.
“Patent License” means any written agreement granting any right with respect to any invention on which a Patent is in existence or a Patent application is
pending, in which agreement Borrower now holds or hereafter acquires any interest.
“Patents” means all letters patent of, or rights corresponding thereto, in the United States or in any other country, all registrations and recordings thereof, and
all applications for letters patent of, or rights corresponding thereto, in the United States or any other country.
“Permitted Indebtedness” means: (i) Indebtedness of Borrower in favor of Lender or Agent arising under this Agreement or any other Loan Document; (ii)
Indebtedness existing on the Closing Date which is disclosed in Schedule 1A; (iii) Indebtedness of up to $3,000,000, in the aggregate, outstanding at any time
secured by a lien described in clause (vii) of the defined term “Permitted Liens”; (iv) Indebtedness to trade creditors incurred in the Ordinary Course of Business,
including Indebtedness incurred in the Ordinary Course of Business with corporate credit cards; (v) Indebtedness that also constitutes a Permitted Investment; (vi)
Subordinated Indebtedness; (vii) other Indebtedness in a principal amount not to exceed $1,000,000 at any time outstanding, (viii) reimbursement obligations in
connection with letters of credit in an amount not to exceed $1,000,000 undrawn at any time, (ix) guarantees of any items of Permitted Indebtedness in clauses (i)
through (viii) above and (x) extensions, refinancing and renewals of any items of Permitted Indebtedness, provided that the principal amount is not increased or the
terms modified to impose materially more burdensome terms upon Borrower or its Subsidiary, as the case may be.
“Permitted Investment” means: (i) Investments existing on the Closing Date which are disclosed in Schedule 1B; (ii) (a) marketable direct obligations issued
or unconditionally guaranteed by the United States of America or any agency or any State thereof maturing within two years from the date of acquisition thereof, (b)
commercial paper maturing no more than two years from the date of creation thereof and currently having a rating of at least A-2 or P-2 from either Standard &
Poor’s Corporation or Moody’s Investors Service, (c) certificates of deposit issued by any bank with assets of at least $500,000,000 maturing no more than two years
from the date of investment therein, (d) money market accounts, and (e) Cash Equivalents; (iii) repurchases of stock from former employees, directors, or consultants
of Borrower under the terms of applicable repurchase agreements at the original issuance price of such securities in an aggregate amount not to exceed $250,000 in
any fiscal year, provided that no Event of Default has occurred, is continuing or would exist after giving effect to the repurchases; (iv) Investments accepted in
connection with Permitted Transfers; (v) Investments (including debt obligations) received in connection with the bankruptcy or reorganization of customers or
suppliers and in settlement of delinquent obligations of, and other disputes with, customers or suppliers arising in the Ordinary Course of Business; (vi) Investments
consisting of notes receivable of, or prepaid royalties and other credit extensions, to customers and suppliers who are not affiliates, in the Ordinary Course of
Business, provided that this subparagraph (vi) shall not apply to Investments of Borrower in any Subsidiary; (vii) Investments consisting of loans not involving the
net transfer on a substantially contemporaneous basis of cash proceeds to employees, officers or directors relating to the purchase of capital stock of Borrower
pursuant to employee stock purchase plans or other similar agreements approved by Borrower’s Board of Directors; (viii) Investments consisting of travel advances
in the Ordinary Course of Business; (ix) Investments in newly-formed Domestic Subsidiaries, provided that such Domestic Subsidiaries enter into a Joinder
Agreement promptly after their formation by Borrower and execute such other documents as shall be reasonably requested by Agent; (x) Investments in any
Subsidiary which is not a Borrower which do not exceed $1,000,000 in cash in the aggregate in any fiscal year; (xi) joint ventures or strategic alliances in the
Ordinary Course of Business; (xii) Investments

consisting of in-licensing of technology or products in the Ordinary Course of Business; (xiii) Permitted Indebtedness that also constitute Investments; (xiv)
additional Investments that do not exceed $1,000,000 in cash in the aggregate in any fiscal year; (xv) Investments constituting treasury management made in
accordance with Borrower’s investment policy, as approved by Borrower’s Board of Directors; (xvi) Investments by Borrower in any other Borrower; (xvii)
Investments utilizing Borrower’s stock as consideration that do not result in a Change in Control; and (xviii) Investments in the MSC Subsidiary in accordance with
Section 7.18.
“Permitted Liens” means any and all of the following: (i) Liens in favor of Agent or Lender; (ii) Liens existing on the Closing Date which are disclosed in
Schedule 1C; (iii) Liens for taxes, fees, assessments or other governmental charges or levies, either not delinquent or being contested in good faith by appropriate
proceedings; provided, that Borrower maintains adequate reserves therefor in accordance with GAAP; (iv) Liens securing claims or demands of materialmen,
artisans, mechanics, carriers, warehousemen, landlords and other like Persons arising in the ordinary course of Borrower’s business and imposed without action of
such parties; provided, that the payment thereof is not yet required; (v) Liens arising from judgments, decrees or attachments in circumstances which do not
constitute an Event of Default hereunder; (vi) the following deposits, to the extent made in the Ordinary Course of Business: deposits under worker’s compensation,
unemployment insurance, social security and other similar laws, or to secure the performance of bids, tenders or contracts (other than for the repayment of borrowed
money) or to secure indemnity, performance or other similar bonds for the performance of bids, tenders or contracts (other than for the repayment of borrowed
money) or to secure statutory obligations (other than liens arising under ERISA or environmental liens) or surety or appeal bonds, or to secure indemnity,
performance or other similar bonds; (vii) Liens on Equipment or software or other intellectual property constituting purchase money liens and liens in connection
with capital leases securing Indebtedness permitted in clause (iii) of “Permitted Indebtedness”; (viii) Liens incurred in connection with Subordinated Indebtedness;
(ix) leasehold interests in leases or subleases and licenses granted in the Ordinary Course of Business and not interfering in any material respect with the business of
the licensor; (x) Liens in favor of customs and revenue authorities arising as a matter of law to secure payment of custom duties that are promptly paid on or before
the date they become due; (xi) Liens on insurance proceeds securing the payment of financed insurance premiums that are promptly paid on or before the date they
become due (provided that such Liens extend only to such insurance proceeds and not to any other property or assets); (xii) statutory and common law rights of set-
off and other similar rights as to deposits of cash and securities in favor of banks, other depository institutions and brokerage firms; (xiii) easements, zoning
restrictions, rights-of-way and similar encumbrances on real property imposed by law or arising in the Ordinary Course of Business so long as they do not materially
impair the value or marketability of the related property; (xiv) licenses that constitute Permitted Transfers; (xv) Liens on cash and cash equivalents securing letters of
credit permitted under clause (viii) of the definition of “Permitted Indebtedness;” and (xvi) Liens incurred in connection with the extension, renewal or refinancing of
the indebtedness secured by Liens of the type described in clauses (i) through (xi) above; provided, that any extension, renewal or replacement Lien shall be limited
to the property encumbered by the existing Lien and the principal amount of the indebtedness being extended, renewed or refinanced (as may have been reduced by
any payment thereon) does not increase.
“Permitted Transfers” means:
(i)
the conveyance, sale, lease, license, transfer or disposition of Inventory (whether as raw material, work in process, finished product or
otherwise) in the Ordinary Course of Business,
(ii)
licenses and similar arrangements for the use of Intellectual Property of Borrower or its Subsidiaries in the Ordinary Course of Business that
could not result in a legal

transfer of title of the licensed property that may be exclusive in respects other than territory or may be exclusive as to territory but only as to discreet geographical
areas outside of the United States of America, in each case unless Agent has provided its consent to any such transaction (such consent not to be unreasonably
withheld, conditioned or delayed),
(iii)
the conveyance, sale, lease, license, transfer or disposition of worn-out, obsolete or surplus Equipment at fair market value in the Ordinary
Course of Business,
(iv)
the conveyance, sale, lease, license, transfer or disposition of other assets having a fair market value of not more than $1,000,000 in the
aggregate in any fiscal year,
(v)
property between Borrower and another Borrower,
(vi)
Permitted Liens, and
(vii)
Permitted Investments.
“Person” means any individual, sole proprietorship, partnership, joint venture, trust, unincorporated organization, association, corporation, limited liability
company, institution, other entity or government.
“Prepayment Charge” shall have the meaning assigned to such term in Section 2.4.
“Prime Rate” means the prime rate as reported in The Wall Street Journal, and if not reported, then the prime rate most recently reported in The Wall Street
Journal.
“Qualified Subsidiary” means any direct or indirect Domestic Subsidiary.
“Receivables” means all of Borrower’s Accounts, Instruments, Documents, Chattel Paper, Supporting Obligations, letters of credit, proceeds of any letter of
credit, and Letter of Credit Rights.
“Required Lenders” means at any time, the holders of more than fifty percent (50%) of the aggregate unpaid principal amount of the 2020 Term Loan
Advances then outstanding.
“Sanctioned Country” shall mean, at any time, a country or territory which is the subject or target of any Sanctions.
“Sanctioned Person” shall mean, at any time, (a) any Person listed in any Sanctions-related list of designated Persons maintained by the Office of Foreign
Assets Control of the U.S. Department of the Treasury or the U.S. Department of State, or by the United Nations Security Council, the European Union or any EU
member state, (b) any Person operating, organized or resident in a Sanctioned Country or (c) any Person controlled by any such Person.
“Sanctions” shall mean economic or financial sanctions or trade embargoes imposed, administered or enforced from time to time by (a) the U.S. government,
including those administered by the Office of Foreign Assets Control of the U.S. Department of the Treasury or the U.S. Department of State, or (b) the United
Nations Security Council, the European Union or Her Majesty’s Treasury of the United Kingdom.
“SBA” has the meaning given to it in Section 7.23.
“SBA Funding Date” shall mean each date on which each of the following has occurred (i) a Lender which is an SBIC funds any portion of the Loan, (ii)
prior written notice of the same

has been provided to Borrower and (iii) a completed Exhibit I to this agreement has been delivered by Borrower to Agent, which shall occur promptly (but in any
event within three (3) Business Days) after the notice provided in clause (ii) above.
“SBIC” has the meaning given to it in Section 7.23.
“SBIC Act” has the meaning given to it in Section 7.23.
“Second Amendment” has the meaning given to it in the preamble to this Agreement.
“Second Amendment Closing Date” means February 1, 2021.
“Secured Obligations” means Borrower’s obligations under this Agreement and any Loan Document, including any obligation to pay any amount now owing
or later arising.
“Subordinated Indebtedness” means Indebtedness subordinated to the Secured Obligations in amounts and on terms and conditions satisfactory to Agent in its
sole discretion.
“Subsidiary” means an entity, whether corporate, partnership, limited liability company, joint venture or otherwise, in which Borrower owns or controls 50%
or more of the outstanding voting securities, including each entity listed on Schedule 1D hereto; provided, however, that the definition of Subsidiary shall not include
the MSC Subsidiary with respect to the representations and warranties provided for in Section 5 and the covenants provided for in Section 7 (other than Section
7.18); provided, further, that, for the avoidance of doubt, (i) the financial statements, reports and other information to be delivered to Lender pursuant to Section 7.1
shall include the MSC Subsidiary on a consolidated and consolidating basis and (ii) the MSC Subsidiary shall not be required under Section 7.14 to execute and
deliver a Joinder Agreement.
“Term Loan Amortization Date” means October 1, 2021; provided, however, that (i) if the Milestone A Event occurs, at the request of Borrower, Term Loan
Amortization Date shall mean October 1, 2022 and (ii) following the effectiveness of the extension described in clause (i), if Lender shall have advanced the 2020
Term C Loan Advances and no Default or Event of Default shall have occurred and is continuing, then at the request of Borrower, the Term Loan Amortization Date
shall mean April 1, 2023; provided that the parties agree that the Term Loan Amortization Date shall mean April 1, 2023 effective as of the Third Amendment
Closing Date.
“Term Loan Interest Rate” means for any day, a floating per annum rate equal to the greater of (a) nine and sixty-five hundredths percent (9.65%) or (b) the
sum of (i) nine and sixty-five hundredths percent (9.65%), plus (ii) the Prime Rate minus three and one-quarter percent (3.25%); provided, however, that in no event
shall the Term Loan Interest Rate exceed 15.0% (provided such limit does not include any Default Rate which may be imposed by Agent).
“Term Loan Maturity Date” means September 1, 2023; provided, however, that if Lender shall have advanced the 2020 Term C Loan Advances and no
Default or Event of Default shall have occurred and is continuing, then at the request of Borrower, the 2020 Term Loan Maturity Date shall mean September 1, 2024;
provided that the parties agree that the Term Loan Maturity Date shall mean September 1, 2024 effective as of the Third Amendment Closing Date.
“Term Note” means a Promissory Note in substantially the form of Exhibit B.
“Third Amendment” has the meaning given to it in the preamble to this Agreement.
“Third Amendment Closing Date” means March 8, 2022.

“Trademark License” means any written agreement granting any right to use any Trademark or Trademark registration, now owned or hereafter acquired by
Borrower or in which Borrower now holds or hereafter acquires any interest.
“Trademarks” means all trademarks (registered, common law or otherwise) and any applications in connection therewith, including registrations, recordings
and applications in the United States Patent and Trademark Office or in any similar office or agency of the United States, any State thereof or any other country or
any political subdivision thereof.
“UCC” means the Uniform Commercial Code as the same is, from time to time, in effect in the State of California; provided, that in the event that, by reason
of mandatory provisions of law, any or all of the attachment, perfection or priority of, or remedies with respect to, Agent’s Lien on any Collateral is governed by the
Uniform Commercial Code as the same is, from time to time, in effect in a jurisdiction other than the State of California, then the term “UCC” shall mean the
Uniform Commercial Code as in effect, from time to time, in such other jurisdiction solely for purposes of the provisions thereof relating to such attachment,
perfection, priority or remedies and for purposes of definitions related to such provisions.
Unless otherwise specified, all references in this Agreement or any Annex or Schedule hereto to a “Section,” “subsection,” “Exhibit,” “Annex,” or “Schedule”
shall refer to the corresponding Section, subsection, Exhibit, Annex, or Schedule in or to this Agreement. Unless otherwise specifically provided herein, any
accounting term used in this Agreement or the other Loan Documents shall have the meaning customarily given such term in accordance with GAAP, and all
financial computations hereunder shall be computed in accordance with GAAP, consistently applied. Unless otherwise defined herein or in the other Loan
Documents, terms that are used herein or in the other Loan Documents and defined in the UCC shall have the meanings given to them in the UCC.
Section 2. 
THE LOAN
1.1
2020 Term Loan Advances.
(a)     Advances.
(i)    Prior to the effectiveness of the First Amendment and the refinancing of the Existing Term Loan Advances as contemplated herein, Lender had
extended certain term loans to Borrower, of which the Existing Term Loan Advances remained outstanding. Agent, Lender and Borrower hereby agree
that, from and after the First Amendment Closing Date, such entire outstanding principal balance of the Existing Term Loan Advances shall for all
purposes hereunder be deemed to constitute and be referred to, and hereby is converted into, the 2020 Term A Loan Advances hereunder, without
constituting a novation. Such conversion of the Existing Term Loan Advances into the 2020 Term A Loan Advances hereunder shall be deemed an
Advance on the First Amendment Closing Date for purposes of this Agreement. Subject to the terms and conditions of this Agreement and the First
Amendment, in furtherance of the foregoing, Borrower shall submit a written request in accordance with this Agreement for, and each Lender will
severally (and not jointly) make, a single Advance on the First Amendment Closing Date in an amount not to exceed its respective 2020 Term A
Commitment (each a “2020 Term A Loan Advance”, and collectively, the “2020 Term A Loan Advances”). For the avoidance of doubt, from and after
the First Amendment Closing Date (and after giving effect to the transactions contemplated pursuant to this clause (i), including the conversion of the
Existing Term Loan Advances) the principal amount of the Existing Term Loan Advances

shall be deemed to be $0 and Lender’s obligation to make any Advances under the Existing Term Commitment shall have terminated.
Notwithstanding any other provision of this Agreement, it is further agreed that Borrower shall not be required to pay any prepayment charge in
connection with the repayment of the Existing Term Loan Advances. As of the Second Amendment Closing Date, it is acknowledged and agreed that
Lender made the 2020 Term A Loan Advances to Borrower on the First Amendment Closing Date in an aggregate amount equal to the 2020 Term
Loan A Commitments.
(ii)    Subject to the terms and conditions of this Agreement (including Section 4.2(a)), on or prior to the earlier of (x) June 30, 2021 and (y) the date
that is 30 days after the date that the Milestone A Event has occurred, Borrower may submit a written request in accordance with this Agreement for,
and each Lender will severally (and not jointly) make, a single 2020 Term B Loan Advance in an amount not to exceed its respective 2020 Term B
Commitment, (each a “2020 Term B Loan Advance”, and collectively, the “2020 Term B Loan Advances”).
(iii)    Subject to the terms and conditions of this Agreement (including Section 4.2(b)), on or after July 1, 2021 but on or prior to April 1, 2022,
Borrower may submit a written request in accordance with this Agreement for, and each Lender will severally (and not jointly) make, a single 2020
Term C Loan Advance in an amount not to exceed its respective 2020 Term C Commitment (each a “2020 Term C Loan Advance”, and collectively,
the “2020 Term C Loan Advances”).
(iv)    Subject to the terms and conditions of this Agreement (including Section 4.2(c)), on or prior to December 15, 2022, Borrower may submit a
written request in accordance with this Agreement for, and each Lender will severally (and not jointly) make, a single 2020 Term D Loan Advance in
an amount not to exceed its respective 2020 Term D Share (each a “2020 Term D Loan Advance”, and collectively, the “2020 Term D Loan
Advances”).
(v)    The 2020 Term A Loan Advances, the 2020 Term B Loan Advances, the 2020 Term C Loan Advances, and the 2020 Term D Loan Advances are
hereinafter referred to each as a “2020 Term Loan Advance” and collectively as the “2020 Term Loan Advances.” The aggregate outstanding principal
amount of the Advances shall not exceed the Maximum Term Loan Amount. Proceeds of any 2020 Term Loan Advance shall be deposited into a
Deposit Account that is subject to a first priority perfected security interest in favor of Agent perfected by an Account Control Agreement.
(b)     Advance Request. To obtain the 2020 Term A Loan Advances, Borrower shall complete, sign and deliver an Advance Request at least one (1)
Business Day before the First Amendment Closing Date and for any other 2020 Term Loan Advance, Borrower shall complete, sign and deliver an Advance
Request at least five (5) Business Days before the applicable Advance Date to Agent. Lender shall fund each applicable 2020 Term Loan Advance in the
manner requested by the applicable Advance Request; provided that each of the applicable conditions precedent to such 2020 Term Loan Advance is satisfied
as of the requested Advance Date.
(c) Interest. The outstanding principal balance of each 2020 Term Loan Advance shall bear interest thereon from such Advance Date at the Term Loan
Interest Rate based on a year consisting of 360 days, with interest computed daily based on the actual number of days elapsed. The Term Loan Interest Rate
will float and change on the day the Prime Rate changes from time to time.

(d) Payment. Borrower will pay (I) all accrued and outstanding interest owing in respect of the Existing Term Loan Advances shall be repaid on
September 1, 2020 and (II) all accrued and unpaid interest owing in respect of each 2020 Term Loan Advance on the first (1st) Business Day of each month,
beginning the month after the applicable Advance Date thereof. Borrower shall repay the aggregate 2020 Term Loan Advances principal balance that is
outstanding on the day immediately preceding the Term Loan Amortization Date, in equal monthly installments of principal and interest (mortgage style),
beginning on the Term Loan Amortization Date and continuing on the first Business Day of each month thereafter until the Secured Obligations (other than
inchoate indemnity obligations) are repaid. Notwithstanding the foregoing, the entire 2020 Term Loan Advances principal balance and all accrued but unpaid
interest hereunder, shall be due and payable on the Term Loan Maturity Date. Borrower shall make all payments under this Agreement without setoff,
recoupment or deduction and regardless of any counterclaim or defense. Lender will initiate debit entries to Borrower’s account as authorized on the ACH
Authorization (i) on each payment date of all periodic obligations payable to Lender under each 2020 Term Loan Advance and (ii) reasonable and invoiced
out-of-pocket legal fees and costs incurred by Agent or Lender in connection with Section 11.11 of this Agreement; provided that, in the event that Lender or
Agent informs Borrower that Lender will not initiate a debit entry to Borrower’s account for a certain amount of the periodic obligations due on a specific
payment date, Borrower shall pay to Lender such amount of periodic obligations in full in immediately available funds on such payment date; provided,
further, that, if Lender or Agent informs Borrower that Lender will not initiate a debit entry as described above later than the date that is three (3) Business
Days prior to such payment date, Borrower shall pay to Lender such amount of periodic obligations in full in immediately available funds on the date that is
three (3) Business Days after the date on which Lender or Agent notifies Borrower of such, and such payment shall be considered timely made and shall not
constitute a default or an Event of Default hereunder. Once repaid, a 2020 Term Loan Advance or any portion thereof may not be reborrowed.
1.2
Maximum Interest. Notwithstanding any provision in this Agreement, the Notes, or any other Loan Document, it is the parties' intent not to contract
for, charge or receive interest at a rate that is greater than the maximum rate permissible by law that a court of competent jurisdiction shall deem applicable hereto
(which under the laws of the State of California shall be deemed to be the laws relating to permissible rates of interest on commercial loans) (the “Maximum Rate”).
If a court of competent jurisdiction shall finally determine that Borrower has actually paid to Lender an amount of interest in excess of the amount that would have
been payable if all of the Secured Obligations had at all times borne interest at the Maximum Rate, then such excess interest actually paid by Borrower shall be
applied as follows: first, to the payment of the Secured Obligations consisting of the outstanding principal; second, after all principal is repaid, to the payment of
Lender’s accrued interest, costs, expenses, professional fees and any other Secured Obligations; and third, after all Secured Obligations are repaid, the excess (if any)
shall be refunded to Borrower.
1.3
Default Interest. In the event any payment is not paid on the scheduled payment date, subject to applicable grace periods, an amount equal to two
percent (2%) of the past due amount shall be payable on demand. In addition, upon the occurrence and during the continuation of an Event of Default hereunder, all
Secured Obligations, including principal, interest, compounded interest, and professional fees, shall bear interest at a rate per annum equal to the rate set forth in
Section 2.1(c), plus five percent (5%) per annum. In the event any interest is not paid when due hereunder, delinquent interest shall be added to principal and shall
bear interest on interest, compounded at the rate set forth in Section 2.1(c) or Section 2.3, as applicable. Notwithstanding the foregoing, for the avoidance of doubt,
nothing in this Section 2.3 shall apply to payments timely made in accordance with Section 2.1(d).

1.4
Prepayment.
(a)
At its option upon at least seven (7) Business Days prior notice to Lender, Borrower may prepay all, but not less than all, of the outstanding
2020 Term Loan Advance by paying the entire principal balance, all accrued and unpaid interest, all unpaid Lender’s fees and expenses accrued to the date of
the prepayment (including the Original End of Term Charge (if then unpaid) and the 2020 End of Term Charge), together with a prepayment charge equal to
the following percentage of the principal 2020 Term Loan Advance amount being prepaid: if such 2020 Term Loan Advance is prepaid in any of the first
twelve (12) months following the First Amendment Closing Date, three percent (3.00%); after twelve (12) months following the First Amendment Closing
Date but on or prior to twenty-four (24) months following the First Amendment Closing Date, two percent (2.00%); after twenty-four (24) months following
the First Amendment Closing Date but on or prior to thirty-six (36) months following the First Amendment Closing Date, one percent (1.00%); and at all
times thereafter, zero percent (0.00%) (each, a “Prepayment Charge”).
(b)
Notwithstanding the foregoing, Agent and Lender agree to waive the Prepayment Charge if Agent and Lender, or any Affiliate of Agent or
Lender (in their sole and absolute discretion) agree in writing to refinance the Advances prior to the Term Loan Maturity Date.
1.5
End of Term Charge.
(a)
On the earliest to occur of (i) July 1, 2021 or (ii) the date that Borrower prepays the outstanding Secured Obligations (other than the Existing
Term Loan Advances, any inchoate indemnity obligations and any other obligations which, by their terms, are to survive the termination of this Agreement) in
full, Borrower shall pay Lender a charge of Seven Hundred Ninety Thousand Dollars ($790,000.00) (the “Original End of Term Charge”). Notwithstanding
the required payment date of such charge, the Original End of Term Charge shall be deemed fully earned by Lender as of the Closing Date.
(b)
On the earliest to occur of (i) the Term Loan Maturity Date or (ii) the date that Borrower prepays the outstanding Secured Obligations (other
than the Existing Term Loan Advances, any inchoate indemnity obligations and any other obligations which, by their terms, are to survive the termination of
this Agreement) in full, Borrower shall pay Lender a charge equal to six and ninety-five hundredths percent (6.95%) multiplied by the aggregate original
principal amount of all 2020 Term Loan Advances extended by Lender (the “2020 End of Term Charge” and together with the Original End of Term Charge,
the “End of Term Charge”). Notwithstanding the required payment date of such charge, the applicable pro rata portion of the 2020 End of Term Charge shall
be deemed fully earned by Lender as of each date a 2020 Term Loan Advance is made.
1.6
Original Loan and Security Agreement Prepayment Charges. Lender and Agent hereby agree that the Prepayment Charge (as defined in the Original
Loan and Security Agreement) and the 2016 Prepayment Charge (as defined in the Original Loan and Security Agreement) are hereby waived.
1.7
Notes. If so requested by Lender by written notice to Borrower, then Borrower shall execute and deliver to Lender (and/or, if applicable and if so
specified in such notice, to any Person who is an assignee of Lender pursuant to Section 11.13) (promptly after Borrower’s receipt of such notice) a Note or Notes to
evidence Lender’s Loans.

1.8
Treatment of Prepayment Charge and End of Term Charge. Borrower agrees that any Prepayment Charge and any End of Term Charge payable shall
be presumed to be the liquidated damages sustained by each Lender as the result of the early termination, and Borrower agrees that it is reasonable under the
circumstances currently existing and existing as of the Closing Date, First Amendment Closing Date, Second Amendment Closing Date and Third Amendment
Closing Date. The Prepayment Charge and the End of Term Charge, together with the outstanding amount of all principal and accrued interest through the
prepayment date and all unpaid Lender’s fees and out-of-pocket expenses under the Loan Documents accrued to the date of the repayment shall also be payable in the
event of (i) a Change in Control or (ii) the Secured Obligations (and/or this Agreement) become due and payable (whether by acceleration or otherwise) or are
satisfied or released by foreclosure (whether by power of judicial proceeding), deed in lieu of foreclosure, or by any other means. Borrower expressly waives (to the
fullest extent it may lawfully do so) the provisions of any present or future statute or law that prohibits or may prohibit the collection of the foregoing Prepayment
Charge and End of Term Charge in connection with any such acceleration. Borrower agrees (to the fullest extent that each may lawfully do so): (a) each of the
Prepayment Charge and the End of Term Charge is reasonable and is the product of an arm’s length transaction between sophisticated business people, ably
represented by counsel; (b) each of the Prepayment Charge and the End of Term Charge shall be payable notwithstanding the then prevailing market rates at the time
payment is made; (c) there has been a course of conduct between the Lenders and Borrower giving specific consideration in this transaction for such agreement to
pay the Prepayment Charge and the End of Term Charge as a charge (and not interest) in the event of prepayment or acceleration; (d) Borrower shall be estopped
from claiming differently than as agreed to in this paragraph. Borrower expressly acknowledges that their agreement to pay each of the Prepayment Charge and the
End of Term Charge to the Lenders as herein described was on the Closing Date, First Amendment Closing Date, Second Amendment Closing Date and Third
Amendment Closing Date and continues to be a material inducement to the Lenders to provide the Term Loans.
Section 3. 
SECURITY INTEREST
1.1
As security for the prompt and complete payment when due (whether on the payment dates or otherwise) of all the Secured Obligations, Borrower
hereby grants to Agent a security interest in all of Borrower’s right, title, and interest in, to and under all of Borrower’s personal property now owned or hereafter
acquired, and other assets including without limitation the following (except as set forth herein) whether now owned or hereafter acquired (collectively, the
“Collateral”): (a) Receivables; (b) Equipment; (c) Fixtures; (d) General Intangibles (other than Intellectual Property); (e) Inventory; (f) Investment Property; (g)
Deposit Accounts; (h) Cash; (i) Goods and other tangible and intangible personal property of Borrower whether now or hereafter owned or existing, leased,
consigned by or to, or acquired by, Borrower and wherever located; and (j) to the extent not otherwise included, all Proceeds of each of the foregoing and all
accessions to, substitutions and replacements for, and rents, profits and products of each of the foregoing; provided, however, that the Collateral shall (i) include all
Accounts and General Intangibles that consist of rights to payment and proceeds from the sale, licensing or disposition of all or any part, or rights in, the Intellectual
Property (the “Rights to Payment”) and (ii) not include (A) more than 65% of the issued and outstanding voting capital stock of any Subsidiary that is incorporated or
organized in a jurisdiction other than the United States or any state or territory thereof or the District of Columbia; (B) Intellectual Property (other than Rights to
Payment); (C) any Equipment or Proceeds thereof that is subject to a Lien that is otherwise permitted by clause (vii) of the definition of “Permitted Lien” hereunder
if inclusion of such Equipment would constitute a breach by Borrower of its agreement with a third-party equipment lessor or lender, provided, that upon the release
of any such Lien such Equipment shall be deemed to be Collateral hereunder and shall be subject to the security interest granted herein; and (D) 100% of the issued
and outstanding capital stock of the MSC Subsidiary. Notwithstanding the foregoing, if a judicial authority (including a U.S. Bankruptcy Court) holds that a security

interest in the underlying Intellectual Property is necessary to have a security interest in the Rights to Payment, and the existence of such security interest would not
otherwise violate or breach any provision in any applicable agreement or contract that is enforceable under the UCC with respect to the applicable Intellectual
Property, then the Collateral shall automatically, and effective as of the Closing Date, include the Intellectual Property to the extent necessary to permit perfection of
Agent’s security interest in the Rights to Payment. Lender hereby agrees to provide Borrower, at Borrower’s expense, with any release, partial termination or other
documents reasonably requested by Borrower to reflect or confirm that the Collateral does not include any property excluded from the definition thereof.
Section 4. 
CONDITIONS PRECEDENT TO LOAN
The obligations of Lender to make the Loan hereunder are subject to the satisfaction by Borrower of the following conditions:
1.1
Closing Date. On or prior to the Closing Date, Borrower shall have delivered to Agent the following:
(a)
executed originals of the Loan Documents, Account Control Agreements, and all other documents and instruments reasonably required by
Agent to effectuate the transactions contemplated hereby or to create and perfect the Liens of Agent with respect to all Collateral, in all cases in form and
substance reasonably acceptable to Agent;
(b)
certified copy of resolutions of Borrower’s board of directors evidencing approval of the Loan and other transactions evidenced by the Loan
Documents;
(c)
certified copies of the Certificate of Incorporation and the Bylaws, as amended through the Closing Date, of Borrower;
(d)
a certificate of good standing for Borrower from its state of incorporation and similar certificates from all other jurisdictions in which it does
business and where the failure to be qualified would have a Material Adverse Effect;
(e)
payment of the Original Facility Charge and reimbursement of Agent’s and Lender’s current expenses reimbursable pursuant to this
Agreement, which amounts may be deducted from the initial Advance;
(f)
all certificates of insurance and copies of each insurance policy required hereunder; and
(g)
such other documents as Agent may reasonably request.
1.2
Further Conditions.
(a)
On or prior the requested Advance Date for the 2020 Term B Loan Advances, Borrower shall have delivered to Agent evidence in form and
substance reasonably satisfactory to Agent that the Milestone A Event shall have occurred.
(b)
On or prior the requested Advance Date for the 2020 Term C Loan Advances, Borrower shall have delivered to Agent evidence in form and
substance reasonably satisfactory to Agent that the Milestone B Event shall have occurred.
(c)
On or prior the requested Advance Date for the 2020 Term D Loan Advances, (i) Agent shall have received a nonrefundable, fully earned
facility charge in

the amount of Forty Two Thousand Five Hundred Dollars ($42,500.00) in good and collected funds, (ii) Borrower shall have delivered such financial and
other information required by Agent in form and substance reasonably satisfactory to it and (iii) Borrower shall have delivered to Agent evidence in form and
substance reasonably satisfactory to Agent that the Milestone C Event shall have occurred.
(d)
On each Advance Date:
(i)    Agent shall have received (i) an Advance Request for the relevant Advance as required by Section 2.1(b), duly executed by Borrower’s
Chief Executive Officer or Chief Financial Officer, and (ii) any other documents Agent may reasonably request.
(ii)    The representations and warranties set forth in this Agreement and in Section 5 shall be true and correct in all material respects on and as
of such Advance Date with the same effect as though made on and as of such date, except to the extent such representations and warranties expressly
relate to an earlier date.
(iii)    Borrower shall be in compliance in all material respects with all the terms and provisions set forth herein and in each other Loan
Document on its part to be observed or performed, and at the time of and immediately after such Advance no Default or Event of Default shall have
occurred and is continuing.
(iv)    The Advance Request in respect of the applicable Advance shall be deemed to constitute a representation and warranty by Borrower on
such Advance Date as to the matters specified in paragraphs (ii) and (iii) of this Section 4.2(b) and as to the matters set forth in such Advance Request.
For the avoidance of doubt, it is understood and agreed that the foregoing are conditions to funding only, and failure to meet any of the foregoing
requirements will not, in and of itself, result in a Default or Event of Default hereunder.
1.3
No Default. As of the Closing Date and each Advance Date, no fact or condition exists that would (or would, with the passage of time, the giving of
notice, or both) constitute an Event of Default.
Section 5. 
REPRESENTATIONS AND WARRANTIES OF BORROWER
Borrower represents and warrants that:
1.1
Corporate Status. Borrower is a corporation duly organized, legally existing and in good standing under the laws of the State of Delaware, and is duly
qualified as a foreign corporation in all jurisdictions in which the nature of its business or location of its properties require such qualifications and where the failure to
be qualified would reasonably be expected to have a Material Adverse Effect. Borrower’s present name, former names (if any), locations, place of formation, tax
identification number, organizational identification number and other information are correctly set forth in Exhibit C.
1.2
Collateral. Borrower owns the Collateral and the Intellectual Property (except for Permitted Transfers), free of all Liens, except for Permitted Liens
and JV Restrictions. Borrower has the power and authority to grant to Agent a Lien in the Collateral as security for the Secured Obligations.

1.3
Consents. Borrower’s execution, delivery and performance this Agreement and all other Loan Documents,
(i)    have been duly authorized by all necessary corporate action of Borrower,
(ii)    will not result in the creation or imposition of any Lien upon the Collateral, other than Permitted Liens and the Liens created by this Agreement
and the other Loan Documents,
(iii)    do not violate any provisions of Borrower’s Certificate of Incorporation, bylaws, or any material law, regulation, order, injunction, judgment,
decree or writ to which Borrower is subject and (iv) do not violate any material contract or agreement or require the consent or approval of any other
Person that has not been obtained. The individual or individuals executing the Loan Documents are duly authorized to do so.
1.4
Material Adverse Effect. No event that has had or could reasonably be expected to have a Material Adverse Effect has occurred and is continuing.
Borrower is not aware of any event likely to occur that is reasonably expected to result in a Material Adverse Effect.
1.5
Actions Before Governmental Authorities. Except as described on Schedule 5.5, there are no actions, suits or proceedings at law or in equity or by or
before any governmental authority now pending or, to the knowledge of Borrower, threatened in writing against or affecting Borrower or its property (i) which
involve any Loan Document or (ii) as to which there is a reasonable possibility of an adverse determination and which, if adversely determined, would reasonably be
expected to result in a Material Adverse Effect.
1.6
Laws. Borrower is not in violation of any law, rule or regulation, or in default with respect to any judgment, writ, injunction or decree of any
governmental authority, where such violation or default is reasonably expected to result in a Material Adverse Effect. Borrower is not in default in any manner under
any provision of any agreement or instrument evidencing indebtedness, or any other material agreement to which it is a party or by which it is bound and for which
such default would reasonably be expected to result in an Material Adverse Effect.
Neither Borrower nor any of its Subsidiaries is an “investment company” or a company “controlled” by an “investment company” under the Investment
Company Act of 1940, as amended. Neither Borrower nor any of its Subsidiaries is engaged as one of its important activities in extending credit for margin stock
(under Regulations X, T and U of the Federal Reserve Board of Governors). Borrower and each of its Subsidiaries has complied in all material respects with the
Federal Fair Labor Standards Act. Neither Borrower nor any of its Subsidiaries is a “holding company” or an “affiliate” of a “holding company” or a “subsidiary
company” of a “holding company” as each term is defined and used in the Public Utility Holding Company Act of 2005. Neither Borrower’s nor any of its
Subsidiaries’ properties or assets has been used by Borrower or such Subsidiary or, to Borrower’s knowledge, by previous Persons, in disposing, producing, storing,
treating, or transporting any hazardous substance other than in material compliance with applicable laws. Borrower and each of its Subsidiaries has obtained all
consents, approvals and authorizations of, made all declarations or filings with, and given all notices to, all Governmental Authorities that are necessary to continue
their respective businesses as currently conducted, except to the extent that the failure to obtain, make or give any of the foregoing would not reasonably be expected
to cause a Material Adverse Effect.
None of Borrower, any of its Subsidiaries, or, to Borrower’s knowledge, any of Borrower’s or its Subsidiaries’ Affiliates or any of their respective agents
acting or benefiting in any capacity in connection with the transactions contemplated by this Agreement is (i) in

violation of any Anti-Terrorism Law, (ii) engaging in or conspiring to engage in any transaction that evades or avoids, or has the purpose of evading or avoiding or
attempts to violate, any of the prohibitions set forth in any Anti-Terrorism Law, or (iii) is a Blocked Person. None of Borrower, any of its Subsidiaries, or, to the
knowledge of Borrower, any of their Affiliates or agents, acting or benefiting in any capacity in connection with the transactions contemplated by this Agreement, (x)
conducts any business or engages in making or receiving any contribution of funds, goods or services to or for the benefit of any Blocked Person, or (y) deals in, or
otherwise engages in any transaction relating to, any property or interest in property blocked pursuant to Executive Order No. 13224, any similar executive order or
other Anti-Terrorism Law. None of the funds to be provided under this Agreement will be used, directly or indirectly, (a) for any activities in violation of any
applicable anti-money laundering, economic sanctions and anti-bribery laws and regulations laws and regulations or (b) for any payment to any governmental official
or employee, political party, official of a political party, candidate for political office, or anyone else acting in an official capacity, in order to obtain, retain or direct
business or obtain any improper advantage, in violation of the United States Foreign Corrupt Practices Act of 1977, as amended.
1.7
Information Correct and Current. No information, report, Advance Request, financial statement, exhibit or schedule furnished, by or on behalf of
Borrower to Agent in connection with any Loan Document or included therein or delivered pursuant thereto contained, contains or will contain any material
misstatement of fact or omitted, omits or will omit to state any material fact necessary to make the statements therein, in the light of the circumstances under which
they were, are or will be made, not misleading in any material respect at the time such statement was made or deemed made. Additionally, any and all financial or
business projections provided by Borrower to Agent shall be provided in good faith based upon assumptions believed to be reasonable at the time.
1.8
Tax Matters. (a) Borrower has filed all federal, state and local tax returns that it is required to file, (b) Borrower has duly paid or fully reserved in
accordance with GAAP for all taxes or installments thereof (including any interest or penalties) as and when due, which have or may become due pursuant to such
returns, and (c) Borrower has paid or fully reserved in accordance with GAAP for any tax assessment received by Borrower for the three (3) years preceding the
Closing Date, if any (including any taxes being contested in good faith and by appropriate proceedings), in each case, other than with respect to taxes that do not
exceed $25,000 in the aggregate.
1.9
Intellectual Property Claims. Borrower is the sole owner of, or otherwise has the right to use, the Intellectual Property. Except as described on
Schedule 5.9, to Borrower’s knowledge, (i) each of the material Copyrights, Trademarks and Patents is valid and enforceable, (ii) no part of the Intellectual Property
has been judged invalid or unenforceable, in whole or in part, and (iii) no claim has been made to Borrower that any part of the Intellectual Property violates the
rights of any third party, except to the extent that any of the foregoing would not reasonably be expected to cause a Material Adverse Effect. Exhibit D is a true,
correct and complete list of each of Borrower’s Patents, registered Trademarks, registered Copyrights, and material agreements under which Borrower licenses
Intellectual Property from third parties (other than shrink-wrap software licenses and other licenses which if terminated could not reasonably be expected to result a
Material Adverse Effect), together with application or registration numbers, as applicable, owned by Borrower or any Subsidiary, in each case as of the Closing Date
and each other date required by Section 7.15. Borrower is not in material breach of, nor has Borrower failed to perform any material obligations under, any of the
foregoing contracts, licenses or agreements and, to Borrower’s knowledge, no third party to any such contract, license or agreement is in material breach thereof or
has failed to perform any material obligations thereunder.

1.10
Intellectual Property. Except as described on Schedule 5.10, Borrower has, or in the case of any proposed business, will have, all rights with respect to
Intellectual Property necessary in the operation or conduct of Borrower’s business as currently conducted and proposed to be conducted by Borrower. Without
limiting the generality of the foregoing, and in the case of Licenses, except for restrictions that are unenforceable under Division 9 of the UCC, Borrower has the
right, to the extent required to operate Borrower’s business, to freely transfer, license or assign all material Intellectual Property without condition, restriction or
payment of any kind (other than license payments in the Ordinary Course of Business and JV Restrictions) to any third party, and Borrower owns or has the right to
use, pursuant to valid licenses, all software development tools, library functions, compilers and all other third-party software and other items that are material to
Borrower’s business and used in the design, development, promotion, sale, license, manufacture, import, export, use or distribution of Borrower Products.
1.11
Borrower Products. Except as described on Schedule 5.11, no Intellectual Property owned by Borrower or Borrower Product has been or is subject to
any actual or, to the knowledge of Borrower, threatened litigation, proceeding (including any proceeding in the United States Patent and Trademark Office or any
corresponding foreign office or agency) or outstanding decree, order, judgment, settlement agreement or stipulation that restricts in any manner Borrower’s use,
transfer or licensing thereof or that may affect the validity, use or enforceability thereof except to the extent any of the foregoing would not reasonably be expected to
cause a Material Adverse Effect. There is no decree, order, judgment, agreement, stipulation, arbitral award or other provision entered into in connection with any
litigation or proceeding that obligates Borrower to grant licenses or ownership interest in any future Intellectual Property related to the operation or conduct of the
business of Borrower or Borrower Products. Borrower has not received any written notice or claim, or, to the knowledge of Borrower, oral notice or claim,
challenging or questioning Borrower’s ownership in any Intellectual Property (or written notice of any claim challenging or questioning the ownership in any
licensed Intellectual Property of the owner thereof) or suggesting that any third party has any claim of legal or beneficial ownership with respect thereto nor, to
Borrower’s knowledge, is there a reasonable basis for any such claim except to the extent any of the foregoing would not reasonably be expected to cause a Material
Adverse Effect. To the knowledge of Borrower, neither Borrower’s use of its Intellectual Property nor the production and sale of Borrower Products infringes the
Intellectual Property or other rights of others in a manner as to be reasonably expected to cause a Material Adverse Effect.
1.12
Financial Accounts. Exhibit E, as may be updated by Borrower in a written notice provided to Agent after the Closing Date, is a true, correct and
complete list of (a) all banks and other financial institutions at which Borrower or any Subsidiary maintains Deposit Accounts and (b) all institutions at which
Borrower or any Subsidiary maintains an account holding Investment Property, and such exhibit correctly identifies the name, address and telephone number of each
bank or other institution, the name in which the account is held, a description of the purpose of the account, and the complete account number therefor.
1.13
Employee Loans. Except as permitted by Section 7.8, Borrower has no outstanding loans to any employee, officer or director of Borrower nor has
Borrower guaranteed the payment of any loan made to an employee, officer or director of Borrower by a third party.
1.14
Subsidiaries. Borrower does not own any stock, partnership interest or other equity securities of any Person, except for Permitted Investments and
each Subsidiary listed on Schedule 1D attached hereto. Attached as Schedule 1D, as may be updated by Borrower in a written notice provided after the Closing Date,
is a true, correct and complete list of each Subsidiary.

Section 6. 
INSURANCE; INDEMNIFICATION
1.1
Coverage. Borrower shall cause to be carried and maintained commercial general liability insurance, on an occurrence form, against risks customarily
insured against in Borrower’s line of business. Such risks shall include the risks of bodily injury, including death, property damage, personal injury, advertising
injury, and contractual liability per the terms of the indemnification agreement found in Section 6.3. Borrower must maintain a minimum of $2,000,000 of
commercial general liability insurance for each occurrence. Borrower has and agrees to maintain a minimum of $2,000,000 of directors’ and officers’ insurance for
each occurrence and $5,000,000 in the aggregate. So long as there are any Secured Obligations outstanding, Borrower shall also cause to be carried and maintained
insurance upon the Collateral to the extent a specific type of Collateral is customarily insured against in Borrower’s business and industry, insuring against all risks of
physical loss or damage howsoever caused, in an amount not less than the full replacement cost of the Collateral, provided that such insurance may be subject to
standard exceptions and deductibles.
1.2
Certificates. Borrower shall deliver to Agent certificates of insurance that evidence Borrower’s compliance with its insurance obligations in Section
6.1 and the obligations contained in this Section 6.2. Borrower’s insurance certificate shall state Agent (shown as “Hercules Capital, Inc., as Agent”) is an additional
insured for commercial general liability, a loss payee for all risk property damage insurance, subject to the insurer’s approval, and a loss payee for property insurance
and additional insured for liability insurance for any future insurance that Borrower may acquire from such insurer. Attached to the certificates of insurance will be
additional insured endorsements for liability and lender’s loss payable endorsements for all risk property damage insurance. All certificates of insurance will provide
for a minimum of thirty (30) days advance written notice to Agent of cancellation (other than cancellation for non-payment of premiums, for which ten (10) days’
advance written notice shall be sufficient) or any other change adverse to Agent’s interests. Any failure of Agent to scrutinize such insurance certificates for
compliance is not a waiver of any of Agent’s rights, all of which are reserved. Borrower shall provide Agent with copies of each insurance policy, and upon entering
or amending any insurance policy required hereunder, Borrower shall provide Agent with copies of such policies and shall promptly deliver to Agent updated
insurance certificates with respect to such policies.
1.3
Indemnity. Borrower agrees to indemnify and hold Agent, Lender and their officers, directors, employees, agents, in-house attorneys, representatives
and shareholders (each, an “Indemnified Person”) harmless from and against any and all claims, costs, expenses, damages and liabilities (including such claims,
costs, expenses, damages and liabilities based on liability in tort, including strict liability in tort), including reasonable attorneys’ fees and disbursements and other
reasonable costs of investigation or defense (including those incurred upon any appeal) (collectively, “Liabilities”), that may be instituted or asserted against or
incurred by such Indemnified Person as the result of credit having been extended, suspended or terminated under this Agreement and the other Loan Documents or
the administration of such credit, or in connection with or arising out of the transactions contemplated hereunder and thereunder, or any actions or failures to act in
connection therewith, or arising out of the disposition or utilization of the Collateral, excluding in all cases Liabilities to the extent resulting solely from any
Indemnified Person’s gross negligence or willful misconduct. Borrower agrees to pay, and to save Agent and Lender harmless from, any and all liabilities with
respect to, or resulting from any delay in paying, any and all excise, sales or other similar taxes (excluding taxes imposed on or measured by the net income of Agent
or Lender) that may be payable or determined to be payable with respect to any of the Collateral or this Agreement; provided, however, that (i) with respect to such
liabilities imposed originally and independently on Lender, Lender shall notify Borrower of any such liabilities within one hundred and eighty (180) days of the
initial date Lender has actual knowledge, or should have had knowledge, of its direct

exposure to such liabilities, and (ii) with respect to all other such liabilities not described in clause (i), Lender shall notify Borrower of any such liabilities within one
hundred and eighty (180) days of the initial date Lender has actual knowledge of its direct exposure to such liabilities. In no event shall any Indemnified Person be
liable on any theory of liability for any special, indirect, consequential or punitive damages (including any loss of profits, business or anticipated savings). This
Section 6.3 shall survive the repayment of indebtedness under, and otherwise shall survive the expiration or other termination of, the Agreement.
Section 7. 
COVENANTS OF BORROWER
Borrower agrees as follows:
1.1
Financial Reports. Borrower shall furnish to Agent the Compliance Certificate in the form of Exhibit F monthly within 30 days after the end of each
month and the financial statements and reports listed hereinafter (the “Financial Statements”):
(a)
as soon as practicable (and in any event within 30 days) after the end of each month, unaudited interim financial statements as of the end of
such month (prepared on a consolidated and consolidating basis, if applicable and customary under accepted accounting practices), including balance sheet
and related statements of income and cash flows accompanied by a report detailing any material contingencies (including the commencement of any material
litigation by or against Borrower) or any other occurrence that would reasonably be expected to have a Material Adverse Effect, all certified by Borrower’s
Chief Executive Officer, Chief Financial Officer or Vice President of Finance to the effect that they have been prepared in accordance with GAAP, except (i)
for the absence of footnotes, (ii) that they are subject to normal year-end adjustments, and (iii) they do not contain certain non-cash items that are customarily
included in quarterly and annual financial statements;
(b)
as soon as practicable (and in any event within 45 days) after the end of each calendar quarter (not including the fourth quarter of each fiscal
year), unaudited interim financial statements as of the end of such calendar quarter (prepared on a consolidated and consolidating basis, if applicable and
customary under accepted accounting practices), including balance sheet and related statements of income and cash flows accompanied by a report detailing
any material contingencies (including the commencement of any material litigation by or against Borrower) or any other occurrence that would reasonably be
expected to have a Material Adverse Effect, all certified by Borrower’s Chief Executive Officer, Chief Financial Officer or Vice President of Finance to the
effect that they have been prepared in accordance with GAAP, except (i) for the absence of footnotes, and (ii) that they are subject to normal year-end
adjustments;
(c)
as soon as practicable (and in any event within 90 days) after the end of each fiscal year, (i) unqualified audited financial statements as of the
end of such year (prepared on a consolidated and consolidating basis, if applicable and customary under accepted accounting practices), including balance
sheet and related statements of income and cash flows, and setting forth in comparative form the corresponding figures for the preceding fiscal year, certified
by Ernst & Young or a firm of independent certified public accountants selected by Borrower and reasonably acceptable to Agent, accompanied by any
management report from such accountants;
(d)
promptly after the sending or filing thereof, as the case may be, copies of any proxy statements, financial statements or reports that Borrower
has made available to holders of its capital stock and copies of any regular, periodic and special reports or

registration statements that Borrower files with the Securities and Exchange Commission or any governmental authority that may be substituted therefor, or
any national securities exchange;
(e)
within sixty (60) days of each fiscal year-end, board approved monthly income statement and balance sheet projections for Borrower’s
following fiscal year. Any board approved changes to such projections shall be delivered to Lender within thirty (30) days of such board approval; and
(f)
budgets, operating plans, updates on clinical trials, and other financial information reasonably requested by Agent.
The executed Compliance Certificate may be sent via email to Agent at legal@herculestech.com. Documents required to be delivered pursuant to this Section
7.1 (to the extent any such documents are included in materials otherwise filed with the Securities and Exchange Commission) may be delivered electronically and if
so delivered, shall be deemed to have been delivered on the date on which Borrower posts such documents, or provides a link thereto on Borrower’s website at
Borrower’s website address of http://www.aveooncology.com/ (or such other website address as Borrower may provide to Agent in writing from time to time);
provided, that: (x) to the extent Agent is otherwise unable to receive any such electronically delivered documents, Borrower shall, upon request by Agent, deliver
paper copies of such documents to Borrower until a written request to cease delivering paper copies is given by Borrower and (y) Borrower shall notify Agent by
electronic mail of the posting of any such documents or provide to Agent by electronic mail electronic versions (i.e., soft copies) of such documents, in each case, to
financialstatements@herculestech.com with a copy to bjadot@herculestech.com.
1.2
Management Rights. Borrower shall permit any representative that Agent or Lender authorizes, including its attorneys and accountants, to inspect the
Collateral and examine and make copies and abstracts of the books of account and records of Borrower at reasonable times and upon reasonable notice during normal
business hours (but in any event no more than twice in any twelve (12) month period unless an Event of Default has occurred and is continuing). In addition, any
such representative shall have the right to meet with management and officers of Borrower to discuss such books of account and records. In addition, Agent or
Lender shall be entitled at reasonable times and intervals to consult with and advise the management and officers of Borrower concerning significant business issues
affecting Borrower. Such consultations shall not unreasonably interfere with Borrower’s business operations. The parties intend that the rights granted Agent and
Lender shall constitute “management rights” within the meaning of 29 C.F.R Section 2510.3-101(d)(3)(ii), but that any advice, recommendations or participation by
Agent or Lender with respect to any business issues shall not be deemed to give Agent or Lender, nor be deemed an exercise by Agent or Lender of, control over
Borrower’s management or policies.
1.3
Further Assurances. Borrower shall from time to time execute, deliver and file, alone or with Agent, any financing statements, security agreements,
collateral assignments, notices, control agreements, or other documents necessary to perfect or give the highest priority to Agent’s Lien on the Collateral (subject to
Permitted Liens). Borrower shall from time to time procure any instruments or documents as may be reasonably requested by Agent, and take all further action that
may be necessary or that Agent may reasonably request, to perfect and protect the Liens granted hereby and thereby. In addition, and for such purposes only,
Borrower hereby authorizes Agent to execute and deliver on behalf of Borrower and to file such financing statements, collateral assignments, notices, control
agreements, security agreements and other documents without the signature of Borrower either in Agent’s name or in the name of Agent as agent and attorney-in-fact
for Borrower. Borrower shall, in its reasonable business judgment,

protect and defend Borrower’s title to the Collateral and Agent’s Lien thereon against all Persons claiming any interest adverse to Borrower or Agent other than
Permitted Liens.
1.4
Compromise of Agreements. Without Lender’s prior written consent, Borrower shall not, nor shall it allow any of its Subsidiaries to, (a) grant any
material extension of the time of payment of any of the Account receivable or General Intangibles other than extensions in the Ordinary Course of Business which
are consistent with past practices, (b) to any material extent, compromise, compound or settle the same for less than the full amount thereof other than in the Ordinary
Course of Business and consistent with past practices, (c) release, wholly or partly, any Person liable for the payment thereof other than in the Ordinary Course of
Business and consistent with past practices, or (d) allow any credit or discount whatsoever thereon other than trade discounts granted by Borrower or such Subsidiary
in the exercise of Borrower’s or such Subsidiary’s reasonable business judgment.
1.5
Indebtedness. Borrower shall not create, incur, assume, guarantee or be or remain liable with respect to any Indebtedness, or permit any Subsidiary so
to do, other than Permitted Indebtedness, or prepay any Indebtedness or take any actions which impose on Borrower an obligation to prepay any Indebtedness, except
Indebtedness to Lender in accordance herewith or for the conversion of Indebtedness into equity securities and the payment of cash in lieu of fractional shares in
connection with such conversion.
1.6
Collateral. Borrower shall at all times keep the Collateral, all Intellectual Property and all other property and assets used in Borrower’s business or in
which Borrower now or hereafter holds any interest free and clear from any legal process or Liens whatsoever (except for Permitted Liens), and shall give Agent
prompt written notice of any legal process affecting the Collateral, such Intellectual Property, such other property and assets, or any Liens thereon. Borrower shall
cause its Subsidiaries to protect and defend such Subsidiary’s title to its assets from and against all Persons claiming any interest adverse to such Subsidiary, and
Borrower shall cause its Subsidiaries at all times to keep such Subsidiary’s property and assets free and clear from any legal process or Liens whatsoever (except for
Permitted Liens), and shall give Agent prompt written notice of any legal process affecting such Subsidiary’s assets. Borrower shall not permit the inclusion in any
contract to which it or a Subsidiary becomes a party of any provisions that restrict or invalidate the granting of a security interest in any of Borrower’s or such
Subsidiary’s property and assets other than with respect to contractual restrictions on Intellectual Property entered into with third-party strategic collaborators that are
not financial institutions in the Ordinary Course of Business (“JV Restrictions”).
1.7
Investments. Borrower shall not directly or indirectly acquire or own, or make any Investment in or to any Person, or permit any of its Subsidiaries so
to do, other than Permitted Investments.
1.8
Distributions. Without the prior written consent of Lender, Borrower shall not, and shall not allow any Subsidiary to, (a) repurchase or redeem any
class of stock or other equity interest other than pursuant to employee, director or consultant repurchase plans or other similar agreements, provided, however, in each
case the repurchase or redemption price does not exceed the original consideration paid for such stock or equity interest by more than $250,000 in the aggregate in
any fiscal year, or (b) declare or pay any cash dividend or make a cash distribution on any class of stock or other equity interest, except that a Subsidiary may pay
dividends or make distributions to Borrower (or to any other Subsidiary of Borrower), or (c) lend money to any employees, officers or directors or guarantee the
payment of any such loans granted by a third party in excess of $250,000 in the aggregate in any fiscal year or (d) waive, release or forgive any indebtedness owed by
any employees, officers or directors in excess of $100,000 in the aggregate in any fiscal year.

1.9
Transfers. Except for Permitted Transfers, Borrower shall not voluntarily or involuntarily transfer, sell, lease, license, lend or in any other manner
convey any equitable, beneficial or legal interest in any material portion of its assets.
1.10
Mergers or Acquisitions. Without Lender’s prior written consent, not to be unreasonably withheld, Borrower shall not merge or consolidate, or permit
any of its Subsidiaries to merge or consolidate, with or into any other business organization (other than mergers or consolidations of (a) a Subsidiary which is not a
Borrower into another Subsidiary or into Borrower or (b) a Borrower into another Borrower), or acquire, or permit any of its Subsidiaries to acquire, all or
substantially all of the capital stock or property of another Person; provided, that Borrower may make (i) acquisitions utilizing cash as consideration that constitute
Permitted Investments and (ii) acquisitions utilizing Borrower’s stock as consideration that do not result in a Change in Control.
1.11
Taxes. Borrower and its Subsidiaries shall pay when due all material taxes, fees or other charges of any nature whatsoever (together with any related
interest or penalties) now or hereafter imposed or assessed against Borrower, Agent, Lender or the Collateral or upon Borrower’s ownership, possession, use,
operation or disposition thereof or upon Borrower’s rents, receipts or earnings arising therefrom. Borrower shall file on or before the due date therefor all material
personal property tax returns in respect of the Collateral. Notwithstanding the foregoing in this Section 7.11, Borrower may contest, in good faith and by appropriate
proceedings, taxes for which Borrower maintains adequate reserves therefor in accordance with GAAP.
1.12
Corporate Changes. Neither Borrower nor any Subsidiary shall change its corporate name, legal form or jurisdiction of formation without twenty (20)
days' prior written notice to Agent. Borrower shall not suffer a Change in Control. Neither Borrower nor any Domestic Subsidiary shall relocate its chief executive
office or its principal place of business unless: (i) it has provided prior written notice to Agent; and (ii) such relocation shall be within the continental United States.
Neither Borrower nor any Subsidiary shall relocate any item of Collateral (other than (v) relocations of clinical trial supplies in the Ordinary Course Business, (w)
Permitted Transfers, (x) sales of Inventory (whether as raw material, work in process, finished product or otherwise) in the Ordinary Course of Business, (y)
relocations of Equipment having an aggregate value of up to $500,000 in any fiscal year, and (z) relocations of Collateral from a location described on Exhibit C to
another location described on Exhibit C) unless (i) it has provided prompt written notice to Agent, (ii) such relocation is within the continental United States and, (iii)
if such relocation is to a third-party bailee, it has used commercially reasonable efforts to obtain a bailee agreement in form and substance reasonably acceptable to
Agent, provided, that it shall deliver such a bailee agreement for any such relocation of assets in excess of $1,000,000.
1.13
Deposit Accounts. Neither Borrower nor any Qualified Subsidiary shall maintain any Deposit Accounts, or accounts holding Investment Property,
except (i) with respect to which Agent has an Account Control Agreement, and (ii) a deposit account maintained in the United Kingdom for funding payroll
obligations with a balance not to exceed $2,000,000 at any time).
1.14
Subsidiaries. Borrower shall notify Agent of each Subsidiary formed subsequent to the Closing Date and, within 15 days of formation, shall cause any
such Qualified Subsidiary to execute and deliver to Agent a Joinder Agreement.
1.15
Notification of Event of Default. Borrower shall notify Agent promptly (and in any event within two (2) Business Days) of the occurrence of any
Event of Default.

1.16
Intellectual Property. Borrower shall update the Intellectual Property information listed on Exhibit D within 30 days of each quarter end.
1.17
Use of Proceeds. Borrower agrees that the proceeds of the Loans shall be used for (a) the refinancing of the Existing Term Loan Advances in full, (b)
the payment of fees, costs and expenses incurred in connection with such refinancing and (c) working capital and general corporate purposes. The proceeds of the
2020 Term Loan Advance will not be used in violation of Anti-Corruption Laws or applicable Sanctions.
1.18
MSC Subsidiary. Borrower shall be permitted to make Investments in the MSC Subsidiary so long as Borrower (i) maintains Liquidity of at least
$40,000,000 minus the aggregate amount of principal payments paid by Borrower to Lender through such date of determination (such resulting amount being
referred to as the “Threshold Amount” or (ii) if Borrower’s Liquidity is less than the Threshold Amount on any date (a “Deficiency Date”), Borrower shall (a)
promptly (and in any event within two (2) Business Days), upon knowledge thereof, notify Lender of such deficiency in writing and (b) procure Cash and/or Cash
Equivalents maintained in Deposit Accounts and/or accounts holding Investment Property that are subject to an Account Control Agreement in an amount such that
after procuring such amounts Borrower shall have Liquidity of at least the lesser of (1) Threshold Amount or (2) the amount of Cash and/or Cash Equivalents and
accounts holding Investment Property of Borrower and its Subsidiaries as determined on a consolidated basis; provided that such procurement(s) shall occur as soon
as commercially practicable but in any event within five (5) business days of Borrower’s knowledge of such Deficiency Date; provided, further, that Borrower shall
not make any Investments in the MSC Subsidiary following a Deficiency Date without the prior written consent of Lender unless clause (b)(1) above has been
satisfied or the condition set forth in the next sentence has been satisfied. If at any time, the application for classification of the MSC Subsidiary as a “security
corporation” under Massachusetts General Laws Ch. 63, Section 38B(a), as amended, supplemented and/or modified, is denied or such classification is revoked (and
such determination is not subject to appeal and all appeal periods have run), Borrower shall take such actions, as soon as commercially practicable, to dissolve the
MSC Subsidiary or merge the MSC Subsidiary with or into Borrower.
1.19
Compliance with Laws.
Borrower shall maintain, and shall cause its Subsidiaries to maintain, compliance in all respects with all applicable laws, rules or regulations (including any
law, rule or regulation with respect to the making or brokering of loans or financial accommodations), and shall, or cause its Subsidiaries to, obtain and maintain all
required governmental authorizations, approvals, licenses, franchises, permits or registrations reasonably necessary in connection with the conduct of Borrower’s
business, except to the extent that any of the foregoing would not reasonably be expected to cause a Material Adverse Effect.
Neither Borrower nor any of its Subsidiaries shall, nor shall Borrower or any of its Subsidiaries permit any Affiliate to, directly or indirectly, knowingly enter
into any documents, instruments, agreements or contracts with any Person listed on the OFAC Lists. Neither Borrower nor any of its Subsidiaries shall, nor shall
Borrower or any of its Subsidiaries, permit any Affiliate to, directly or indirectly, (i) conduct any business or engage in any transaction or dealing with any Blocked
Person, including, without limitation, the making or receiving of any contribution of funds, goods or services to or for the benefit of any Blocked Person, (ii) deal in,
or otherwise engage in any transaction relating to, any property or interests in property blocked pursuant to Executive Order No. 13224 or any similar executive order
or other Anti-Terrorism Law, or (iii) engage in or conspire to engage in any transaction that evades or avoids, or has the purpose of evading or avoiding, or attempts
to violate, any of the prohibitions set forth in Executive Order No. 13224 or other Anti-Terrorism Law.

Borrower has implemented and maintains in effect policies and procedures designed to ensure material compliance by Borrower, its Subsidiaries and their
respective directors, officers, employees and agents with Anti-Corruption Laws and applicable Sanctions, and Borrower, its Subsidiaries and their respective officers
and employees and, to the knowledge of Borrower, its directors are in compliance with Anti-Corruption Laws and applicable Sanctions in all material respects.
None of Borrower, any of its Subsidiaries or any of their respective directors, officers or employees, or to the knowledge of Borrower, any agent for Borrower
or its Subsidiaries that will act in any capacity in connection with or benefit from the credit facility established hereby, is a Sanctioned Person. No Loan, use of
proceeds or other transaction contemplated by this Agreement will violate Anti-Corruption Laws or applicable Sanctions.
1.20
Transactions with Affiliates. Borrower shall not and shall not permit any Subsidiary to, directly or indirectly, enter into or permit to exist any
transaction of any kind with any Affiliate of Borrower or such Subsidiary on terms that are less favorable to Borrower or such Subsidiary, as the case may be, than
those that might be obtained in an arm’s length transaction from a Person who is not an Affiliate of Borrower or such Subsidiary; provided, however, that the
foregoing shall not apply to any transactions expressly permitted by this Agreement.
1.21
Minimum Cash. Borrower shall maintain at all times unrestricted Cash in Deposit Accounts that are subject to an Account Control Agreement in an
amount not less than the sum of (i) Ten Million Dollars ($10,000,000) plus (ii) the amount of Borrower’s accounts payable under GAAP not paid after the 120th day
following the invoice date for such account payable; provided, that upon the earlier to occur of January 1, 2023, or such date on which the 2020 Term D Loan
Advances are advanced by Lender to Borrower, Borrower shall at all times thereafter maintain unrestricted Cash in Deposit Accounts that are subject to an Account
Control Agreement in an amount not less than the sum of (x) Fifteen Million Dollars ($15,000,000) plus (y) the amount of Borrower’s accounts payable under GAAP
not paid after the 120th day following the invoice date for such account payable.
1.22
Net Product Revenue. As of the last day of each month (commencing with June 2022), Borrower shall not permit Net Product Revenue for the trailing
six- (6) month period ended on such date to be an amount less than 65% of projected Net Product Revenue for such period set forth in the Forecast. Notwithstanding
anything in the foregoing to the contrary, Borrower shall not be required to comply with the first sentence of this Section 7.22 for any particular month solely to the
extent that for each day of such month, Borrower maintained unrestricted Cash in Deposit Accounts or an account holding Cash Equivalents, in each case, subject to
Account Control Agreements in an aggregate amount equal to or greater than the Secured Obligations.
1.23
SBA. One or more affiliates of Agent have received a license from the U.S. Small Business Administration (“SBA”) to extend loans as a small
business investment company (“SBIC”) pursuant to the Small Business Investment Act of 1958, as amended, and the associated regulations (collectively, the “SBIC
Act”). Portions of the Loan to Borrower may be by any Lender that is a SBIC on any SBA Funding Date. The documentary deliverables described in Exhibit I to this
Agreement shall be completed by Borrower on or before each SBA Funding Date and delivered to Agent. Exhibit I is hereby automatically incorporated in this
Agreement as of the Second Amendment Closing Date without any further action of the parties hereto, and Agent, each Lender and Borrower agree to the terms of
such Exhibit I.

Section 8. 
INTENTIONALLY DELETED.
Section 9. 
EVENTS OF DEFAULT
The occurrence of any one or more of the following events shall be an Event of Default:
1.1
Payments. Borrower fails to pay any amount when due under this Agreement, the Notes or any of the other Loan Documents and such default
continues for more than three business days after the due date thereof; or
1.2
Covenants. Borrower breaches or defaults in the performance of any covenant or Secured Obligation under this Agreement or any of the other Loan
Documents, and (a) with respect to a default under any covenant under this Agreement (other than under Sections 6, 7.5, 7.6, 7.7, 7.8, 7.9, 7.10, 7.13, 7.15, 7.17,
7.18, 7.19, 7.21, 7.22 or 7.23) such default continues for more than ten (10) business days after the earlier of the date on which (i) Agent or Lender have given notice
of such default to Borrower and (ii) Borrower has actual knowledge of such default or (b) with respect to a default under any of Sections 6, 7.5, 7.6, 7.7, 7.8, 7.9,
7.10, 7.13, 7.15, 7.17, 7.18, 7.19, 7.21, 7.22 or 7.23, the occurrence of such default; or
1.3
Material Adverse Effect. A circumstance has occurred that would have a Material Adverse Effect; or
1.4
Other Loan Documents. The occurrence of any default under any Loan Document not otherwise specifically referenced in this Section 9 or any other
agreement between Borrower and Lender and such default continues for more than ten business (10) days after the earlier of (a) Lender has given written notice of
such default to Borrower, or (b) Borrower has actual knowledge of such default; or
1.5
Representations. Any representation or warranty made by Borrower in any Loan Document shall have been false or misleading in any material respect
when made; or
1.6
Insolvency. Borrower (A) (i) shall make an assignment for the benefit of creditors; or (ii) shall be unable to pay its debts as they become due, or be
unable to pay or perform under the Loan Documents; or (iii) shall file a voluntary petition in bankruptcy; or (iv) shall file any petition, answer, or document seeking
for itself any reorganization, arrangement, composition, readjustment, liquidation, dissolution or similar relief under any present or future statute, law or regulation
pertinent to such circumstances; or (v) shall seek or consent to or acquiesce in the appointment of any trustee, receiver, or liquidator of Borrower or of all or any
substantial part (i.e., 33-1/3% or more) of the assets or property of Borrower; or (vi) shall cease operations of its business as its business has normally been conducted
for a period of more than five consecutive business days, or terminate substantially all of its employees; or (vii) becomes insolvent; or (viii) Borrower or its directors
or majority shareholders shall take any action initiating any of the foregoing actions described in clauses (i) through (vii); or (B) either (i) sixty (60) days shall have
expired after the commencement of an involuntary action against Borrower seeking reorganization, arrangement, composition, readjustment, liquidation, dissolution
or similar relief under any present or future statute, law or regulation, without such action being dismissed or all orders or proceedings thereunder affecting the
operations or the business of Borrower being stayed; or (ii) a stay of any such order or proceedings shall thereafter be set aside and the action setting it aside shall not
be timely appealed; or (iii) Borrower shall file any answer admitting or not contesting the material allegations of a petition filed against Borrower in any such
proceedings; or (iv) the court in which such proceedings are pending shall enter a decree or order granting the relief sought in any such proceedings; or (v) sixty (60)
days shall have expired after the appointment, without the consent or acquiescence of Borrower, of any trustee, receiver

or liquidator of Borrower or of all or any substantial part of the properties of Borrower without such appointment being vacated; or
1.7
Attachments; Judgments. Any material portion of Borrower’s assets is attached or seized, or a levy is filed against any such assets, or a judgment or
judgments for the payment of money, individually or in the aggregate, of at least $500,000 shall be rendered against Borrower and shall remain unsatisfied,
unvacated, or unstayed for a period of twenty (20) days after the entry thereof (provided that no Advance will be made prior to the satisfaction, vacation, or stay of
such judgment, order, or decree), or Borrower is enjoined or in any way prevented by court order from conducting any material part of its business; or
1.8
Other Obligations. The occurrence of any default under (a) any agreement or obligation of Borrower involving any Indebtedness in excess of
$500,000, or (b) the occurrence of any default under any agreement or obligation of Borrower that could reasonably be expected to have a Material Adverse Effect.
Section 10. 
REMEDIES
1.1
General. Upon and during the continuance of any one or more Events of Default, (i) Agent may, and at the direction of the Required Lenders shall,
accelerate and demand payment of all or any part of the Secured Obligations together with a Prepayment Charge and declare them to be immediately due and payable
(provided, that upon the occurrence of an Event of Default of the type described in Section 9.6, all of the Secured Obligations shall automatically be accelerated and
made due and payable, in each case without any further notice or act), (ii) Agent may, at its option, sign and file in Borrower’s name any and all collateral
assignments, notices, control agreements, security agreements and other documents it deems necessary or appropriate to perfect or protect the repayment of the
Secured Obligations, and in furtherance thereof, Borrower hereby grants Agent an irrevocable power of attorney coupled with an interest, and (iii) Agent may notify
any of Borrower’s account debtors to make payment directly to Agent, compromise the amount of any such account on Borrower’s behalf and endorse Agent’s name
without recourse on any such payment for deposit directly to Agent’s account. Agent may, and at the direction of the Required Lenders shall, exercise all rights and
remedies with respect to the Collateral under the Loan Documents or otherwise available to it under the UCC and other applicable law, including the right to release,
hold, sell, lease, liquidate, collect, realize upon, or otherwise dispose of all or any part of the Collateral and the right to occupy, utilize, process and commingle the
Collateral. All Agent’s rights and remedies shall be cumulative and not exclusive.
1.2
Collection; Foreclosure. Upon the occurrence and during the continuance of any Event of Default, Agent may, and at the direction of the Required
Lenders shall, at any time or from time to time, apply, collect, liquidate, sell in one or more sales, lease or otherwise dispose of, any or all of the Collateral, in its then
condition or following any commercially reasonable preparation or processing, in such order as Agent may elect. Any such sale may be made either at public or
private sale at its place of business or elsewhere. Borrower agrees that any such public or private sale may occur upon ten (10) calendar days’ prior written notice to
Borrower. Agent may require Borrower to assemble the Collateral and make it available to Agent at a place designated by Agent that is reasonably convenient to
Agent and Borrower. The proceeds of any sale, disposition or other realization upon all or any part of the Collateral shall be applied by Agent in the following order
of priorities:
First, to Agent and Lender in an amount sufficient to pay in full Agent’s and Lender’s costs and professionals' and advisors' fees and expenses as
described in. Section 11.11;

Second, to Lender in an amount equal to the then unpaid amount of the Secured Obligations (including principal, interest, and the Default Rate
interest), in such order and priority as Agent may choose in its sole discretion; and
Finally, after the full and final payment in Cash of all of the Secured Obligations, to any creditor holding a junior Lien on the Collateral, or to
Borrower or its representatives or as a court of competent jurisdiction may direct.
Agent shall be deemed to have acted reasonably in the custody, preservation and disposition of any of the Collateral if it complies with the obligations of a secured
party under the UCC.
1.3
No Waiver. Agent shall be under no obligation to marshal any of the Collateral for the benefit of Borrower or any other Person, and Borrower
expressly waives all rights, if any, to require Agent to marshal any Collateral.
1.4
Cumulative Remedies. The rights, powers and remedies of Agent hereunder shall be in addition to all rights, powers and remedies given by statute or
rule of law and are cumulative. The exercise of any one or more of the rights, powers and remedies provided herein shall not be construed as a waiver of or election
of remedies with respect to any other rights, powers and remedies of Agent.
Section 11. 
MISCELLANEOUS
1.1
Severability. Whenever possible, each provision of this Agreement shall be interpreted in such manner as to be effective and valid under applicable
law, but if any provision of this Agreement shall be prohibited by or invalid under such law, such provision shall be ineffective only to the extent and duration of such
prohibition or invalidity, without invalidating the remainder of such provision or the remaining provisions of this Agreement.
1.2
Notice. Except as otherwise provided herein, any notice, demand, request, consent, approval, declaration, service of process or other communication
(including the delivery of Financial Statements) that is required, contemplated, or permitted under the Loan Documents or with respect to the subject matter hereof
shall be in writing, and shall be deemed to have been validly served, given, delivered, and received upon the earlier of: (i) the day of transmission by electronic mail
or hand delivery or delivery by an overnight express service or overnight mail delivery service; or (ii) the third calendar day after deposit in the United States mails,
with proper first class postage prepaid, in each case addressed to the party to be notified as follows:
(a)
If to Agent:
HERCULES CAPITAL, INC.
Legal Department
Attention: Chief Legal Officer and Mr. Bryan Jadot
400 Hamilton Avenue, Suite 310
Palo Alto, CA 94301
email: legal@herculestech.com
Telephone: 650-289-3060
(b)
If to Lender:
HERCULES CAPITAL, INC.
HERCULES CAPITAL FUNDING TRUST 2018-1
HERCULES CAPITAL FUNDING TRUST 2019-1
Legal Department

Attention: Chief Legal Officer and Mr. Bryan Jadot
400 Hamilton Avenue, Suite 310
Palo Alto, CA 94301
email: legal@herculestech.com
Telephone: 650-289-3060
(c)
If to Borrower:
AVEO PHARMACEUTICALS, INC.
Attention: Chief Financial Officer
30 Winter Street
Boston, MA 02108
Facsimile: 617-995-4995
Telephone: 857-400-0101
With copies (which shall not constitute notice) to:
AVEO PHARMACEUTICALS, INC.
Attention: Legal
30 Winter Street
Boston, MA 02108
Facsimile: 617-995-4995
Telephone: 857-400-0101
            WILMER CUTLER PICKERING HALE AND DORR LLP
Attention: George W. Shuster Jr., Esq.
60 State Street
Boston, MA 02109
Facsimile: 617-526-5000
Telephone: 617-526-6572
or to such other address as each party may designate for itself by like notice.
1.3
Entire Agreement; Amendments.
(a)
This Agreement and the other Loan Documents constitute the entire agreement and understanding of the parties hereto in respect of the subject matter
hereof and thereof, and supersede and replace in their entirety any prior proposals, term sheets, letters, negotiations or other documents or agreements, whether
written or oral, with respect to the subject matter hereof or thereof (including Agent’s revised proposal letter dated December 6, 2017). None of the terms of this
Agreement or any of the other Loan Documents may be amended except by an instrument executed by each of the parties hereto.
(b)
None of this Agreement, any other Loan Document, or any terms hereof or thereof may be amended, supplemented or modified except in accordance
with the provisions of this Section 11.3(b). The Required Lenders and Borrower party to the relevant Loan Document may, or, with the written consent of the
Required Lenders, Agent and Borrower party to the relevant Loan Document may, from time to time, (i) enter into written amendments, supplements or
modifications hereto and to the other Loan Documents for the purpose of adding any provisions to this Agreement or the other Loan Documents or changing in any
manner the rights of Lender or of Borrower hereunder or thereunder or (ii) waive, on such terms and conditions as the Required Lenders or Agent, as the case may
be, may specify in such instrument, any of the requirements of this Agreement or the other Loan Documents or any default or Event of Default and its consequences;
provided, however, that no such waiver and

no such amendment, supplement or modification shall (A) forgive the principal amount or extend the final scheduled date of maturity of any Loan, extend the
scheduled date of any amortization payment in respect of the 2020 Term Loan Advances, reduce the stated rate of any interest or fee payable hereunder or extend the
scheduled date of any payment thereof, or increase the amount or extend the expiration date of any Lender’s respective portion of the applicable 2020 Term
Commitments, in each case without the written consent of each Lender directly affected thereby; (B) eliminate or reduce the voting rights of any Lender under this
Section 11.3(b) without the written consent of such Lender; (C) reduce any percentage specified in the definition of Required Lenders, consent to the assignment or
transfer by Borrower of any of its rights and obligations under this Agreement and the other Loan Documents, release all or substantially all of the Collateral or
release a Borrower from its obligations under the Loan Documents (except with respect to a transfer or transaction expressly permitted under this Agreement), in
each case without the written consent of all Lenders; or (D) amend, modify or waive any provision of Section 11.19 without the written consent of Agent. Any such
waiver and any such amendment, supplement or modification shall apply equally to each Lender and shall be binding upon Borrower, Lender, Agent and all future
holders of the Loans.
1.4
No Strict Construction. The parties hereto have participated jointly in the negotiation and drafting of this Agreement. In the event an ambiguity or
question of intent or interpretation arises, this Agreement shall be construed as if drafted jointly by the parties hereto and no presumption or burden of proof shall
arise favoring or disfavoring any party by virtue of the authorship of any provisions of this Agreement.
1.5
No Waiver. The powers conferred upon Agent and Lender by this Agreement are solely to protect their rights hereunder and under the other Loan
Documents and its interest in the Collateral and shall not impose any duty upon Agent or Lender to exercise any such powers. No omission or delay by Agent or
Lender at any time to enforce any right or remedy reserved to it, or to require performance of any of the terms, covenants or provisions hereof by Borrower at any
time designated, shall be a waiver of any such right or remedy to which Agent or Lender is entitled, nor shall it in any way affect the rights of Agent or Lender to
enforce such provisions thereafter.
1.6
Survival. All agreements, representations and warranties contained in this Agreement and the other Loan Documents or in any document delivered
pursuant hereto or thereto shall be for the benefit of Agent and Lender and shall survive the execution and delivery of this Agreement and the expiration or other
termination of this Agreement. Section 6.3, 11.13, 11.14 and 11.19 shall survive the termination of this Agreement.
1.7
Successors and Assigns. The provisions of this Agreement and the other Loan Documents shall inure to the benefit of and be binding on Borrower and
its permitted assigns (if any). Borrower shall not assign its obligations under this Agreement or any of the other Loan Documents without Agent’s express prior
written consent, and any such attempted assignment shall be void and of no effect. Except as set forth in Section 11.13, Agent and Lender may assign, transfer, or
endorse their rights hereunder and under the other Loan Documents without prior notice to Borrower, and all of such rights shall inure to the benefit of Agent’s and
Lender’s successors and assigns.
1.8
Governing Law. This Agreement and the other Loan Documents have been negotiated and delivered to Agent and Lender in the State of California,
and shall have been accepted by Agent and Lender in the State of California. Payment to Agent and Lender by Borrower of the Secured Obligations is due in the
State of California. This Agreement and the other Loan Documents shall be governed by, and construed and enforced in accordance with, the laws of the State of
California, excluding conflict of laws principles that would cause the application of laws of any other jurisdiction.

1.9
Consent to Jurisdiction and Venue. All judicial proceedings (to the extent that the reference requirement of Section 11.10 is not applicable) arising in
or under or related to this Agreement or any of the other Loan Documents may be brought in any state or federal court located in the State of California. By execution
and delivery of this Agreement, each party hereto generally and unconditionally: (a) consents to nonexclusive personal jurisdiction in Santa Clara County, State of
California; (b) waives any objection as to jurisdiction or venue in Santa Clara County, State of California; (c) agrees not to assert any defense based on lack of
jurisdiction or venue in the aforesaid courts; and (d) irrevocably agrees to be bound by any judgment rendered thereby in connection with this Agreement or the other
Loan Documents. Service of process on any party hereto in any action arising out of or relating to this Agreement shall be effective if given in accordance with the
requirements for notice set forth in Section 11.2, and shall be deemed effective and received as set forth in Section 11.2. Nothing herein shall affect the right to serve
process in any other manner permitted by law or shall limit the right of either party to bring proceedings in the courts of any other jurisdiction.
1.10
Mutual Waiver of Jury Trial / Judicial Reference.
(a)
Because disputes arising in connection with complex financial transactions are most quickly and economically resolved by an experienced and
expert Person and the parties wish applicable state and federal laws to apply (rather than arbitration rules), the parties desire that their disputes be resolved by
a judge applying such applicable laws. EACH OF BORROWER, AGENT AND LENDER SPECIFICALLY WAIVE ANY RIGHT IT MAY HAVE TO
TRIAL BY JURY OF ANY CAUSE OF ACTION, CLAIM, CROSS-CLAIM, COUNTERCLAIM, THIRD-PARTY CLAIM OR ANY OTHER CLAIM
(COLLECTIVELY, “CLAIMS”) ASSERTED BY BORROWER AGAINST AGENT, LENDER OR THEIR ASSIGNEES OR BY AGENT, LENDER OR
ITS ASSIGNEE AGAINST BORROWER. This waiver extends to all such Claims, including Claims that involve Persons other than Agent, Borrower and
Lender; Claims that arise out of or are in any way connected to the relationship among Borrower, Agent and Lender; and any Claims for damages, breach of
contract; tort, specific performance, or any equitable or legal relief of any kind, arising out of this Agreement, any other Loan Document.
(b)
If the waiver of jury trial set forth in Section 11.10(a) is ineffective or unenforceable, the parties agree that all Claims shall be resolved by
reference to a private judge sitting without a jury, pursuant to Code of Civil Procedure Section 638, before a mutually acceptable referee or, if the parties
cannot agree, a referee selected by the Presiding Judge of the Santa Clara County, California. Such proceeding shall be conducted in Santa Clara County,
California, with California rules of evidence and discovery applicable to such proceeding.
(c)
In the event Claims are to be resolved by judicial reference, either party may seek from a court identified in Section 11.9, any prejudgment
order, writ or other relief and have such prejudgment order, writ or other relief enforced to the fullest extent permitted by law notwithstanding that all Claims
are otherwise subject to resolution by judicial reference.
1.11
Professional Fees. Borrower promises to pay Agent’s and Lender’s reasonable fees and expenses necessary to finalize the loan documentation,
including but not limited to reasonable attorneys fees, UCC searches, filing costs, and other reasonable miscellaneous expenses. In addition, Borrower promises to
pay any and all reasonable attorneys' and other professionals' fees and expenses incurred by Agent and Lender after the Closing Date in connection with or related to:
(a) the Loan; (b) the administration, collection, or enforcement of the Loan; (c) the amendment or modification of the Loan Documents; (d) any waiver, consent,

release, or termination under the Loan Documents; (e) the protection, preservation, audit, field exam, sale, lease, liquidation, or disposition of Collateral or the
exercise of remedies with respect to the Collateral; (f) any legal, litigation, administrative, arbitration, or out of court proceeding in connection with or related to
Borrower or the Collateral, and any appeal or review thereof; and (g) any bankruptcy, restructuring, reorganization, assignment for the benefit of creditors, workout,
foreclosure, or other action related to Borrower, the Collateral, the Loan Documents, including representing Agent or Lender in any adversary proceeding or
contested matter commenced or continued by or on behalf of Borrower’s estate, and any appeal or review thereof
1.12
Confidentiality. Agent and Lender acknowledge that certain items of Collateral and information provided to Agent and Lender by Borrower
(including, without limitation, under Sections 7.1 and 7.2 of this Agreement) are confidential and proprietary information of Borrower (the “Confidential
Information”) and agrees to exercise the same degree of care that Lender exercises with respect to its own proprietary information of the same types to maintain the
confidentially of any such Confidential Information received in connection with this Agreement. Lender agrees that any Confidential Information it may obtain shall
not be disclosed to any other person or entity in any manner whatsoever, in whole or in part, without the prior written consent of Borrower, except that Agent and
Lender may disclose any such information: (a) to its own directors, officers, employees, accountants, counsel and other professional advisors and to its affiliates if
Agent or Lender in its sole discretion determines that any such party should have access to such information in connection with such party’s responsibilities in
connection with the Loan or this Agreement and, provided that such recipient of such Confidential Information either (i) agrees to be bound by the confidentiality
provisions of this paragraph or (ii) is otherwise subject to confidentiality restrictions that reasonably protect against the disclosure of Confidential Information; (b) if
such information is generally available to the public; (c) if required in any report, statement or testimony submitted to any governmental authority having jurisdiction
over Agent or Lender; (d) if required in response to any summons or subpoena or in connection with any litigation, to the extent permitted or deemed advisable by
Agent’s or Lender’s counsel; (e) to comply with any legal requirement or law applicable to Agent or Lender; (f) to the extent reasonably necessary in connection with
the exercise of any right or remedy under any Loan Document, including Agent ’s sale, lease, or other disposition of Collateral after default; (g) to any participant or
Assignee of Agent or Lender or any prospective participant or Assignee; provided, that such participant or Assignee or prospective participant or Assignee agrees in
writing to be bound by this Section prior to disclosure; or (h) otherwise with the prior consent of Borrower; provided, that any disclosure made in violation of this
Agreement shall not affect the obligations of Borrower or any of its affiliates or any guarantor under this Agreement or the other Loan Documents. Lender hereby
acknowledges that Borrower is a publicly traded company and the trading in securities of Borrower is subject to applicable securities legislation. Lender hereby
further acknowledges that as a result of the disclosure that may be made to it of any Confidential Information, it may possess material, non-public information of
Borrower. Accordingly, Lender hereby acknowledges that any trading by its employees, officers, agents or representatives in the securities of Borrower may entail
the violation by Lender, its employees, officers, agents or representatives of applicable securities and other legislation and regulations.
1.13
Assignment of Rights. Borrower acknowledges and understands that Agent or Lender may sell and assign all or part of its interest hereunder and under
the Note(s) and Loan Documents to any person or entity other than a person or entity reasonably deemed by Lender to be a direct competitor of Borrower (an
“Assignee”). After such assignment the term “Agent” or “Lender” as used in the Loan Documents shall mean and include such Assignee, and such Assignee shall be
vested with all rights, powers and remedies of Agent and Lender hereunder with respect to the interest so assigned; but with respect to any such interest not so
transferred, Agent and Lender shall retain all rights, powers and remedies hereby given. No such assignment by Agent or Lender shall relieve Borrower of any of its
obligations hereunder. Lender agrees that

in the event of any transfer by it of the Note(s), it will endorse thereon a notation as to the portion of the principal of the Note(s), which shall have been paid at the
time of such transfer and as to the date to which interest shall have been last paid thereon.
1.14
Revival of Secured Obligations. This Agreement and the Loan Documents shall remain in full force and effect and continue to be effective if any
petition is filed by or against Borrower for liquidation or reorganization, if Borrower becomes insolvent or makes an assignment for the benefit of creditors, if a
receiver or trustee is appointed for all or any significant part of Borrower’s assets, or if any payment or transfer of Collateral is recovered from Agent or Lender. The
Loan Documents and the Secured Obligations and Collateral security shall continue to be effective, or shall be revived or reinstated, as the case may be, if at any time
payment and performance of the Secured Obligations or any transfer of Collateral to Agent, or any part thereof is rescinded, avoided or avoidable, reduced in
amount, or must otherwise be restored or returned by, or is recovered from, Agent, Lender or by any obligee of the Secured Obligations, whether as a “voidable
preference,” “fraudulent conveyance,” or otherwise, all as though such payment, performance, or transfer of Collateral had not been made. In the event that any
payment, or any part thereof, is rescinded, reduced, avoided, avoidable, restored, returned, or recovered, the Loan Documents and the Secured Obligations shall be
deemed, without any further action or documentation, to have been revived and reinstated except to the extent of the full, final, and indefeasible payment to Agent or
Lender in Cash.
1.15
Counterparts. This Agreement and any amendments, waivers, consents or supplements hereto may be executed in any number of counterparts, and by
different parties hereto in separate counterparts, each of which when so delivered shall be deemed an original, but all of which counterparts shall constitute but one
and the same instrument.
1.16
No Third-Party Beneficiaries. No provisions of the Loan Documents are intended, nor will be interpreted, to provide or create any third-party
beneficiary rights or any other rights of any kind in any Person other than Agent, Lender and Borrower unless specifically provided otherwise herein, and, except as
otherwise so provided, all provisions of the Loan Documents will be personal and solely among Agent, Lender and Borrower.
1.17
Specific Performance. The parties hereto hereby declare that it is impossible to measure in money the damages which will accrue to Lender by reason
of Borrower’s failure to perform any of the obligations under this Agreement and agree that the terms of this Agreement shall be specifically enforceable by Lender.
If Lender institutes any action or proceeding to specifically enforce the provisions hereof, any Person against whom such action or proceeding is brought hereby
waives the claim or defense therein that Lender has an adequate remedy at law, and such Person shall not offer in any such action or proceeding the claim or defense
that such remedy at law exists.
1.18
Termination of Right to Invest / Right to Convert. Notwithstanding anything to the contrary in this Agreement, the parties hereto hereby affirm and
acknowledge that any participation rights, rights of first refusal, rights to invest, conversion rights, notice rights, and similar rights contained in the Original Loan and
Security Agreement but omitted from this Agreement have permanently and irrevocably expired, are terminated, and are of no further force and effect. Without
limiting the generality of the foregoing, the parties hereto affirm and acknowledge the termination of the participation rights, rights of first refusal, rights to invest,
and conversion rights contained in Section 8.1 of the Original Loan and Security Agreement and of the notice provisions contained in Section 8.2 of the Original
Loan and Security Agreement (collectively, the “Former Rights”). Further, each party hereto permanently and irrevocably waives, and is retroactively deemed to
have waived, (i) any obligation or requirement of the other parties hereto or thereto to perform under, or failure to perform any of such parties’ obligations under, the
Former Rights; (ii) any breach of any covenant in connection with the

Former Rights; and (iii) any rights, causes of action, or remedies arising from or accruing to such waiving party as a result of the such obligations, requirements,
breaches or other deficiencies described in clauses (i) and (ii) of this Section 11.18.
1.19
Agency.
(a)
Lender hereby irrevocably appoints Hercules Capital, Inc. to act on its behalf as Agent hereunder and under the other Loan Documents and authorizes
Agent to take such actions on its behalf and to exercise such powers as are delegated to Agent by the terms hereof or thereof, together with such actions and powers
as are reasonably incidental thereto.
(b)
Lender agrees to indemnify Agent in its capacity as such (to the extent not reimbursed by Borrower and without limiting the obligation of Borrower to
do so), according to its respective 2020 Term Commitment percentage (based upon the total outstanding 2020 Term Loan Advances) in effect on the date on which
indemnification is sought under this Section 11.19, from and against any and all liabilities, obligations, losses, damages, penalties, actions, judgments, suits, costs,
expenses or disbursements of any kind whatsoever that may at any time be imposed on, incurred by or asserted against Agent in any way relating to or arising out of,
this Agreement, any of the other Loan Documents or any documents contemplated by or referred to herein or therein or the transactions contemplated hereby or
thereby or any action taken or omitted by Agent under or in connection with any of the foregoing. The agreements in this Section shall survive the payment of the
Loans and all other amounts payable hereunder.
(c)
Agent in Its Individual Capacity. The Person serving as Agent hereunder shall have the same rights and powers in its capacity as a Lender as any other
Lender and may exercise the same as though it were not Agent and the term “Lender” shall, unless otherwise expressly indicated or unless the context otherwise
requires, include each such Person serving as Agent hereunder in its individual capacity.
(d)
Exculpatory Provisions. Agent shall have no duties or obligations to any Lender except those expressly set forth herein and in the other Loan
Documents. Without limiting the generality of the foregoing, Agent shall not:
(i) be subject to any fiduciary or other implied duties to any Lender, regardless of whether any default or any Event of Default has occurred
and is continuing;
(ii) have any duty to any Lender to take any discretionary action or exercise any discretionary powers, except discretionary rights and powers
expressly contemplated hereby or by the other Loan Documents that Agent is required to exercise as directed in writing by Lender,
provided that Agent shall not be required to take any action that, in its opinion or the opinion of its counsel, may expose Agent to liability
or that is contrary to any Loan Document or applicable law; and
(iii)except as expressly set forth herein and in the other Loan Documents, have any duty to any Lender to disclose, and Agent shall not be
liable for the failure to disclose, any information relating to Borrower or any of its Affiliates that is communicated to or obtained by any
Person serving as Agent or any of its Affiliates in any capacity.
(e)
Agent shall not be liable to any Lender for any action taken or not taken by it (i) with the consent or at the request of Lender or as Agent shall believe
in good faith shall be

necessary, under the circumstances or (ii) in the absence of its own gross negligence or willful misconduct.
(f)
Agent shall not be responsible to any Lender for or have any duty to any Lender to ascertain or inquire into (i) any statement, warranty or
representation made in or in connection with this Agreement or any other Loan Document, (ii) the contents of any certificate, report or other document delivered
hereunder or thereunder or in connection herewith or therewith, (iii) the performance or observance of any of the covenants, agreements or other terms or conditions
set forth herein or therein or the occurrence of any default or Event of Default, (iv) the validity, enforceability, effectiveness or genuineness of this Agreement, any
other Loan Document or any other agreement, instrument or document or (v) the satisfaction of any condition set forth in Section 4 or elsewhere herein, other than to
confirm receipt of items expressly required to be delivered to Agent.
(g)
Reliance by Agent. Agent may rely, and shall be fully protected in acting, or refraining to act, upon, any resolution, statement, certificate, instrument,
opinion, report, notice, request, consent, order, bond or other paper or document that it has no reason to believe to be other than genuine and to have been signed or
presented by the proper party or parties or, in the case of cables, telecopies and telexes, to have been sent by the proper party or parties. In the absence of its gross
negligence or willful misconduct, Agent may conclusively rely, as to the truth of the statements and the correctness of the opinions expressed therein, upon any
certificates or opinions furnished to Agent and conforming to the requirements of this Agreement or any of the other Loan Documents. Agent may consult with
counsel, and any opinion or legal advice of such counsel shall be full and complete authorization and protection in respect of any action taken, not taken or suffered
by Agent hereunder or under any Loan Documents in accordance therewith. Agent shall have the right at any time to seek instructions concerning the administration
of the Collateral from any court of competent jurisdiction. Agent shall not be under any obligation to exercise any of the rights or powers granted to Agent by this
Agreement and the other Loan Documents at the request or direction of Lenders unless Agent shall have been provided by Lender with adequate security and
indemnity against the costs, expenses and liabilities that may be incurred by it in compliance with such request or direction.
1.20
Publicity. None of the parties hereto nor any of its respective member businesses and Affiliates shall, without the other parties’ prior written consent
(which shall not be unreasonably withheld or delayed), publicize or use (a) the other party's name (including a brief description of the relationship among the parties
hereto), logo or hyperlink to such other parties’ web site, separately or together, in written and oral presentations, advertising, promotional and marketing materials,
client lists, public relations materials or on its web site (together, the " Publicity Materials"); (b) the names of officers of such other parties in the Publicity Materials;
and (c) such other parties’ name, trademarks, servicemarks in any news or press release concerning such party; provided however, notwithstanding anything to the
contrary herein, no such consent shall be required (i) to the extent necessary to comply with the requests of any regulators, legal requirements or laws (including any
securities laws or regulations) applicable to such party, pursuant to any listing agreement with any national securities exchange (so long as such party provides prior
notice to the other party hereto to the extent reasonably practicable) and (ii) to comply with Section 11.12.
11.21 Amendment and Restatement. This Agreement amends and restates in its entirety the Original Loan and Security Agreement effective as of the date
hereof.  Anything contained herein to the contrary notwithstanding, this Agreement is not intended to and shall not serve to effect a novation of the “Secured
Obligations” (as defined in the Original Loan and Security Agreement).  Instead, it is the express intention of the parties hereto to reaffirm the indebtedness,
obligations and liabilities created under the Original Loan and Security Agreement which is secured by the Collateral pursuant to the terms of the applicable Loan
Documents, except as

modified hereby.  Each Borrower acknowledges and confirms that the liens and security interests granted pursuant to the applicable Loan Documents secure the
applicable indebtedness, liabilities and obligations of Borrower to Lenders under the Original Loan and Security Agreement, as amended and restated by this
Agreement, the Loan Documents shall continue in full force and effect in accordance with their terms unless otherwise amended by the parties thereto, and that the
term “Secured Obligations” as used in the Loan Documents (or any other term used therein to describe or refer to the indebtedness, liabilities and obligations of
Borrower to Agent and Lenders) includes, without limitation, the indebtedness, liabilities and obligations of Borrower under this Agreement, and under the Original
Loan and Security Agreement, as amended and restated hereby, as the same further may be amended, modified, supplemented and/or restated from time to time.  The
Loan Documents and all agreements, instruments and documents executed or delivered in connection with any of the foregoing shall each be deemed to be amended
to the extent necessary to give effect to the provisions of this Agreement.  Each reference to the “Loan and Security Agreement” in any Loan Document shall mean
and be a reference to this Agreement (as further amended, restated, supplemented or otherwise modified from time to time).
(SIGNATURES TO FOLLOW)

IN WITNESS WHEREOF, Borrower, Agent and Lender have duly executed and delivered this Amended and Restated Loan and Security Agreement as of the
day and year first above written.
BORROWER:
AVEO PHARMACEUTICALS, INC.
Signature:    ________________________
Name:        Erick Lucera
Title:        Chief Financial Officer
Accepted in Palo Alto, California:
AGENT:
HERCULES CAPITAL, INC.
Signature:    _______________________
Print Name:    Jennifer Choe
Title:        Associate General Counsel
LENDER:
HERCULES CAPITAL, INC.
Signature:    _______________________
Print Name:    Jennifer Choe
Title:        Associate General Counsel
HERCULES CAPITAL FUNDING TRUST 2018-1
Signature:    _______________________
Print Name:    Jennifer Choe
Title:        Associate General Counsel
HERCULES CAPITAL FUNDING TRUST 2019-1
Signature:    _______________________

Print Name:    Jennifer Choe
Title:        Associate General Counsel

[EXHIBITS AND SCHEDULES INTENTIONALLY OMITTED. ON FILE WITH THE AGENT.]
    

LICENSE AGREEMENT
BY AND BETWEEN
EUSA PHARMA (UK) LIMITED
AND
AVEO PHARMACEUTICALS, INC
Dated: December 18, 2015

TABLE OF CONTENTS
ARTICLE 1. DEFINITIONS
1
ARTICLE 2. DEVELOPMENT AND COMMERCIALIZATION
13
2.2    Plans and Meetings
14
2.3    Clinical Trials in the Territory
16
2.4    Sharing of Partner Clinical and Other Data
17
2.5    Sharing of AVEO Clinical and Other Data
18
2.6    Record Keeping
19
2.7    Communications with Regulatory Authorities
19
2.8    Adverse Event/Safety Reporting Protocol
20
2.9    Legal Compliance
21
2.10    Technology Transfer
21
2.11    Support by AVEO
21
2.12    Supply of License Product
22
2.13    Recalls
22
ARTICLE 3. LICENSE GRANTS
23
3.1    Licenses to Partner
23
3.2    Sublicensing by Partner
23
3.3    Compliance with KHK Agreement
24
3.4    Use of Patents and Know-How
26
3.5    Reservation of Rights
26
3.6    No Implied Licenses
26
3.7    Technology Sublicensed from Third Parties
26
3.8    Cross-Territory Sales
27
3.9    Inventions by Service Providers
27
- i -

ARTICLE 4. COMPENSATION
28
4.1    Research and Development Funding
28
4.2    Milestone Payments
28
4.3    Royalty Payments
30
4.4    Royalty Reduction
30
4.5    Joint Development Cost Sharing
31
4.6    Amounts Due to KHK
32
4.7    Quarterly Payment Timing
32
4.8    Royalty Reports
32
4.9    Payment Method
32
4.10    No Credits or Refunds
32
4.11    Taxes
33
4.12    Value Added Tax
33
4.13    Blocked Currency
33
4.14    Foreign Exchange
33
4.15    Partner Records; Inspection
33
4.16    AVEO Records; Inspection
35
4.17    Interest
36
ARTICLE 5. PATENTS
36
5.1    Ownership and Disclosure of Inventions
36
5.2    Prosecution of Patents
37
5.3    Patent Term Extensions
39
5.4    Infringement of Patents by Third Parties
40
5.5    Infringement of Third-Party Rights
43
5.6    Patent Marking
43
- ii -

5.7    Patent Oppositions and Other Proceedings
43
5.8    In-Licensed Patents
43
5.9    Trademarks
46
ARTICLE 6. CONFIDENTIALITY
46
6.1    Core Confidential Information
46
6.2    Treatment of Confidential Information
47
6.3    Authorized Disclosure
47
6.4    Termination of Prior Agreements
47
6.5    Publicity
48
6.6    Publications
49
ARTICLE 7. REPRESENTATIONS AND WARRANTIES
49
7.1    General Representations and Warranties
49
7.2    AVEO’s Warranties
49
7.3    AVEO’s Covenants
52
7.4    Partner’s Warranties and Covenants
53
7.5    Disclaimer Concerning Technology
54
ARTICLE 8. INDEMNIFICATION
54
8.1    Indemnification by Partner
54
8.2    Indemnification by AVEO
55
8.3    Procedure
57
8.4    Insurance
57
8.5    Limitation of Liability
57
ARTICLE 9. TERM AND TERMINATION
58
9.1    Term
58
9.2    Termination for Breach
58
- iii -

9.3    Termination for Bankruptcy
59
9.4    Termination for Patent Challenge
59
9.5    Elective Termination
59
9.6    AVEO’s Rights upon Certain Terminations
59
9.7    Grant Back
61
9.8    Partner’s Rights upon Certain Terminations
61
9.9    Survival
61
ARTICLE 10. DISPUTE RESOLUTION
61
10.1    Seeking Consensus
61
10.2    Arbitration
62
10.3    Governing Law
63
10.4    Injunctive Relief; Remedy for Breach of Exclusivity
63
10.5    Patent Disputes
64
ARTICLE 11. MISCELLANEOUS
64
11.1    Export Control
64
11.2    Entire Agreement; Amendment
64
11.3    Bankruptcy
64
11.4    Force Majeure
65
11.5    Notices
65
11.6    Maintenance of Records
66
11.7    Construction
66
11.8    Ambiguities
66
11.9    Assignment
66
11.10    Independent Contractors
67
11.11    Counterparts
67
- iv -

11.12    Severability
67
11.13    Headings
67
11.14    No Waiver
67
11.15    No Third Party Beneficiaries
67
11.16    Costs
67
11.17    Further Assurances
67
- v -

LICENSE AGREEMENT
This LICENSE AGREEMENT (this “Agreement”) is entered into as of December 18, 2015 (the “Effective Date”) by and between EUSA PHARMA
(UK) LIMITED, with its principal offices at Breakspear Park, Breakspear Way, Hemel Hempstead, HP24TZ, United Kingdom (“Partner”), and AVEO
PHARMACEUTICALS, INC., a Delaware corporation with its principal offices at One Broadway, 14  Floor, Cambridge, MA 02142 (“AVEO”). AVEO and
Partner may be referred to herein each, individually, as a “Party” or, collectively, as the “Parties.”
RECITALS
WHEREAS, AVEO and KHK (as defined herein) have previously entered into the KHK Agreement (as defined herein) under which they have collaborated
in the development, manufacture and commercialization of products incorporating the proprietary compound known as tivozanib for the treatment of cancer, with
AVEO holding the rights to develop and commercialize such products outside of Asia;
WHEREAS, Partner is engaged in the development and commercialization of specialty pharmaceutical products in Europe and other countries around the
world; and
WHEREAS, Partner is interested in obtaining an exclusive right and license to develop and commercialize tivozanib in the Field (as defined herein) in the
countries listed in Exhibit A (the “Partner Territory”), and AVEO is willing to grant such rights and licenses to Partner, while retaining all rights outside of the Field
and the Partner Territory, all as more particularly set forth below.
NOW, THEREFORE, in consideration of the foregoing premises and the covenants and obligations set forth in this Agreement, the Parties agree as follows:
ARTICLE 1.
DEFINITIONS
The initially capitalized terms below in this Article have the following meanings as used throughout this Agreement. Derivative forms of these defined terms
shall be interpreted accordingly.
1.1
“Affiliate” means, with respect to a Party, any entity that, directly or indirectly, through one or more intermediaries, controls, is controlled by or is
under common control with such Party. For this purpose, “control” means the ownership of fifty percent (50%) or more of the voting securities entitled to elect the
directors or management of the entity, or the actual power to elect or direct the management or policies of the entity, whether by law, contract or otherwise.
1.2
“Annual Regulatory Report” has the meaning given in Section 2.4(a).
1.3
“AVEO Indemnitees” has the meaning given it in Section 8.1(a).
1.4
“AVEO Program Inventions” means any and all Inventions made after the Effective Date (a) that relate to (i) the Licensed Compound or Licensed
Products, (ii) any method of making, using (including a method of administration or dosage form) or testing the Licensed Compound or Licensed Products, or (iii)
any article necessary or useful to practice (or in the case of testing, of or for the presence of) any method described in clause (ii) above, and (b) that are
th
- 1 -

Controlled by AVEO and discovered, made, or conceived solely by employees of AVEO or its Affiliates or Third Parties acting on behalf of or in conjunction with
AVEO or its Affiliates, other than Partner Program Inventions or Joint Inventions.
1.5
“AVEO Program Invention Patents” means all Patents claiming or disclosing AVEO Program Inventions.
1.6
“AVEO Territory” means all countries and their respective possessions other than the Partner Territory and the KHK Territory.
1.7
“AVEO’s Knowledge” means the actual knowledge of AVEO’s President and Chief Executive Officer, Chief Financial Officer, Chief Medical Officer,
Vice President of Corporate Development and Alliance Management, Senior Corporate Counsel and Vice President of Technical Operations, and in respect of any
intellectual property matters means that such people have made diligent enquiries of AVEO’s external intellectual property counsel.
1.8
“Business Day” means a day other than Saturday, Sunday or a public holiday in New York, New York USA or England.
1.9
“Calendar Year” means each successive period of twelve (12) calendar months commencing on 1st January.
1.10
“Clinical Regulatory Filings” means data, filings or materials relating to Licensed Compounds or Licensed Products submitted to the applicable
Regulatory Authorities, including (a) data derived from clinical trials, and (b) data, filings or materials relating to or contained in any CMC or DMF.
1.11
“CMC” means the Chemistry, Manufacturing and Controls portion of any application for Marketing Approval.
1.12
“Combination Products” means products in forms suitable for human applications that contain a Licensed Compound together with one or more
other active ingredients that are sold either as a fixed dose/unit or as separate doses/units in a single package.
1.13
“Commercial Plan” has the meaning given it in Section 2.2(d).
1.14
“Commercially Reasonable Efforts” means the efforts required in order to carry out a task in a diligent and sustained manner without undue
interruption, pause or delay, which level is at least commensurate with the level of efforts that a biopharmaceutical company would devote to a product of similar
potential and having similar commercial and scientific advantages and disadvantages resulting from such company’s own research efforts (i.e., explicitly ignoring the
royalty, milestone and all other payments due AVEO under this Agreement), taking into account its safety and efficacy, the competitiveness of alternative products,
its proprietary position, pricing, reimbursement and other market-specific factors, and all other relevant factors. Commercially Reasonable Efforts requires (without
limitation) that the Party exerting such efforts (a) promptly assign responsibility for its obligations to specific employee(s) who are held accountable for progress and
monitor such progress on an ongoing basis, (b) set and continue to seek to achieve specific and meaningful objectives for carrying out such obligations, and (c) make
and implement decisions and allocate resources designed to advance progress with respect to such objectives, in each case in a commercially reasonable manner.
1.15
“Competing Product” means any pharmaceutical product or product candidate that: (a) contains (i) [**]. For the purpose of this Competing Product
definition, [**] means any
- 2 -

composition of matter [**]. For purposes of this Competing Product definition, [**] during the Term.
1.16
“Competitive Infringement” has the meaning given it in Section 5.4(b).
1.17
“Confidential Information” means all proprietary confidential non-public information received by either Party (the “Receiving Party”) from the
other Party (the “Disclosing Party”) or disclosed by either Party to the other Party pursuant to this Agreement, which information is disclosed under circumstances
reasonably indicating that it is confidential. As between the Parties, the KHK Agreement is the Confidential Information of AVEO. Notwithstanding the foregoing,
Confidential Information shall not include information that, in each case as demonstrated by competent written documentation:
(a)    is publicly disclosed and made generally available to the public by the Disclosing Party, either before or after it becomes known to the Receiving
Party;
(b)    was known to the Receiving Party, without obligation to keep it confidential, prior to the date of disclosure by the Disclosing Party;
(c)    is subsequently disclosed to the Receiving Party by a Third Party lawfully in possession thereof without obligation to keep it confidential and
without a breach of such Third Party’s obligations of confidentiality;
(d)    has been publicly disclosed or made generally available to the public other than through any act or omission of the Receiving Party in breach of
this Agreement; or
(e)    has been independently developed by the Receiving Party without the aid, application or use of the Disclosing Party’s Confidential Information
(the competent written proof of which must be contemporaneous with such independent development).
1.18
“Control” means, with respect to any Know-How, Patent Right or other intellectual property right, possession by a Party, directly or through an
Affiliate controlled by such Party (whether by ownership or license (other than pursuant to this Agreement)) of the ability to grant a license or sublicense as provided
for herein without violating the terms of any pre-existing written agreement with any Third Party. Any Patent, Know-How or other intellectual property right that is
licensed or acquired by a Party following the Effective Date and that would otherwise be considered to be under the Control of a Party shall not be deemed to be
under the Control of such Party if the application of such definition in the context of any licenses or sublicenses granted to the other Party under this Agreement
would require the granting Party to make any additional payments or royalties to a Third Party in connection with such license or sublicense grants, unless the other
Party agrees to pay the additional payments or royalties to the Third Party.
1.19
“Debtor” has the meaning given it in Section 11.3.
1.20
“Dispute” has the meaning given it in Section 10.1.
1.21
“Distributor” means any non-sublicensee Third Party (i.e., any Third Party that is not granted a sublicense of the Licensed Technology) that has been
granted the right to distribute or resell in the Partner Territory any quantities of Licensed Product, which quantities are sold by Partner or its Affiliates or
Sublicensees.
- 3 -

1.22
“DMF” means a Drug Master File in the United States or equivalent filing or filing serving a similar purpose in another regulatory jurisdiction.
1.23
“Dollar” or “$” means United States Dollars.
1.24
“EMA” means European Medicines Agency.
1.25
“FDA” means the United States Food and Drug Administration or any successor entity.
1.26
“Field” means the diagnosis, prevention and treatment of any diseases and conditions in humans other than non-oncologic diseases or conditions of
the eye in humans.
1.27
“First Commercial Sale” means, with respect to any Licensed Product, the first sale by Partner or one of its Affiliates or Sublicensees to a Third
Party of such Licensed Product in a country in the Partner Territory after Marketing Approval of such Licensed Product has been obtained in such country; which for
the avoidance of doubt, shall include named patient sales even if made prior to such Marketing Approval.
1.28
“Force Majeure” has the meaning given it in Section 11.4.
1.29
“FTE” means a full-time equivalent person year of scientific, technical, regulatory or professional work. An FTE shall consist of [**] hours per year,
with any portion of an FTE calculated based upon hours worked divided by such annual total.
1.30
“FTE Rate” means [**] Dollars ($[**]) per FTE.
1.31
“GAAP” means U.S. generally accepted accounting principles, consistently applied.
1.32
“Generic Product” means, with respect to a Licensed Product in any country in the Partner Territory, any pharmaceutical product that contains the
Licensed Compound and that is distributed by a Third Party under a Marketing Approval approved by a Regulatory Authority in reliance, in whole or in part, on the
prior approval (or on safety or efficacy data submitted in support of the prior approval) of such Licensed Product, including any product authorized for sale in the EU
pursuant to a provision of Articles 10, 10a or 10b of Parliament and Council Directive 2001/83/EC as amended (including an application under Article 6.1 of
Parliament and Council Regulation (EC) No 726/2004 that relies for its content on any such provision) or in any other country or jurisdiction pursuant to all
equivalents of such provisions; provided, however, that a product licensed or produced by Partner or its Affiliates or Sublicensee(s) (i.e., an authorized generic
product) will not constitute a Generic Product.
1.33
“Independent Study” has the meaning given it in Section 2.2(c).
1.34
“Indication” shall mean a distinct primary disease or medical condition (e.g., heart failure) including in relation to cancer, different forms of cancer
(e.g. skin cancer or lung cancer) and in respect of cancer different cancer subtypes for which it is necessary to undertake separate clinical trials (not including phase I
clinical trials) to obtain Marketing Approval for a product for such form of cancer (e.g. small cell lung cancer and non-small cell lung cancer or squamous non-small
cell lung cancer and non-squamous non-small cell lung cancer or hepatocellular carcinoma and hepatoblastoma shall be separate Indications). Different lines of
treatment for the same cancer subtype are not separate indications. Thus the Parties agree that (i) first line treatment and third line monotherapy treatment of RCC
will not be considered separate
- 4 -

Indications. The parties also agree that if it is necessary to undertake a separate registrational clinical trial to obtain Marketing Approval for a Combination Product
including the Licensed Compound and a checkpoint inhibitor, that will be considered a separate Indication for purposes of this Agreement.
1.35
“Infringement” has the meaning given it in Section 5.4(a).
1.36
“Invention” means any and all patentable inventions first conceived or reduced to practice by or on behalf of either Party or any of its Affiliates or
sublicensees in the course of development activities in respect of the Licensed Technology under this Agreement. Inventorship of all Inventions shall be determined
in accordance with United States patent law.
1.37
“Joint Development Plan” has the meaning given it in Section 2.2(b).
1.38
“Joint Inventions” means any and all Inventions, other than AVEO Program Inventions or Partner Program Inventions, that are discovered, made, or
conceived jointly by (a) employees of AVEO or its Affiliates or Third Parties acting on behalf of or in conjunction with AVEO or its Affiliates and (b) employees of
Partner or its Affiliates or Sublicensees or Third Parties acting on behalf of or in conjunction with Partner or its Affiliates or Sublicensees, such that a party under
each of prong (a) and prong (b) are both named as joint inventors.
1.39
“Joint Patents” means all Patents that claim Joint Inventions.
1.40
“JSC” has the meaning given it in Section 2.2(a).
1.41
“Key Launch Countries” means France, Germany, Italy, Spain, United Kingdom and the Key Non-EU Licensed Countries.
1.42
“Key Non-EU Licensed Countries” means Brazil, Argentina, Venezuela, Australia and South Africa, provided that the Parties may change this by
documented mutual agreement by the JSC under the procedure in Section 2.1.
1.43
“KHK” means Kyowa Hakko Kirin Co., Ltd., a Japanese corporation with its principal offices at 1-6-1, Ohtemachi, Chiyoda-ku, Tokyo, 100-8185,
Japan.
1.44
“KHK Agreement” means that certain License Agreement entered into as of December 21, 2006 by and between AVEO and KHK, as amended from
time to time.
1.45
“KHK Indemnitees” has the meaning given it in Section 8.1(b).
1.46
“KHK Territory” means the following countries and their respective territories and possessions: Afghanistan, Bahrain, Bangladesh, Bhutan, Brunei,
Cambodia, India, Indonesia, Iran, Iraq, Israel, Japan, Jordan, Kuwait, Laos, Lebanon, Malaysia, Maldives, Mongolia, Myanmar, Nepal, North Korea, Oman,
Pakistan, People’s Republic of China (including Hong Kong and Macao), Philippines, Qatar, Saudi Arabia, Singapore, South Korea, Sri Lanka, Syria, Taiwan,
Thailand, Timor Leste, Turkey, United Arab Emirates, Vietnam and Yemen.
1.47
“Know-How” means (i) all information, techniques, data, inventions, practices, methods, processes, knowledge, know-how, skill, experience,
technical data, test results (including pharmacological, toxicological, clinical, analytical and quality control data, regulatory submissions, correspondence and
communications, and marketing, distribution, pricing, cost, manufacturing, patent and legal data or descriptions), and (ii) compositions of matter, assays and other
materials.
- 5 -

1.48
“Licensed Compound” means 1-[2-chloro-4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-3-(5-methyl-1,2-oxazol-3-yl)urea, otherwise known as
tivozanib and any and all acids, bases, salts, stereoisomers, racemates, tautomers, polymorphs, complexes, chelates, crystalline and amorphous forms, prodrugs,
solvates (including hydrates) metabolites and metabolic precursors (whether active or inactive) thereof.
1.49
“Licensed Know-How” means all Know-How that (a) is Controlled by AVEO as of the Effective Date of this Agreement or thereafter during the
Term, and (b) is necessary or reasonably useful in the research, development, manufacture and commercialization of any Licensed Compound, Licensed Product, or
method of using (including methods of administration) or testing any of the foregoing (or any article necessary or useful to practice any such method) including but
not limited to all Clinical Regulatory Filings, Safety Data and CMC data related to such Know-How Controlled by AVEO after the Effective Date, but excluding any
Know-How in-licensed by AVEO after the Effective Date for which AVEO would owe a Third Party consideration if AVEO grants rights thereunder to Partner
(unless Partner agrees in writing to pay such consideration), and further subject to the limited use of data from AVEO’s Independent Studies prior to Opt-In as
described in Section 2.2(c). For purposes of clarity, Licensed Know-How includes (a), to the extent Controlled by AVEO, “Licensed Know-How” licensed by KHK
to AVEO pursuant to the KHK Agreement and (b) the Know-How listed in Exhibit C. AVEO will provide instructions to its contractors identified in Exhibit C for
them to disclose such items of Know-How listed in Exhibit C to Partner after the Effective Date within six (6) months of the Effective Date but earlier if and as
required and on a timely basis for the Marketing Approval submission to the EMA for the Licensed Product in RCC, and to respond to requests for further
information from the EMA as it considers such submission, and shall take all additional actions reasonably necessary to facilitate such transfer (other than payment
of monies or relinquishment of other rights of AVEO). If required by any such contractor, AVEO will pay the reasonable costs incurred by such contractor in
transferring such Licensed Know-How listed in Exhibit C. The Licensed Know-How disclosed by the contractors instead of directly by AVEO shall nevertheless be
deemed disclosed by AVEO under this Agreement for purposes of the “Confidential Information” definition.
1.50
“Licensed Patents” means (a) the Listed AVEO Patents, (b) the AVEO Program Invention Patents, (c) AVEO’s interest in the Joint Patents and (d) all
other Patents Controlled by AVEO during the Term that claim or otherwise cover the Licensed Compound or any Licensed Product, or any method of making, using
(including methods of administration) or testing of any of the foregoing, but excluding any Patent in-licensed by AVEO after the Effective Date for which AVEO
would owe a Third Party consideration if AVEO grants rights thereunder to Partner.
1.51
“Licensed Product Biomarker” means any and all biomarkers (including metabolite, DNA, RNA and protein profiles) discovered or developed by or
on behalf of AVEO or Partner during the Term that (a) are for use with (including use in clinical testing of or use in any decision whether to prescribe), or (b) relate
to, are associated with or are correlated with patient populations and/or tumors that do or do not respond to treatment with, in the case of each of (a) and (b), any one
(1) or more Licensed Product(s). For purposes of clarity, Licensed Product Biomarkers include biomarker tests for detecting and measuring levels of any of the
biomarker molecules described in the preceding sentence, whether in the form of testing products, test kits or tests performed at a centralized testing laboratory. Any
such biomarker or biomarker test is a Licensed Product Biomarker regardless of its stage of discovery, development, advancement or commercialization, and whether
or not the biomarker or biomarker test is already validated or recognized by any Regulatory Authority. For purposes of this definition, biomarkers or biomarker tests
“discovered or developed by or on behalf of Partner” include those discovered or developed by Partner’s Affiliates, Sublicensees or contractors.
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1.52
“Licensed Product” means (a) any and all pharmaceutical compositions that contain the Licensed Compound and (b) other than for purposes of
Article 4 hereof, a Licensed Product Biomarker intended for use in the Field discovered or developed by or on behalf of Partner or its Affiliates.
1.53
“Licensed Technology” means both Licensed Patents and Licensed Know-How.
1.54
“Listed AVEO Patents” means (a) all patents and patent applications listed in Exhibit B as may be updated from time to time during the Term; (b) all
patent applications (including provisional and utility applications) claiming priority to or common priority with or based on any of the foregoing, including all
divisionals, continuations, continuations-in-part, patents of addition and substitutions of any of the foregoing; (c) all patents issuing on any of the foregoing, and all
reissues, reexaminations, renewals and extensions of any of the foregoing, (d) all counterparts to the foregoing in other countries; and (e) all supplementary
protection certificates, restoration of patent term and other similar rights of AVEO and its Affiliates based on any of the foregoing.
1.55
“Losses” has the meaning given it in Section 8.1.
1.56
“M&A Event” has the meaning given it in Section 11.9.
1.57
“Marketing Approval” means, with respect to a Licensed Product, all approvals (including supplements, amendments, pre- and post-approvals),
licenses, registrations and authorizations (other than Pricing Approval) of any national, supra-national (e.g. the EMA), regional, state or local regulatory agency,
department, bureau, commission, council or other governmental authority necessary for the manufacture, distribution, use or sale of such Licensed Product in a
regulatory jurisdiction. For clarity, the Marketing Approvals with respect to the Licensed Products in the Partner Territory shall be issued in the name of Partner or its
designated Affiliate or Sublicensee.
1.58
“Net Sales” means the gross amount invoiced by Partner or its Affiliates and Sublicensees (and by Distributors if used by Partner to sell Licensed
Products in France, Germany, Italy, Spain, United Kingdom, Belgium, Netherlands, Luxembourg, Austria, Poland, Portugal, Denmark, Finland, Iceland, Norway and
Sweden) for the sale of Licensed Products in the Partner Territory (for the avoidance of doubt, such sales shall include named patient sales if sold for a profit but not
if disposed of for free or at cost), less any of the following applicable deductions related to such sale and, except in the case of (e), included in the invoiced amounts:
(a) normal, customary trade discounts (including volume discounts), credits, chargebacks, reductions, and rebates, and allowances and adjustments for rejections,
recalls, outdated products, returns, in each event whether voluntary or required; (b) freight, shipping, insurance, sales, use, excise, value-added and similar customs,
taxes, tariffs or duties imposed on such sale, transfer, or other disposition; (c) credits actually given or allowances actually made for wastage replacement,
governmental program rebates, indigent patient and similar programs to provide Licensed Product on a no-profit or at-cost basis, to the extent actually deducted from
the gross amount invoiced and either not required to be paid by, or refunded to, the customer or other payor; (d) amounts repaid or credits taken by reason of
rejections, defects or returns or because of retroactive price reductions (to be clear, other than retroactive price reductions granted as part of any collections efforts or
to resolve uncollectible accounts) or due to recalls or government laws or regulations requiring rebates; (e) an allowance for bad debt and uncollectible accounts, not
to exceed [**] percent ([**]%) of the gross amount invoiced and not to exceed the amount of the allowance actually used by the invoicing entity to account for bad
debt and uncollectible accounts with respect to such invoiced amounts to prepare the invoicing entity’s audited financial statements for financial reporting purposes.
Even if there is overlap between any of deductions
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(a)-(d), each individual item shall only be deducted once in each Net Sales calculation. Bad debt and uncollectible accounts shall be addressed solely by the
deduction of the allowance provided for in clause (e) above in this paragraph, and any write-off of bad debt or uncollectible accounts shall not be deemed
encompassed in any of deductions (a)-(d). Net Sales shall not include amounts for any Licensed Product furnished to a Third Party for which payment is not intended
to be and is not received, such as Licensed Products used in clinical trials or Licensed Products distributed as promotional or free goods and free named patient
supplies; provided that the amounts of such Licensed Products so made available are reasonable for the intended purpose and within customary amounts; and
provided, further, that this sentence is not intended to address accounting for quantities of Licensed Products associated with bad debt or uncollectible accounts
(which, to be clear, shall be dealt with only under clause (e) above).
Net Sales excludes amounts from sales or other dispositions of Licensed Product between Partner and any of its Affiliates or Sublicensees, solely to the extent
that such entity purchasing a Licensed Product resells such Licensed Product to a Third Party and such resale is included in Net Sales.
Net Sales includes sales to any Distributor. If, in addition to or in lieu of a transfer price paid for quantities of Licensed Product supplied, any Distributor
provides consideration to Partner or its Affiliates or Sublicensees in connection with the grant of rights to distribute any Licensed Product, then such consideration
shall be included in the calculation of Net Sales in the quarter in which it is received by Partner, its Affiliates or Sublicensees.
Net Sales amounts shall be determined from the books and records of Partner and its Affiliates and Sublicensees maintained in accordance with GAAP
consistently applied, and such amounts shall be calculated using the same accounting principles used for other products of Partner and its Affiliates and Sublicensees
for financial reporting purposes.
On a country-by-country basis, on expiry of the Royalty Term in a country, sales of a Licensed Product in such country shall not be included in determining
Net Sales for the purpose of establishing aggregate global Net Sales for the sales milestones in Section 4.2(c) or the royalty rates in Section 4.3.
In the event that a Licensed Product is sold in any country in the form of a Combination Product, Net Sales of such Combination Product shall be adjusted by
multiplying actual Net Sales of such Combination Product in such country calculated pursuant to the foregoing definition of “Net Sales” by the fraction A/(A+B),
where A is the average invoice price in such country of any Licensed Product that contains the Licensed Compound as such Combination Product as its sole active
ingredient(s), if sold separately in such country and B is the average invoice price in such country of each product that contains active ingredient(s) other than the
Licensed Compound contained in such Combination Product as its sole active ingredient(s), if sold separately in such country; provided that the invoice price in a
country for each Licensed Product that contains only the Licensed Compound and each product that contains solely active ingredient(s) other than the Licensed
Compound, included in the Combination Product shall be for a quantity comparable to that used in such Combination Product and of substantially the same class,
purity and potency or functionality, as applicable. If either such Licensed Product that contains the Licensed Compound as its sole active ingredient or a product that
contains the active ingredient(s) (other than the Licensed Product), in the Combination Product as its sole active ingredient(s) is not sold separately in a particular
country, the Parties shall negotiate in good faith a reasonable adjustment to Net Sales in such country that takes into account the medical contribution to the
Combination Product of and all other factors reasonably relevant to the relative value of, the Licensed Compound, on the one hand and all of the other active
ingredient(s), as applicable, collectively, on the other hand, provided that until such negotiation
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and adjustment is completed, the Parties agree that Net Sales shall be calculated under the assumption that the Licensed Compound and each other active ingredient
in the Combination Product have equal value.
1.59
“Ophthotech Agreement” means the Research and Exclusive License Agreement between Ophthotech Corporation and AVEO dated November 10,
2014.
1.60
“Opt-In” has the meaning given it in Section 2.2(c).
1.61
“Other Licensee(s)” means any Third Party to which AVEO, KHK or any of their respective Affiliates has granted a license or sublicense to research,
develop, manufacture or commercialize the Licensed Compound or a Licensed Product outside of the Partner Territory or for use outside of the Field.
1.62
“Partner Indemnitees” has the meaning given it in Section 8.2.
1.63
“Partner Know-How” means all Know-How that Partner develops or owns or Controls during the Term that relates in any way to the Licensed
Compound or Licensed Products, or method of making, using (including methods of administration) or testing of any of the foregoing (or any article necessary or
useful to practice any such method). The Partner Know-How includes all clinical data generated in clinical trials of the Licensed Product by or on behalf of Partner or
its Affiliates subject to the limited use of data from Partner’s Independent Studies prior to Opt-In as described in Section 2.2(c).
1.64
“Partner Patents” means all Patents that claim Partner Program Inventions.
1.65
“Partner Program Inventions” means any and all Inventions that (a) relate to (i) the research, manufacture, development, commercialization and/or
use of Licensed Compound or Licensed Products in the Field, (ii) any method of making, using (including a method of administration or dosage form) or testing the
Licensed Compound or Licensed Products for use in the Field, or (iii) any article necessary or useful to practice (or in the case of testing, of or for the presence of)
any method described in clause (ii) above, and (b) that are Controlled by Partner and discovered, made, or conceived solely by employees of Partner or its Affiliates
or Third Parties acting on behalf of or in conjunction with Partner or its Affiliates.
1.66
“Partner Region” means any of (i) Europe, (ii) Latin America (excluding Mexico), (iii) Africa and South Africa, or (iv) Australasia and New
Zealand, with each Partner Region including the countries listed under such Partner Region in Exhibit A.
1.67
“Partner Territory” has the meaning set forth in the Recitals above.
1.68
“Partner Third-Party Claim” has the meaning given it in Section 8.2(c).
1.69
“Party” and “Parties” have the meanings given such terms in the opening paragraph of this Agreement.
1.70
“Patent” means any patent application or patent anywhere in the world, including all of the following kinds: provisional, utility, divisional,
continuation, continuation-in-part, and substitution applications; and utility, re-issue, re-examination, renewal and extended patents, and patents of addition, and any
supplementary protection certificates, restoration of patent terms and other similar rights.
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1.71
“Pharmstandard Agreement” the License Agreement between JSC Pharmstandard Ufimskiy Vitamin Plant and AVEO dated 4 August 2015.
1.72
“Plans” means, as applicable, any Joint Development Plan, any Commercial Plan and/or any study design for an Independent Study.
1.73
“Pricing Approval” means the approval or governmental decision establishing a price for a Licensed Product that can be charged to consumers and
will be reimbursed by the applicable government authority(ies) in such country.
1.74
“Prior Agreement” means the Confidential Disclosure Agreement between the Parties effective September 10, 2015.
1.75
“Program Invention Patent Rights” means all Patents that claim Program Inventions.
1.76
“Program Inventions” means, collectively, AVEO Program Inventions, Partner Program Inventions and Joint Program Inventions.
1.77
“Prosecuting Party” has the meaning given it in Section 5.2(c)(ii).
1.78
“RCC” means renal cell carcinoma.
1.79
“Regulatory Authority” means any national, supra-national, regional, state or local regulatory agency, department, bureau, commission, council or
other governmental entity in the Partner Territory involved in the granting of Marketing Approval for biological or pharmaceutical products.
1.80
“Regulatory Documentation” shall mean (i) AVEO’s NDA for the Licensed Compound submitted to the FDA in 2012; (ii) the regulatory dossier, or
MAA, for the RCC indication in electronic CTD format that is suitable for immediate submission to the EMA (provided that the Parties agree that for all purposes
under this Agreement the MAA shall be deemed suitable for immediate submission to the EMA upon such submission by Partner, and that the subsequent evaluation
of such MAA by the EMA shall have no bearing on such suitability); and (iii) AVEO’s completed manufacturing process validation protocols, final reports, and
master validation for the Licensed Products, and (iv) to the extent relating to the Licensed Compound and necessary for Partner’s exercise of its rights under this
Agreement (a) any and all other INDs, registrations, licenses, authorizations and approvals; (b) reports and material correspondence submitted to or received from
Regulatory Authorities and supporting documents with respect thereto, in each case (a) and (b) that are in the possession, custody or control of AVEO and existing at
the Effective Date
1.81
“[**]” has the meaning given it in Section 5.4(i)(ii)(A).
1.82
“Royalty Term” means, on a Licensed Product-by-Licensed Product and country-by-country basis, the period beginning on the First Commercial Sale
of such Licensed Product in such country until the later to occur of (a) ten (10) years after the Effective Date, (b) the expiration of regulatory data exclusivity or
market exclusivity in such country, or (c) the expiration of the last Valid Claim claiming or covering the composition, use or manufacture of the Licensed Product in
the country in which such Licensed Product is manufactured or sold.
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1.83
“Safety Data” means adverse event information and other information (if any) required by one (1) or more Regulatory Authorities to be reported to
such Regulatory Authorities under applicable laws.
1.84
“SEC” has the meaning given it in Section 6.5(c)(iii).
1.85
“Sublicensee” means a Third Party to whom Partner (or its Affiliate) has granted a sublicense under any Licensed Technology and shall not include a
Distributor.
1.86
“Term” has the meaning given in Section 9.1.
1.87
“Third Party” means any person or entity other than a Party or an Affiliate of a Party.
1.88
“Third-Party Claim” has the meaning given it in Section 8.1(a).
1.89
“United States Business Day” means any day other than a Saturday, Sunday, or a day in which banks in New York, New York are closed.
1.90
“Valid Claim” means a claim of an issued and unexpired patent within the Licensed Patents which has not been: (a) disclaimed, cancelled, withdrawn
or abandoned, (b) dedicated to the public, (c) declared invalid, unenforceable, unpatentable or revoked by a decision of a court, government agency other authority of
competent jurisdiction from which no appeal can be or has been taken, or (d) admitted to be invalid or unenforceable through reexamination, reissue or otherwise.
1.91
“Value Added Tax” shall mean (a) in relation to any jurisdiction within the EU, the tax imposed by the Council Directive on the common system of
value added tax (2006/112) and any national legislation implementing that directive together with legislation supplemental thereto and the equivalent tax (if any) in
that jurisdiction; and (b) in any other country, any other value added, goods and services or similar tax chargeable on the supply or deemed supply of goods or
services under applicable legislation; but, in each event, excluding any US sales tax.
1.92
“Withholding Taxes” has the meaning given it in Section 4.11.
ARTICLE 2.
DEVELOPMENT AND COMMERCIALIZATION
2.1
Diligence Obligations. Partner shall use Commercially Reasonable Efforts, at its sole cost and expense, to (i) commercialize the Licensed Product for
the RCC Indication (if Marketing Approval is granted) in the Partner Territory, (ii) subject to AVEO’s full compliance with its obligations under Sections 2.10 and
2.11, file an application for, and diligently seek, Marketing Approval of a Licensed Product for the treatment of RCC with the EMA aiming for a target filing date of
either February 8, 2016 or March 7, 2016, and (iii) thereafter (but not later than [**] after obtaining Marketing Approval from the EMA), file an application for
Marketing Approval of a Licensed Product for the treatment of RCC in each of the Key Non-EU Licensed Countries unless Partner provides a reasonable reason why
not to file in such country and in which case the Parties shall agree a replacement country. AVEO shall provide data and support for such filing in accordance with
Sections 2.10 and 2.11. The scope of such commercialization activities shall include using Commercially Reasonable Efforts to seek Marketing Approval in the Key
Launch Countries and each of the Key Non-EU Licensed Countries and upon receipt of Marketing Approval, (ii) using Commercially Reasonable Efforts to seek
Pricing Approval, and (iii) using Commercially Reasonable Efforts to launch the Licensed Product in each country
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where Marketing Approval and Pricing Approval is obtained, provided that the Pricing Approval is reasonably acceptable to Partner, and (iv) Commercially
Reasonable Efforts thereafter to actively promote to the appropriate audience(s) all Licensed Products that have Marketing Approval and Commercially Reasonable
Efforts to fill the market demand for them in the countries where they are approved. Partner shall use Commercially Reasonable Efforts to launch all Licensed
Products in the Key Launch Countries within [**] days of receiving Marketing Approval and Pricing Approval in such country, provided that the Pricing Approval is
reasonably acceptable to Partner. Partner shall perform all of the foregoing activities in accordance with the prevailing industry standards and in compliance with all
applicable laws. Partner shall not be relieved of its diligence obligations hereunder by the granting of any sublicense(s). The activities and achievements of any
Sublicensee(s) shall be counted, however, towards Partner’s performance hereunder. After the Effective Date and through the submission by Partner of the
application for Marketing Approval of the Licensed Product for the treatment of RCC with the EMA, Partner shall, on a reasonable and timely basis, (a) take all
actions necessary to prepare and deliver to AVEO any information or materials required from Partner for the completion of such submission, (b) provide its
comments to AVEO, if any, on draft submission documents and (c) otherwise cooperate with AVEO in AVEO’s preparation of the submission.
2.2
Plans and Meetings.
(a)
Joint Steering Committee. The Parties will establish a joint steering committee (the “JSC”) to provide advice and make recommendations on
how to conduct the overall collaboration.  The JSC shall meet once every [**] months within each Calendar Year and may be conducted by telephone,
videoconference or in person, provided that there is at least [**] per Calendar Year. Any in-person JSC meetings shall be held on an alternating basis between
AVEO’s and EUSA’s facilities, unless otherwise agreed by the Parties. Each Party shall be responsible for its own expenses in attending such meetings. Each Party
shall keep the other reasonably informed, through the JSC, of the details and progress of the activities in its respective territory. The JSC will consist of
[**] representatives appointed by AVEO and [**] representatives appointed by Partner. The initial members of the JSC will be nominated by the Parties promptly
following the Effective Date. Such representatives shall be individuals suitable in seniority and experience and having delegated authority to make decisions of the
JSC with respect to matters within the scope of the JSC’s responsibilities; provided that it is understood that such individuals may need to seek appropriate authority
from the relevant Party with respect to certain matters. Either Party may replace its respective JSC representatives at any time with prior written notice to the other
Party; provided that such replacement is of comparable authority and scope of functional responsibility within that Party’s organization as the person he or she is
replacing. Each Party will designate one of its [**] representatives who possesses a thorough understanding of the scientific and business issues relevant to this
Agreement to act as the co-chair of the JSC. The co-chairs will be responsible for ensuring that activities occur as set forth in this Agreement, including ensuring that
the JSC meetings occur, material recommendations and decisions of the JSC are properly reflected in minutes of the JSC, and any dispute is given prompt attention
and resolved in accordance with Article 10 of this Agreement. During each meeting of the JSC, the JSC shall discuss (i) progress made in developing and
commercializing Licensed Products in the Field since the previous meeting; (ii) the coordination of the attendance at, presentations and other matters relating to the
promotion of Licensed Products in the Field at international seminars and conferences by KHK, Partner, AVEO and Other Licensees; and (iii) any modifications to
Plans that have been made since the previous meeting and the reasons for such modifications, it being understood that no modifications may be made to such a plan
that would result in failure of the diligence obligations in Section 2.1 to be satisfied. The JSC shall review and discuss the overall strategy for the development,
manufacturing and commercialization of the Licensed Products in the Field, and coordinate the Parties’ respective activities for the Licensed Products between the
Partner Territory and the
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AVEO Territory; provided that, AVEO shall be responsible for all activities and decisions with respect to the AVEO Territory and Partner shall be responsible for all
activities and decisions with respect to the Partner Territory in the Field.
(b)
In coordination of activities, the Parties shall consider joint development opportunities. Any agreements between the Parties to conduct joint
development activities shall be reflected in a joint development plan, to be reviewed and agreed upon by the Parties (the “Joint Development Plan”). If the Parties
agree to a Joint Development Plan, then no later than thirty (30) days prior to each anniversary of the creation of such Joint Development Plan, the Parties shall agree
to an updated Joint Development Plan. If either Partner or AVEO, or any of their respective (sub)licensees, desires to conduct a new clinical study or program which
is not included in the Joint Development Plan, either, for example, to generate data for use in the development or promotion of the Licensed Product, or for
reimbursement or pricing purposes, the proposing Party would present the proposed design and associated costs of such study or series of studies to the JSC. If the
other Party agrees, the Parties would amend the Joint Development Plan to include such study or program as a jointly-funded study or program and the associated
costs would be deemed joint development costs and shared pursuant to a cost-sharing ratio to be agreed to by the Parties, and all resulting data and Know-How would
be available for use by each Party in each of their respective territories. With respect to development activities that are not mutually agreed to within the Joint
Development Plan, each party shall have the right to conduct Independent Studies.
(c)
Independent Studies. In the event that a Party, or any of its respective (sub)licensees, proposes a study that the other Party does not desire to
co-fund (each, an “Independent Study”), the proposing Party would have the right to proceed with such Independent Study; provided, however, such Party would be
solely responsible for the conduct and costs of such trial, and the non-funding party would have no rights to use any resulting data or Know-How for regulatory or
commercialization purposes, except with respect to Safety Data or other information necessary to support Safety Data disclosure requirements in any filings with
regulatory agencies in its territory, unless and until such non-funding Party “opts-in” to co-fund such study (the “Opt-In”). If a Party Opts-In it may use the resulting
data and Know-How for any purpose consistent with the provisions of this Agreement. A Party conducting an Independent Study shall provide regular updates to the
other Party at each JSC meeting on the progress and results of the Independent Study. At the conclusion of an Independent Study, the Party conducting the Study
shall disclose in writing to the other Party all data from the Independent Study and all other relevant documentation and information relating to the Independent
Study reasonably requested by the other Party to allow the other Party to make a fully informed decision on whether to Opt-In. Should the other Party elect to Opt-In,
it must do so within [**] days of disclosure of all such data, documentation and information. With respect to AVEO’s planned phase 3 RCC study targeting the third
line RCC setting (intended to support FDA approval for first and third line RCC and an EMA approval for third line RCC to complement the first line RCC
approval), Partner may elect to Opt-In by reimbursing AVEO for fifty percent (50%) of AVEO’s total costs for such study, such reimbursement not to exceed a total
of Twenty Million Dollars ($20,000,000). Should Partner elect to Opt-In to such study, it must do so within [**] days of disclosure in writing to Partner of all data
from the study and all other relevant documentation and information relating to the study reasonably requested by Partner that would (a) support an application for
Marketing Approval with the EMA or in one of the Key Launch Countries if Marketing Approval for the RCC Indication has been refused or (b) support an
application for extension of Marketing Approval with the EMA or in one of the Key Launch Countries if Marketing Approval for the RCC Indication has been
granted. With respect to AVEO’s planned phase 1 combination studies with a checkpoint inhibitor, Partner may elect to Opt-In by reimbursing AVEO for fifty percent
(50%) of AVEO’s total costs for such studies, such reimbursement not to exceed a total Two Million Dollars ($2,000,000), upon approval of
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the application for Marketing Approval for the Licensed Product by the EMA. For any other Independent Studies conducted by either Party, the funding Party and
non-funding Party may elect to discuss potential terms for an Opt-In that would include a mutually agreeable (i) reimbursement by the non-funding Party and (ii) to
the extent applicable, rate of cost-sharing for any ongoing and expected subsequent development costs related thereto pursuant to an agreed upon cost-sharing ratio;
provided that, the non-funding Party may not elect to Opt-In following regulatory approval in the particular indication being studied, unless otherwise mutually
agreed to by the Parties.
(d)
Commercial Plans. Beginning [**] days after submission of the first application for Marketing Approval of a Licensed Product in the Partner
Territory, Partner shall deliver to AVEO a written plan that summarizes, by country in the Partner Territory, sales expectations, target audience, promotional and
launch activities and anticipated commercialization expense for Licensed Products (the “Commercial Plan”). Once Partner begins to deliver Commercial Plans to
AVEO, Partner shall provide an updated Commercial Plan to AVEO on at least an annual basis, at the same time that an annual update to the Joint Development Plan
is made (if the Parties have entered into a Joint Development Plan), and shall notify AVEO of any material changes in the Commercial Plan no later than at the next
JSC meeting. The Parties agree that the Commercial Plan shall not be subject to any prior approval or consent of AVEO.
(e)
Activities of Affiliates and Sublicensees. The Parties shall include in each Plan and update thereto the accomplishments and activities of its
respective Affiliates and sublicensees in the development and commercialization of Licensed Products for the Field in its territory as if such accomplishments or
activities were such Parties’.
(f)
Disclosure to KHK. Partner hereby acknowledges and agrees that this Agreement, any agreement between Partner and a Sublicensee, the
Plans, all updates thereto, and all other plans, reports, data and information provided to AVEO hereunder may be disclosed to KHK in accordance with and subject to
the KHK Agreement provided that it is subject to the terms of Article 6 hereof. Upon Partner’s reasonable request AVEO shall seek KHK’s written consent to Partner
attending the annual Development Committee (as defined in the KHK Agreement) meeting to discuss the AVEO Annual Development Plan (as defined in the KHK
Agreement).
2.3
Clinical Trials in the Territory.
(a)
KHK. Partner acknowledges that, under Section 3.8 of the KHK Agreement, KHK (whether itself or through its Affiliates, its licensees and
distributors) retains the right to conduct clinical trials of Licensed Product in the Partner Territory if needed to support KHK’s (or its Affiliate’s or its licensee’s or
distributor’s) development or commercialization of Licensed Products for the KHK Territory, subject to the prior written consent of AVEO, such consent not be
unreasonably withheld, delayed or conditioned. Under the KHK Agreement, KHK has agreed to provide advance notification to AVEO before seeking to commence
(i.e. before filing any clinical trial application to enable) such trials in the Partner Territory in order to obtain such consent, and so that KHK and AVEO and/or
Partner, as applicable, may choose to coordinate their activities to the extent such parties desire to do so.
(b)
KHK. To the extent that either Party receives any notification from KHK with respect to the proposed conduct of clinical trials in the Partner
Territory in the Field, such Party shall promptly notify the other Party thereof, and the Parties shall cooperate with each other in good faith on an appropriate response
to KHK with respect thereto and in discussions with each other and with KHK with respect to KHK’s proposed conduct of clinical trials in the
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Partner Territory; provided that, as between the Parties, Partner shall make the final decision with regard to such response.
(c)
AVEO. If AVEO intends to conduct any clinical trials in the Partner Territory, it shall provide advance notification to Partner before seeking to
commence (i.e. before filing any clinical trial application to enable) such clinical trials. AVEO shall consult with Partner as to the scope and location of such clinical
trials, take Partner’s views into account and shall not conduct such clinical trials (or any aspects of them) if Partner can demonstrate that they would be reasonably
likely to materially affect Partner’s development and/or commercialization of Licensed Products in any part of the Partner Territory. Partner, having been advised of
the scope and location of such proposed clinical trials, hereby grants consent to AVEO’s conduct of clinical trials in the Partner Territory for (i) the planned phase 3
RCC study targeting the third line RCC setting (intended to support FDA approval for first and third line RCC and an EMA approval for third line RCC to
complement the first line RCC approval) and (ii) the planned phase 1 combination studies of the Licensed Product with a checkpoint inhibitor.
(d)
Partner. If Partner intends to conduct any clinical trials in the AVEO Territory (other than in the countries and for the reason specified in the
last sentence of this paragraph), it shall provide advance notification to AVEO before seeking to commence (i.e. before filing any clinical trial application to enable)
such clinical trials. Partner shall consult with AVEO as to the scope and location of such clinical trials, take AVEO’s views into account and shall not conduct such
clinical trials (or any aspects of them) if AVEO can demonstrate that they would be reasonably likely to materially affect AVEO’s development and/or
commercialization of Licensed Products in any part of the AVEO Territory. Under the Pharmstandard Agreement, AVEO does not have the right to conduct, or to
consent to Partner conducting, clinical trials in Azerbaijan, Armenia, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Moldova, Russian Federation, Tajikistan,
Turkmenistan, Uzbekistan and Ukraine.
2.4
Sharing of Partner Clinical and Other Data.
(a)
Annual Reports. From time to time (but no less frequently than annually), Partner shall disclose to AVEO a written summary, in a form
reasonably acceptable to AVEO, of clinical data with respect to Licensed Compounds and Licensed Products generated by or under authority of Partner since the last
such disclosure. It is understood that Partner’s obligation to provide summaries under this Section 2.4 can be fulfilled by providing a copy of the annual report
describing clinical development with respect to Licensed Products (each an “Annual Regulatory Report”) conducted by or on behalf of Partner, that Partner (or
others acting under its authority, including Sublicensees) provides to Regulatory Authorities in the Partner Territory, it being understood that such Annual Reports
shall be the Confidential Information of Partner and subject to the terms of Article 6 herein.
(b)
Access to Information. Subject to the limitation on the ability of a Party to use data from Independent Studies conducted by the other Party
prior to Opt-In as described in Section 2.2(c), upon the request of AVEO delivered reasonably in advance, Partner shall provide prompt and complete access to and
the right to use for purposes of the development and commercialization of Licensed Compounds and Licensed Products for any purpose outside the Partner Territory,
any clinical data, Clinical Regulatory Filings, Safety Data and CMC data generated by Partner, its Affiliates and its Sublicensees. Partner shall include its
Sublicensees’ Clinical Regulatory Filings data, Safety Data and CMC data in its reports to AVEO hereunder (or cause the Sublicensee to provide such a report to
AVEO), and shall provide access to its Sublicensees’ Clinical Regulatory Filings and CMC data on the same basis as if the Sublicensees were such Party. If requested
by AVEO, the Parties shall discuss any of Partner’s Annual Regulatory Reports or other filings or data shared by Partner hereunder. In addition to the
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reports, filings or data required to be shared as stated above in this Section 2.4, if reasonably necessary for AVEO or its Affiliates, KHK or Other Licensees to have
access to the underlying raw data, case report forms or other original documents (including laboratory notebooks) generated by or on behalf of Partner (or its
Affiliates and Sublicensees), Partner shall provide copies, or if required by Regulatory Authorities, access to the originals, of such items it being understood that such
reports, filings and data shall be the Confidential Information of Partner and subject to the terms of Article 6 herein.
(c)
KHK Access. Partner acknowledges that KHK has the right under the KHK Agreement to obtain access to any reports, filings and data
provided by Partner (and its Affiliates and Sublicensees) hereunder; provided that such data shall be kept confidential and shall not be used to compete with Partner.
Should Partner produce any data from an Independent Study in which AVEO does not elect to Opt-In, AVEO shall provide such data to KHK.
2.5
Sharing of AVEO Clinical and Other Data.
(a)
Annual Reports. Within thirty (30) days from the Effective Date and from time to time thereafter (but no less frequently than annually),
AVEO shall disclose to Partner a written summary, in a form reasonably acceptable to Partner, of clinical data with respect to Licensed Compounds and Licensed
Products generated by or under authority of AVEO since the last such disclosure. It is understood that AVEO’s obligation to provide summaries under this Section 2.5
can be fulfilled by providing a copy of the Annual Regulatory Report conducted by or on behalf of AVEO, that AVEO (or others acting under its authority, including
sublicensees) provides to Regulatory Authorities in the AVEO Territory (each an “Annual Regulatory Report”). AVEO shall provide Partner with a copy of each of
the AVEO Overall Clinical Development Plan (as defined in the KHK Agreement) and the AVEO Clinical Development Plan (as defined in the KHK Agreement) at
the same time as it provides copies of such documents to KHK.
(b)
Access to Information. Subject to the limitation on the ability of a Party to use data from Independent Studies conducted by the other Party
prior to Opt-In as described in Section 2.2(c), upon the request of Partner delivered reasonably in advance, AVEO shall provide prompt and complete access to and
the right to use for purposes of the development and commercialization of Licensed Compounds and Licensed Products for any purpose in the Partner Territory in the
Field, any clinical data, Clinical Regulatory Filings, Safety Data and CMC data generated by AVEO, its Affiliates and its sublicensees, as necessary or useful to
practice in the Field. AVEO shall include its sublicensees’ Clinical Regulatory Filings data, Safety Data and CMC data in its reports to AVEO hereunder (or cause the
sublicensee to provide such a report to AVEO), and shall provide access to its sublicensees’ Clinical Regulatory Filings and CMC data on the same basis as if the
sublicensees were such Party. If requested by Partner, the Parties shall discuss any of AVEO’s Annual Regulatory Reports or other filings or data shared by AVEO
hereunder. In addition to the reports, filings or data required to be shared as stated above in this Section 2.5, if reasonably necessary for Partner or its Affiliates or
Sublicensees to have access to the underlying raw data, case report forms or other original documents (including laboratory notebooks) generated by or on behalf of
AVEO (or its Affiliates and sublicensees), AVEO shall provide copies, or if required by Regulatory Authorities, access to the originals, of such items, it being
understood that such reports, filings and data shall be the Confidential Information of AVEO and subject to the terms of Article 6 herein.
(c)
Partner Access. The Parties acknowledge that Partner, as a sublicensee of AVEO under the KHK Agreement, has the right under the KHK
Agreement to obtain access to any reports, filings and data related to Licensed Products in the Field provided by KHK to AVEO under the KHK Agreement; it being
understood that (i) such reports, filings and data shall
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be deemed AVEO’s Confidential Information for purposes of this Agreement, and (ii) such access shall not be construed in any way to permit Partner (or its Affiliates
or Sublicensees) to use such reports, filings or data outside of the scope of the licenses granted to Partner hereunder. Such reports shall be provided by AVEO to
Partner within 7 days of receipt by AVEO and if Partner requests AVEO to obtain access to any of KHK’s reports, filings and data related to Licensed Products in the
Field then AVEO shall obtain such access from KHK on Partner’s behalf.
2.6
Record Keeping. Each Party shall maintain complete and accurate records of all work (including research, development, clinical, manufacturing and
commercialization) it conducts (itself or through its Affiliates or Third Parties) under this Agreement and all results, data and developments made pursuant to its
efforts under this Agreement. Such records shall be complete and accurate and shall fully and properly reflect all work done and results achieved in the performance
of this Agreement in sufficient detail and in good scientific manner appropriate for patent and regulatory purposes. Such records shall be maintained for as long as
required by applicable law.
2.7
Communications with Regulatory Authorities.
(a)
Each Party shall keep the other Party informed on an ongoing basis regarding its (or its Affiliate’s or sublicensee’s) regulatory strategy, planned
regulatory submissions and material communications with Regulatory Authorities with respect to all Licensed Products. Partner shall not communicate with
Regulatory Authorities in the AVEO Territory regarding any Licensed Compound or Licensed Product without AVEO’s advance written consent, such consent not to
be unreasonably withheld, delayed or conditioned. Partner shall not communicate with Regulatory Authorities in the KHK Territory regarding any Licensed
Compound or Licensed Product without KHK’s advance written consent, which AVEO shall seek upon Partner’s request and which shall not be unreasonably
withheld, delayed or conditioned. In addition, Partner shall promptly furnish to AVEO copies of all correspondence that Partner (or its Affiliate or Sublicensee)
receives from, or submits to, any Regulatory Authority (including contact reports concerning conversations or substantive meetings) relating to any Licensed
Product. Partner shall also provide to AVEO any meeting minutes that reflect material communications with any Regulatory Authority regarding a Licensed Product.
(b)
AVEO shall not communicate with Regulatory Authorities inside of the Partner Territory regarding any Licensed Compound or Licensed
Product without Partner’s advance written consent, such consent not to be unreasonably withheld, delayed or conditioned. In addition, AVEO shall promptly furnish
to Partner copies of all correspondence that AVEO (or its Affiliate or Other Licensee) receives from, or submits to, any Regulatory Authority (including contact
reports concerning conversations or substantive meetings) relating to any Licensed Product. AVEO shall also provide to Partner any meeting minutes that reflect
material communications with any Regulatory Authority regarding a Licensed Product.
(c)
Subject to Partner’s agreement to the scope and location of any clinical trials to be conducted by AVEO in the Field in the Partner Territory in
accordance with Section 2.3(c), AVEO shall not be required to obtain Partner’s consent to communicate with Regulatory Authorities with respect to such clinical
trials, and notwithstanding the provisions of Section 2.2(a), Partner shall have no responsibility or decision making authority for activities and decisions of AVEO
with respect to such clinical trials conducted by AVEO in the Partner Territory.
(d)
Subject to AVEO’s agreement to the scope and location of any clinical trials to be conducted by Partner in the Field in the AVEO Territory in
accordance with Section
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2.3(d), Partner shall not be required to obtain AVEO’s consent to communicate with Regulatory Authorities with respect to such clinical trials, and notwithstanding
the provisions of Section 2.2(a), AVEO shall have no responsibility or decision making authority for activities and decisions of Partner with respect to such clinical
trials conducted by Partner in the AVEO Territory.
(e)
Partner acknowledges that KHK has the right to attend and observe (but not participate actively in) any material meeting or material
conference call between Partner and any Regulatory Authority regarding Licensed Products in the Partner Territory and, if requested by AVEO, Partner shall
reasonably cooperate with AVEO in coordinating the logistics of any such attendance or observation by KHK.
2.8
Adverse Event/Safety Reporting Protocol. Within [**] days of the Effective Date, the Parties shall mutually agree in writing as to a detailed
protocol regarding the exchange of all adverse event information on an ongoing basis, including a timeline. Such protocol must provide a timeline and scope for
reporting between the Parties that is at least sufficient to allow both Parties and KHK, and their other licensees and sublicensees to satisfy their reporting obligations
to Regulatory Authorities during the Term, worldwide. Once the protocol is agreed, each Party shall comply with it, and may propose updates to it from time to time.
Each Party shall reasonably consider the other’s proposed updates and not withhold consent to any such updates that are needed to allow a Party to satisfy its
reporting requirements to Regulatory Authorities (current or future, worldwide). Each Party shall require its Affiliates, Other Licensees, distributors (including the
Distributors) and sublicensees, as applicable, to also comply with such protocol.
2.9
Legal Compliance. In conducting any development activities hereunder, each Party shall, and shall cause its Affiliates and Sublicensees/Other
Licensees (as appropriate) to, use Commercially Reasonable Efforts to ensure that its employees, agents, clinical institutions and clinical investigators comply with
all applicable Regulatory Authority statutory and regulatory requirements with respect to Licensed Products, including those regarding protection of human subjects,
financial disclosure by clinical investigators, approvals by research ethics committees, Good Clinical Practices, Good Laboratory Practices, Good Manufacturing
Practices, and any conditions imposed by a reviewing research ethics committee or Regulatory Authority, and comparable laws, statutes and regulatory requirements
throughout the Partner Territory/AVEO Territory, as applicable.
2.10
Technology Transfer. AVEO shall transfer to Partner, at no cost to Partner, in support of Partner’s application for Marketing Approval with the EMA:
(i) AVEO’s NDA for the Licensed Compound submitted to the FDA in 2012; (ii) the regulatory dossier, or MAA, for the RCC Indication in electronic CTD format
that is suitable for immediate submission to the EMA; and (iii) the Licensed Know-How set out in Exhibit C within [**] months of the Effective Date but earlier if
and as required and on a timely basis for the Marketing Approval submission to the EMA for the Licensed Product in RCC, and to respond to requests for further
information from the EMA as it considers such submission. AVEO shall also transfer to Partner or its nominee, at no cost to Partner, the benefit of and interest in the
orphan drug designation for the Licensed Product with number EU/3/10/747 (the “Orphan Drug Designation”) free from all encumbrances. AVEO shall or shall
procure that any of its Affiliates will as soon as reasonably possible after the Effective Date sign any notices, applications, submissions, reports and other
instruments, documents, correspondence or filings presented to it by Partner or its nominee that are necessary for: (i) the transfer to Partner or its nominee of the
Orphan Drug Designation; or (ii) maintaining, renewing or varying the Orphan Drug Designation  in the period from the Effective Date until the transfer of the
Orphan Drug Designation.
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2.11
Support by AVEO. Partner may from time to time request the additional reasonable assistance of AVEO in supporting Partner’s development,
regulatory affairs and manufacturing activities with respect to Licensed Products in the Partner Territory. Such support shall be provided as follows:
(a)
Until the grant of Marketing Approval by the EMA for the RCC Indication, in relation to the filing, and preparation for filing of the MAA for
the RCC Indication and responding to questions from the EMA in relation to the MAA for the RCC Indication, AVEO shall provide an average (for the period from
the Effective Date to the grant of Marketing Approval by the EMA for the RCC Indication) of approximately [**] hours of ad hoc assistance per month to Partner
and its Affiliates and contractors in relation to all aspects of such MAA (e.g. CMC, Medical Affairs etc.) at no cost to Partner and shall use reasonable endeavors to
answer all requests as promptly as possible and provide full and complete answers to the extent that the relevant information is known to and documentation held by
AVEO. Partner agrees to reimburse AVEO at the FTE Rate at the end of each three month period following the Effective Date to the extent that AVEO has provided
more than [**] hours of such assistance during such three month period, with a true-up to the average of [**] hours per month to be completed by the Parties at the
end of each subsequent three month period.
(b)
In relation to all support requested by AVEO other than that described in Section 2.11(a):
(i)
With regard to ad hoc questions from Partner and its Affiliates and contractors AVEO shall provide answers to such questions free of
charge; and
(ii)
With regard to Partner projects that require sustained support by AVEO in excess of [**] hours in a three month period until the grant of
Marketing Approval by the EMA for the RCC Indication, upon mutual written agreement of the Parties as to the scope and timing of such support, AVEO will use
Commercially Reasonable Efforts to provide such agreed-upon support activities to Partner. Partner shall reimburse AVEO for its reasonable costs and expenses
incurred in performing such additional agreed-upon support activities, including fully-burdened FTE-based compensation for its employees at the FTE Rate and all
out of pocket expenses at cost, in each case within [**] days of a receipt of an invoice therefor provided that Partner has previously approved in writing all FTE costs
and expenses.
(c)
For the avoidance of doubt, AVEO shall be responsible for the costs of support provided by vendors and consultants to AVEO in connection
with preparation of the MAA, including without limitation PAREXEL International Corporation, prior to the delivery to Partner of the regulatory dossier, or MAA,
for the RCC Indication in electronic CTD format that is suitable for immediate submission to the EMA (“MAA Delivery”), but AVEO shall not be responsible for
such costs after March 7, 2016. Partner shall be responsible for the costs of support provided by vendors and consultants, including without limitation PAREXEL
International Corporation, after MAA Delivery, or after March 7, 2016, if that occurs prior to MAA Delivery.
2.12
Supply of License Product. Partner shall be responsible for the manufacturing and supply of the Licensed Products for the Partner Territory;
provided, however, that AVEO will introduce Partner to its contract manufacturing vendors (Hamari, Masy Systems, Catalent and Almac) and will use reasonable
good faith efforts to assist Partner in its efforts to establish such supply.
2.13
Recalls.
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(a)
Notification. Each Party shall, within [**] hours, notify the other Party in writing if it determines that any event, incident or circumstance has
occurred which may result in the need for a “recall” or “market withdrawal” (or similar event as defined in the applicable national, state or local laws and regulations
in the Partner Territory) (hereinafter referred to as a “Recall”) of a Licensed Product or any lot(s) thereof. AVEO shall also promptly notify Partner if AVEO receives
any such notification from KHK or any other entity with respect to an actual or potential Recall in the KHK Territory or any other country. Partner acknowledges that
AVEO may disclose to KHK any information about an actual or potential Recall in the Partner Territory, including information obtained from Partner hereunder.
(b)
Allocation of Responsibility for Recalls. If at any time (i) any Regulatory Authority issues a request, directive or order for a Recall of a
Licensed Product in the Partner Territory, or (ii) a court of competent jurisdiction orders a Recall of a Licensed Product in the Partner Territory, then the Parties shall
promptly consult with each other on the appropriate course of action to be undertaken and the Parties shall reasonably cooperate with each other in the
implementation of any Recall in the Partner Territory, provided that Partner shall have final decision-making authority with respect thereto. Partner shall bear all costs
and expenses for the Recall in the Partner Territory.
ARTICLE 3.
LICENSE GRANTS
3.1
Licenses to Partner. Subject to the terms and conditions of this Agreement, AVEO hereby grants to Partner during the Term, an exclusive, royalty-
bearing (in accordance with Article 4) license or sublicense, as applicable, under the Licensed Technology (i) to research, develop, manufacture, use, sell, offer for
sale and import Licensed Compound and Licensed Products for the Field, including to supply the Licensed Product on a named patient basis, in the Partner Territory;
and (ii) to make, have made and use the Licensed Compounds and Licensed Products anywhere in the world for purposes of the activities described in clause (i) and
(ii) subject to Section 2.3(d), to clinically test Licensed Products in the AVEO Territory and, subject to the prior written consent of KHK to be sought by AVEO and
which shall not be unreasonably withheld, delayed or conditioned, the KHK Territory, solely for the purposes of the activities described in clause (i). The license
granted to Partner in this Section 3.1 shall be sublicenseable solely as provided in Section 3.2, but shall otherwise be non-assignable and non-transferable (except as
part of assigning this Agreement pursuant to Section 11.9).
3.2
Sublicensing by Partner. Partner shall be entitled to grant sublicenses under its license of Section 3.1 subject to all of the following:
(a)
Partner may choose such Sublicensees in its own discretion and the number of its Sublicensees shall not be limited;
(b)
Partner must provide AVEO with a true, accurate and complete copy of each sublicense within [**] United States Business Days after
execution;
(c)
such Sublicensees cannot further sublicense except if all of the following conditions are satisfied: (i) the further sublicenses must be on terms
consistent with this Agreement, including this Section 3.2; and (ii) the economic terms of the further sublicenses must be such that the further sublicensing does not
reduce the consideration that will be paid to AVEO hereunder, relative to what it would have been had Partner’s direct Sublicensee conducted the activities;
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(d)
each sublicense shall be subject to the terms and conditions of this Agreement and the KHK Agreement, and Partner shall ensure that its
agreements with Sublicensees are consistent with and impose obligations consistent with the terms and conditions regarding Sublicensees set forth in this Agreement
and the KHK Agreement. Without limiting the generality of the foregoing, Partner shall in particular require its Sublicensees to make available Clinical Regulatory
Filings, Safety Data, and underlying detailed data to AVEO and/or KHK as required by Section 2.4. In addition to the foregoing, in any sublicense Partner shall
obtain ownership of or the right to grant KHK and its Affiliates and licensees, including AVEO, a royalty-free license having at least the same scope as the license of
Section 3.3(e) under: (i) all Patents claiming inventions developed by or for the Sublicensee in Licensed Product-related activities that if invented by Partner would
be Partner Program Inventions; and (ii) all Know-How developed in such activities that if owned or Controlled by Partner would be Partner Know-How;
(e)
Partner shall remain responsible for each of its and its Affiliates’ Sublicensees’ compliance with the applicable terms and obligations of this
Agreement, and any breach thereof by any such Sublicensee shall be deemed a breach of this Agreement by Partner; and
(f)
Partner shall not be entitled to grant sublicenses in Germany, France, Italy, Spain and the United Kingdom; provided that Partner shall be
entitled to grant sublicenses to its Affiliates in such countries, subject to the sublicense automatically terminating upon such Affiliate ceasing to be an Affiliate of
Partner.
3.3
Compliance with KHK Agreement.
(a)
Partner acknowledges that the licenses granted to it pursuant to Section 3.1 include sublicenses to Know-How and Patents that have been
licensed to AVEO by KHK pursuant to the KHK Agreement, and that such sublicenses are subject to the terms and conditions of the KHK Agreement. In the event of
any conflict or inconsistency between this Agreement (or any agreement with an Affiliate or Sublicensee entered into under this Agreement) and the KHK
Agreement, the Parties shall reasonably cooperate with each other and, if necessary, with KHK to implement terms under this Agreement (or such other agreement
with an Affiliate or Sublicensee) that comply with the terms set forth in the KHK Agreement, subject to Section 3.3(c).
(b)
AVEO shall have the sole right and responsibility for interacting with KHK with respect to any matter requiring such interaction with KHK
under this Agreement or the KHK Agreement.
(c)
AVEO shall obtain Partner’s consent, which may be withheld in Partner’s absolute discretion, before exercising its right to terminate the KHK
Agreement, as set forth in Section 10.4 of the KHK Agreement, with respect to any country within Partner Territory.
(d)
AVEO shall furnish Partner with copies of all notices received by AVEO relating to any alleged breach or default by AVEO under the KHK
Agreement. Subject to consultation with Partner, AVEO shall use Commercially Reasonable Efforts to cure any such breach or default. Notwithstanding the
foregoing, if AVEO is unable to address the alleged breach or default within the [**] day cure period set forth in Section 9.2 of the KHK Agreement, and KHK elects
to terminate the KHK Agreement, then the following provisions shall apply:
(i)
The sublicense granted by AVEO to Partner under the KHK Agreement shall survive in accordance with the terms of Section 10.7 of
the KHK Agreement.
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(ii)
Notwithstanding the foregoing, if Partner (or any of its Affiliates or Sublicensees) have contributed to the breach or default giving rise
to KHK’s termination of the KHK Agreement, AVEO shall have the right to terminate this Agreement in its entirety upon written notice to Partner and the effects of
termination set forth in Sections 9.6 and 9.7 shall apply, except that, if requested by AVEO, Partner shall (and shall require its Affiliates and Sublicensees to) grant
the rights, and perform the activities, set forth in Sections 9.6 and 9.7 directly to KHK.
(e)
Grant-Back License.
(i)
To AVEO. Subject to the limitations on the use of clinical data from Independent Studies set forth in Section 2.2(c), Partner hereby
grants to AVEO a non-exclusive, royalty-free, irrevocable, sublicensable license under such Partner Program Inventions, Partner Patents and Partner Know-How (i)
to research, develop, register, use, distribute, manufacture, package, promote, market, sell, offer for sale and import Licensed Compound and any Licensed Product in
the AVEO Territory, provided that such proposed use or practice will not cause any detriment to the Licensed Product or its commercialization in the Partner
Territory, and (ii) to make and have made Licensed Compound and any Licensed Product worldwide for purposes of the activities described in clause (i), and (iii)
subject to Section 2.3(c), to clinically test Licensed Products anywhere in the world to obtain data to support any application for Marketing Approval in the AVEO
Territory. AVEO shall provide Partner a copy of any such sublicense agreement within [**] Business Days of consummation of such sublicense agreement.
(ii)
To KHK – Licensed Compound.To the extent that any Partner Program Invention or Partner Patent or Partner Know-How constitutes
AVEO Product IP (as defined in the KHK Agreement), Partner hereby grants to AVEO an exclusive, irrevocable, royalty-free license, with the right to grant
sublicenses to KHK, under such Partner Program Invention, Partner Patent and Partner Know-How for KHK and its Other Licensees (i) to research, develop, register,
use, distribute, manufacture, package, promote, market, sell, offer for sale and import Licensed Compound and any Licensed Product (but excluding Licensed
Product Biomarkers which are dealt with in Section 3.3(e)(iii) below) in the KHK Territory, (ii) to make and have made Licensed Compound and any Licensed
Product (but excluding Licensed Product Biomarkers which are dealt with in Section 3.3(e)(iii) below) worldwide for purposes of the activities described in clause
(i), and (iii) to clinically test Licensed Products anywhere in the world to obtain data to support any application for Marketing Approval in the KHK Territory.
(iii)
To KHK – Licensed Product Biomarkers. To the extent that any Partner Program Invention or Partner Patent or Partner Know-How
constitutes AVEO Product IP (as defined in the KHK Agreement), Partner hereby grants to AVEO a non-exclusive, irrevocable, royalty-free license, with the right to
grant sublicenses to KHK, under such Partner Program Invention, Partner Patent and Partner Know-How for KHK and its Other Licensees (i) to research, develop,
use, sell, offer for sale and import Licensed Product Biomarkers in the KHK Territory, (ii) to make and have made Licensed Compound and any Licensed Product
worldwide for purposes of the activities described in clause (i), and (iii) to clinically test Licensed Products anywhere in the world to obtain data to support any
application for Marketing Approval in the KHK Territory
(iv)
Partner retains the right under any Partner Program Invention or Partner Patent or Partner Know-How that constitutes AVEO Product IP
(as defined in the KHK Agreement) to research develop, manufacture and have manufactured Licensed Compounds and Licensed Products on a worldwide basis in
furtherance of Partner’s development and/or commercialization of Licensed Products for the Field in the Partner Territory. Such licenses in
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Sections 3.3(e)(ii) and (iii) may be sublicensed by KHK in accordance with Section 4.6 of the KHK Agreement. AVEO shall provide Partner a copy of any such
sublicense agreement within four (4) United States Business Days of receipt from KHK.
3.4
Use of Patents and Know-How. Each Party hereby covenants that it (and its Affiliates and sublicensees, as applicable) shall not practice the Patents
or Know-How licensed to such Party hereunder outside the scope of the licenses to such Party under this Agreement.
3.5
Reservation of Rights. Notwithstanding the scope of the license granted to Partner under Section 3.1, AVEO and its Affiliates and Other Licensees
shall at all times reserve the right to make or have made the Licensed Compound and Licensed Product in the Partner Territory solely for use outside of the Partner
Territory or for use outside of the Field worldwide. In addition, no right, title or interest is granted by either Party whether expressly or by implication to or under any
Patents or Know-How, other than those rights and licenses expressly granted in this Agreement.
3.6
No Implied Licenses. Except as explicitly set forth in this Agreement, neither Party grants under its intellectual property (including Patents) any
license, express or implied, to the other Party.
3.7
Technology Sublicensed from Third Parties. The licenses granted under this Article 3, to the extent they include (or come to include) sublicenses
under Patents or Know-How of a Third Party, shall be subject to the terms and conditions of the agreement governing the license under which the sublicense is
granted. If a good faith dispute between a Third Party (including KHK) and the Party that entered into a license with such Third Party arises about the interpretation
of any provision of the agreement governing such Third Party license (including the KHK Agreement), the other Party shall use its Commercially Reasonable Efforts
to ensure that its actions, if any, under this Agreement do not detrimentally affect the ability of the allegedly breaching Party to contest the interpretation advanced by
such Third Party; provided, however, that in no event shall the obligation to exercise such Commercially Reasonable Efforts require such Party to waive any rights
granted to it under this Agreement or otherwise available to it at law or in equity.
3.8
Cross-Territory Sales.
(a)
The Parties recognize that it is possible that Licensed Products originally sold by Partner (or its Affiliate, Sublicensee or distributor) in the
Partner Territory may be imported and resold in the AVEO Territory or the KHK Territory. Partner shall take reasonable measures to prevent any such imports and/or
sales, to the full extent permitted by law. Without limiting the foregoing, Partner shall, and shall cause its Affiliates, Sublicensees and distributors to, (a) label
Licensed Products sold by it as being for sale in the Partner Territory (or a country thereof); and (b) refrain from selling Licensed Products to any entity that Partner
or its Affiliate, Sublicensee or distributor has reason to believe will resell quantities of Licensed Product in the AVEO Territory or the KHK Territory.
(b)
The Parties recognize that it is possible that Licensed Products originally sold by AVEO or KHK (or its Affiliate, Other Licensee or distributor)
in the AVEO Territory or KHK Territory may be imported and resold in the Partner Territory. AVEO shall, and shall procure that KHK shall, take reasonable
measures to prevent any such imports and/or sales, to the full extent permitted by law. Without limiting the foregoing, AVEO shall, and shall cause its Affiliates,
Sublicensees and distributors and KHK to, (a) label Licensed Products sold by it as being for sale in the AVEO Territory or KHK Territory (or a country thereof); and
(b) other than as may occur pursuant to the Ophthotech Agreement, refrain from selling Licensed Products to
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any entity that AVEO or KHK or its Affiliate, Other Licensee or distributor has reason to believe will resell quantities of Licensed Product in the Partner Territory.
3.9
Inventions by Service Providers.
(a)
From all contractors performing services in connection with the manufacture, research, development and/or commercialization of Licensed
Compounds and Licensed Products (excluding Sublicensees who will be entitled to sell the Licensed Product for their own account), Partner shall (i) obtain the
royalty-free right of access and use by AVEO, KHK and its Other Licensees (including further sublicenses by KHK and such Other Licensees) to Clinical Regulatory
Filings and Safety Data developed by any such contractors, as well as all underlying original data and documentation as described in Section 2.5, for purposes of
development and commercialization of Licensed Products in the Field in the AVEO Territory and the KHK Territory under this Agreement, and (ii) obtain the
royalty-free right to grant to AVEO non-exclusive sublicenses (including the right of AVEO to grant further sublicenses, and further sublicenses by such
sublicensees), having at least the same scope as the license to AVEO in Section 3.5(d), under the Patents and Know-How developed by such contractors in the course
of conducting activities with respect to Licensed Compounds or Licensed Products that if claiming an invention invented by Partner or Know-How owned or
Controlled by Partner would be Partner Program Inventions or Partner Patents or Partner Know-How. Information provided by a Partner contractor (or of a Partner
contractor provided by Partner) to AVEO under this Section 3.9(a) shall be the Confidential Information of Partner and subject to the Terms of Article 6 herein.
Partner shall ensure that any and all Inventions made after the Effective Date (a) that relate to (i) the Licensed Compound or Licensed Products, (ii) any method of
making, using (including a method of administration or dosage form) or testing the Licensed Compound or Licensed Products, or (iii) any article necessary or useful
to practice (or in the case of testing, of or for the presence of) any method described in clause (ii) above, and that are discovered, made, or conceived solely by
employees of Partner or its Affiliates or Third Parties acting on behalf of or in conjunction with Partner or its Affiliates, other than Licensed Technology, are
Controlled by Partner.
(b)
From all contractors performing services in connection with the manufacture, research, development and/or commercialization of Licensed
Compounds or Licensed Products (excluding KHK and Other Licensees, who will be entitled to sell the Licensed Product for their own account), AVEO shall (i)
obtain the royalty-free right of access and use by Partner and its Affiliates and Sublicensees (including further sublicenses by such Sublicensees) to Clinical
Regulatory Filings and Safety Data developed by any such contractors as well as all underlying original data and documentation as described in Section 2.4, for
purposes of development and commercialization of Licensed Products in the Field in the Partner Territory under this Agreement, and (ii) obtain the royalty-free right
to grant to Partner non-exclusive Sublicenses (including the right of Partner to grant further Sublicenses, and further sublicenses by such Sublicensees), having at
least the same scope as the license to Partner in Section 3.1, under the Patents and Know-How developed by such contractors in the course of conducting activities
with respect to Licensed Compounds or Licensed Products that if claiming an invention invented by AVEO or Know-How owned or Controlled by AVEO would be
AVEO Program Inventions or AVEO Know-How. Information provided by an AVEO contractor (or of a AVEO contractor provided by AVEO) to Partner and its
Sublicensees under this Section 3.9(b) shall be the Confidential Information of AVEO and subject to the terms of Article 6 herein. AVEO shall ensure that any and all
Inventions made after the Effective Date (a) that relate to (i) the Licensed Compound or Licensed Products, (ii) any method of making, using (including a method of
administration or dosage form) or testing the Licensed Compound or Licensed Products, or (iii) any article necessary or useful to practice (or in the case of testing, of
or for the presence of) any method described in clause (ii) above, and that are discovered, made, or
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conceived solely by employees of AVEO or its Affiliates or Third Parties acting on behalf of or in conjunction with AVEO or its Affiliates, other than Partner
Program Inventions or Joint Inventions, are Controlled by AVEO.
ARTICLE 4.
COMPENSATION
4.1
Research and Development Funding. Partner will pay to AVEO for the research and development costs incurred by AVEO to fund activities directly
in furtherance of Licensed Product clinical, regulatory and manufacturing process development in support of obtaining Marketing Approval (a) Two Million Five
Hundred Thousand Dollars ($2,500,000) within fifteen (15) days of the Effective Date and provision of a valid tax invoice to Partner by AVEO for such amount (in
the form of Exhibit E), and (b) Four Million Dollars ($4,000,000) upon EMA grant of Marketing Approval for the RCC Indication. Partner shall notify AVEO of
such approval promptly AVEO shall provide a valid tax invoice to Partner for such amount which shall be payable by Partner within fifteen (15) days of receipt of
such invoice.
4.2
Milestone Payments.
(a)
Regulatory Milestones for RCC. Partner will pay to AVEO the following nonrefundable (but without prejudice to Partner’s right to bring a
claim for breach of this Agreement, including damages for loss) milestone payments once each upon the first occurrence of the corresponding event as set forth
below:
Event Milestone
Event Payment
Reimbursement approval for the RCC Indication in each of the Key Launch Countries other than the
Key Non-EU Licensed Countries
$2,000,000,
per country, up to $10,000,000 total
Grant of Marketing Approval in 3 of 5 of the Key Non-EU Licensed Countries
$2,000,000
(b)
Regulatory Milestones for Other Indications. Partner will pay to AVEO the following nonrefundable milestone payments upon each
Licensed Product Indication achieved in addition to the RCC Indication, for up to a maximum of three additional Indications, and a Combination Product comprising
the Licensed Compound and a checkpoint inhibitor, as described in Section 1.34 above shall be considered a separate Indication:
Event Milestone
Event Payment
EMA filing for Marketing Approval
$2,000,000
EMA grant of Marketing Approval
$5,000,000
(c)
Sales Milestones. Partner will pay to AVEO as additional consideration for the exclusive license grant, the following one-time sales milestone
payments in respect of the first Calendar Year in which aggregate global Net Sales of all Licensed Products in that Calendar Year in the Partner Territory achieve the
thresholds set out below:
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Calendar Year Net Sales of Licensed Products
Payment
First Calendar Year in which aggregate global Net Sales of all Licensed Products for that Calendar Year
in the Partner Territory surpass $[**]
[**]
First Calendar Year in which aggregate global Net Sales of all Licensed Products for that Calendar Year
in the Partner Territory surpass $[**]
[**]
First Calendar Year in which aggregate global Net Sales of all Licensed Products for that Calendar Year
in the Partner Territory surpass $[**]
[**]
First Calendar Year in which aggregate global Net Sales of all Licensed Products for that Calendar Year
in the Partner Territory surpass $[**]
[**]
First Calendar Year in which aggregate global Net Sales of all Licensed Products for that Calendar Year
in the Partner Territory surpass $[**]
[**]
First Calendar Year in which aggregate global Net Sales of all Licensed Products for that Calendar Year
in the Partner Territory surpass $[**]
[**]
First Calendar Year in which aggregate global Net Sales of all Licensed Products for that Calendar Year
in the Partner Territory surpass $[**]
[**]
For the sake of clarity, each sales milestone payment is separate and may only be earned once, but if more than one Net Sales threshold is reached in the same
Calendar Year, all of such sales milestone amounts shall be due and owing at the end of such year. The aggregate amount of the sales milestone payments that may be
paid to AVEO during the Term if all seven thresholds are satisfied is Three Hundred Thirty Five Million Dollars ($335,000,000).
(d)
Payments by Partner under this Section 4.3 shall be payable to AVEO within thirty (30) days after such achievement (whether achieved by or
on behalf of Partner, its Affiliate or any Sublicensee, or any other entity acting on behalf of any of them).
(e)
Partner shall notify AVEO of the achievement of each of the foregoing milestones within fifteen (15) days after each such achievement. Any
milestone payments shall be reflected on a valid tax invoice provided to Partner by AVEO.
4.3
Royalty Payments. Partner shall pay AVEO royalties, calculated as a percentage of annual Net Sales of Licensed Products in the Partner Territory,
using the following royalty rates:
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Amount of annual Net Sales
Royalty Rate
For that portion of Net Sales in any given Calendar Year of less than or equal to $[**]
[**]%
For that portion of Net Sales in any given Calendar Year of greater than $[**], but less than or equal to
$[**]
[**]%
For that portion of Net Sales in any given Calendar Year of greater than $[**], but equal to or less than
$[**]
[**]%
For that portion of Net Sales in any given Calendar Year of greater than $[**]
[**]%
The obligation to pay royalties under this Section 4.3 shall continue on a country-by-country basis and a Licensed Product by Licensed Product basis in the
Partner Territory until the expiration of the Royalty Term for such Licensed Product in such country or the effective date of termination of this Agreement pursuant to
Article 9.
4.4
Royalty Reduction.
(a)
Notwithstanding the foregoing, if it becomes necessary for Partner or its Affiliates or Sublicensees to access patent rights claiming priority
from [**] in order to make, use or sell a Licensed Product in the Partner Territory (i.e., if it issues and covers the Licensed Product actually being commercialized,
and withstands any challenge KHK may choose to bring), then:
(i)
Partner acknowledges that KHK will be responsible for taking a license thereunder (on an exclusive or non-exclusive basis) or another
similar right (such as a covenant not to sue) and for sublicensing (or otherwise transferring such license to AVEO and/or Partner and their respective Affiliates or
sublicensees) in accordance with the terms of the KHK Agreement. Partner also acknowledges that KHK’s financial responsibility for any consideration due the
licensor or damages assessed based on such Partner’s exercise of the rights that KHK obtains shall be limited (A) overall, to the amount of sublicensing revenue that
KHK receives from AVEO with respect to this Agreement, and (B) with respect to consideration due to KHK’s licensor on Net Sales hereunder, to the amount of
sublicensing revenue that KHK receives from AVEO based on Net Sales hereunder with any remaining amounts payable by Partner;
(ii)
Subject to consultation with Partner, AVEO shall enforce the provisions of Section 5.6 of the KHK Agreement against KHK if KHK
fails to comply with aforementioned obligations under the KHK Agreement; and
(iii)
To the extent that AVEO is notified by KHK of KHK’s intent to commence any formal challenge to any such patents, AVEO will notify
Partner and the Parties shall reasonably cooperate with each other and with KHK to discuss and seek to reach a common understanding whether such challenge
would be likely to have a material adverse effect on AVEO’s or Partner’s (or their respective Affiliates’ or sublicensees’) ability to commercialize the Licensed
Product in the Partner Territory and the most sensible course of action weighing the relevant probabilities, costs and benefits.
(b)
If, at any time during the Royalty Term for a Licensed Product in a country in the Partner Territory, one or more Generic Products is
commercially available in such country and, for the calendar quarter for which a royalty payment is being made by Partner hereunder such Generic Product(s) in the
aggregate have a market share of more than [**]
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percent ([**]%) of the aggregate market share of such Licensed Product and Generic Products (based on data provided by a reliable data source mutually acceptable
to the Parties) as measured by unit sales in such country, then the royalties payable for such calendar quarter under Section 4.3 for such Licensed Product in such
country shall be reduced by [**] percent ([**]%).
(c)
Subject to Section 4.4(a), in the event that Partner requires a license of any Third Party rights in respect of the development, manufacture, use
or sale of Licensed Products in any country in the Partner Territory, Partner will be responsible for obtaining license; provided that, Partner may deduct any
reasonable legal costs incurred by Partner, its Affiliates and Sublicensees together with any royalties on Net Sales of the Licensed Product payable to such Third
Party as follows: [**] percent ([**]%) of such payments will be deducted from royalties due to AVEO on account of Net Sales of the Licensed Product in those
countries where AVEO is due such a royalty and in respect of which Partner, its Affiliates and Sublicensees have incurred legal costs; provided that this will not
reduce AVEO’s royalty to less than [**] percent ([**]%) of the amount otherwise due. Deductions not exhausted in any calendar quarter may be carried into future
calendar quarters.
4.5
Joint Development Cost Sharing. In connection with any Joint Development Plan agreed by AVEO and Partner under Section 2.2(b), on a quarterly
basis, the Parties shall exchange records of their respective costs and expenses. Following such exchange, there will be a dollar-for-dollar true-up: (i) if the applicable
costs and expenses of Partner exceed Partner’s agreed share of the applicable costs and expenses, AVEO shall pay to Partner the amount of such excess, and (ii) if the
applicable costs and expenses of AVEO exceed AVEO’s agreed share of the applicable costs and expenses, Partner shall pay to AVEO the amount of such excess.
4.6
Amounts Due to KHK. AVEO shall be responsible for all payment obligations to (a) KHK under the KHK Agreement, and (b) any other Third Party
licensor of AVEO under license agreements existing as of the Effective Date, on account of the exploitation of Licensed Products in the Partner Territory.
4.7
Quarterly Payment Timing. All royalties due under Section 4.3 shall be paid quarterly, on a country-by-country basis, within forty five (45) days
after the end of the relevant calendar quarter for which royalties are due or, if later, within seven (7) days after AVEO has provided Partner with a valid tax invoice
for such amount.
4.8
Royalty Reports.
(a)
Reports. Within thirty (30) days after the end of each calendar quarter, Partner shall provide to AVEO a final written report stating:
(i)
a statement of the amount of gross sales of Licensed Products in the Partner Territory during such calendar quarter;
(ii)
an itemized calculation of Net Sales (A) in the Partner Territory as a whole and (B) on a country-by-country basis, showing for both (A)
and (B) deductions provided for in the definition of Net Sales during such calendar quarter; and
(iii)
a calculation of the royalty payment due on such Net Sales for such calendar quarter.
(b)
Certain Requirements. Each report shall provide the information required on a country-by-country and Licensed Product-by-Licensed
Product basis. Without limiting the generality of the foregoing, Partner shall require its Affiliates and Sublicensees to
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account for its Net Sales and to provide such reports with respect thereto as if such sales were made by Partner.
4.9
Payment Method. Except as provided in Section 4.13 regarding blocked currency, all payments due under this Agreement to AVEO shall be made by
bank wire transfer in immediately available funds to an account designated by AVEO. All payments hereunder shall be made in Dollars. Each Party shall bear all
fees, commissions and any other costs charged by its own bank in connection with bank transfers under this Agreement.
4.10
No Credits or Refunds. All payments to AVEO hereunder shall be noncreditable and nonrefundable, except only (a) without prejudice to Partner’s
right to bring a claim for breach of this Agreement, including damages for loss and (b) to the extent that an audit conducted pursuant to Section 4.15 below confirms
that Partner had overpaid amounts to AVEO, in which case Partner may credit such overpaid amounts against future amounts payable to AVEO hereunder.
4.11
Taxes. Partner shall be responsible for and may withhold from payments made to AVEO under this Agreement any taxes required to be withheld by
Partner under applicable law. Accordingly, if any such taxes are levied on such payments due hereunder (“Withholding Taxes”), Partner shall (a) deduct the
Withholding Taxes from the payment amount, (b) pay all applicable Withholding Taxes to the proper taxing authority, and (c) send evidence of the obligation
together with proof of tax payment to AVEO within thirty (30) days following that tax payment. If AVEO has the possibility to apply for any exemption from, or
reduction in the rate of, withholding taxes under any double taxation or similar agreement or treaty in force from time to time and requests Partner’s assistance, the
Parties shall reasonably cooperate in seeking such exemption or reduction.
4.12
Value Added Tax. Notwithstanding anything contained in Section 4.11, this Section 4.12 shall apply with respect to value added tax (“VAT”). All
payments by Partner to AVEO under this Agreement shall be exclusive of VAT, which shall not be deducted or offset from any amount payable by Partner to AVEO
under this Agreement. If any VAT is chargeable in respect of any payments, Partner shall pay VAT at the applicable rate in respect of any such payments following
the receipt of a VAT invoice in the appropriate form issued by AVEO in respect of those payments, such VAT to be payable on the later of the due date of the payment
of the payments to which such VAT relates and thirty (30) days after the receipt by Partner of the applicable invoice relating to that VAT payment.
4.13
Blocked Currency. In each country where the local currency is blocked and cannot be removed from the country, royalties accrued in that country
shall be paid to AVEO in the country in local currency by deposit in a local bank designated by AVEO, unless the Parties otherwise agree.
4.14
Foreign Exchange. If any currency conversion shall be required in connection with the calculation of amounts payable hereunder, such conversion
shall be made using the average of the exchange rates for the purchase and sale of Dollars, as reported by The Wall Street Journal. on the last Business Day of the
calendar quarter to which such payment pertains. With any payment in relation to which a currency conversion is performed to calculate the amount of payment due,
Partner, shall provide to AVEO a true, accurate and complete copy of The Wall Street Journal exchange rates used in the calculation.
4.15
Partner Records; Inspection
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(a)
Partner shall keep, and ensure that its Affiliates keep, complete and accurate records of its costs and expenses incurred under the Joint
Development Plan and any Independent Study conducted by Partner, and its sales and other dispositions (including use in clinical trials, or provision on a
compassionate use basis, or as marketing samples, or as named patient sales) of the Licensed Products including all such records that may be necessary for the
purposes of calculating all payments due under this Agreement. Such records shall be kept for a period of five (5) years from the end of the calendar quarter in which
such costs or expenses were incurred or such sale or other disposition was made. Partner shall make such records available for inspection by an accounting firm
selected by AVEO under Section 4.15(c) at Partner’s premises on reasonable notice during regular business hours (in accordance with the remaining provisions of
this Section 4.15) no more than once in any Calendar Year.
(b)
Upon timely request and at least thirty (30) days’ prior written notice from AVEO, Partner shall permit such audit to be conducted during
regular business hours in such a manner as to not unnecessarily interfere with Partner’s normal business activities. Such audit shall be limited to results in any period
that has not previously been audited under this Section 4.15, not to exceed five (5) years prior to the audit notification.
(c)
At AVEO’s expense no more than once per Calendar Year, AVEO has the right to retain an independent certified public accountant from a
nationally recognized accounting firm to perform on behalf of AVEO an audit, conducted in accordance with GAAP, of such books and records of Partner and its
Affiliates as are deemed necessary by the independent public accountant to report on Net Sales for the period or periods requested by AVEO and the correctness of
any report or payments made under this Agreement (all subject to subsection (b)).
(d)
Partner shall ensure that its Sublicensees keep complete and accurate records of such Sublicensee’s costs and expenses incurred under the Joint
Development Plan and any Independent Study conducted by Partner, and sales and other dispositions (including use in clinical trials, provision on a compassionate
use basis, or as marketing samples, or as named patient sales) of the Licensed Products including all such records that may be necessary for the purposes of
calculating all payments due under this Agreement. Partner shall require that such Sublicensee make such records available for inspection by Partner or an
independent accounting firm selected by Partner, at least once during any Calendar Year in which the agreement between Partner and any Sublicensee is in effect and
thereafter for a period of five (5) years after the Calendar Year to which the audit pertains. Upon the reasonable request of AVEO with respect to any such
Sublicensee, and no more than once in any five Calendar Years, Partner shall exercise its audit rights with respect such Sublicensee and shall report the results of
such audit to AVEO in accordance with Section 4.15(f).
(e)
All information, data, documents and abstracts referred to in this Section 4.15 shall be used only for the purpose of verifying compliance with
this Agreement, shall be treated as Partner’s Confidential Information subject to the obligations of this Agreement and need neither be retained more than one (1)
year after completion of an audit hereof, if an audit has been requested; nor more than five (5) years from the end of the Calendar Year to which each shall pertain;
nor more than three (3) years after the date of the expiration or termination of this Agreement.
(f)
Audit results shall be shared between the Parties, and may be provided by AVEO to KHK. The auditor shall be bound by written obligations to
Partner (and, where applicable, any Sublicensee) of confidentiality and non-use (other than uses required by this Section 4.15).
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(g)
If the audit reveals an underpayment, Partner shall promptly pay to AVEO the amount of such undisputed underpayment plus interest in
accordance with Section 4.17. If the audit reveals that the undisputed monies owed by Partner to AVEO has been understated by more than ten percent (10%) for the
period audited, Partner shall, in addition, pay the reasonable costs of such audit. If the audit reveals an undisputed overpayment, the amount of such overpayment
shall be payable to Partner as provided in Section 4.10.
4.16
AVEO Records; Inspection
(a)
AVEO shall keep, and ensure that its Affiliates keep, complete and accurate records of its costs and expenses incurred under the Joint
Development Plan and any Independent Study conducted by AVEO including all such records that may be necessary for the purposes of calculating all payments due
by or to AVEO under this Agreement. AVEO shall make such records available for inspection by an accounting firm selected by Partner under Section 4.16(c) at
Partner’s premises on reasonable notice during regular business hours (in accordance with the remaining provisions of this Section 4.16) no more than once in any
Calendar Year. Such records shall be kept for a period of five (5) years from the end of the calendar quarter in which such costs or expenses were incurred.
(b)
Upon timely request and at least thirty (30) days’ prior written notice from Partner, AVEO shall permit such audit to be conducted during
regular business hours in such a manner as to not unnecessarily interfere with AVEO’s normal business activities. Such audit shall be limited to results in any period
that has not previously been audited under this Section 4.16, not to exceed five (5) years prior to the audit notification.
(c)
At Partner’s expense no more than once per Calendar Year, Partner has the right to retain an independent certified public accountant from a
nationally recognized accounting firm to perform on behalf of Partner an audit, conducted in accordance with GAAP, of such books and records of AVEO and its
Affiliates as are deemed necessary by the independent public accountant to report on its costs and expenses incurred under the Joint Development Plan and any
Independent Study and the correctness of any report or payments made under this Agreement (all subject to subsection (b)).
(d)
AVEO shall ensure that its licensees and contractors keep complete and accurate records of such licensees’ and contractors’ costs and expenses
incurred under the Joint Development Plan and any Independent Study conducted by AVEO including all such records that may be necessary for the purposes of
calculating all payments due under this Agreement. AVEO shall require that such licensees and contractors make such records available for inspection by Partner or
an independent accounting firm selected by Partner, at least once during any Calendar Year.
(e)
All information, data, documents and abstracts referred to in this Section 4.16 shall be used only for the purpose of verifying compliance with
this Agreement, shall be treated as AVEO’s Confidential Information subject to the obligations of this Agreement and need neither be retained more than one (1) year
after completion of an audit hereof, if an audit has been requested; nor more than five (5) years from the end of the Calendar Year to which each shall pertain; nor
more than three (3) years after the date of the expiration or termination of this Agreement.
(f)
Audit results shall be shared between the Parties. The auditor shall be bound by written obligations to AVEO (and, where applicable, any
licensee or contractor) of confidentiality and non-use (other than uses required by this Section 4.16.
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(g)
If the audit reveals an underpayment by AVEO, AVEO shall promptly pay to Partner the amount of such undisputed underpayment plus
interest in accordance with Section 4.17. If the audit reveals that the undisputed monies owed by AVEO to Partner has been understated by more than ten percent
(10%) for the period audited, AVEO shall, in addition, pay the reasonable costs of such audit.
4.17
Interest. If either Party fails to make any payment due to the other Party under this Agreement, then interest shall accrue from the date the particular
payment is due until paid at a rate equal to the Dollars prime or equivalent rate per annum quoted by The Wall Street Journal on the first Business Day after such
payment is due, plus [**] percent ([**]%).
ARTICLE 5.
PATENTS
5.1
Ownership and Disclosure of Inventions.
(a)
AVEO Program Inventions. AVEO shall solely own the AVEO Program Inventions and the AVEO Program Invention Patents.
(b)
Partner Program Inventions. Partner shall solely own the Partner Program Inventions and Partner Program Invention Patents.
(c)
Joint Inventions. AVEO and Partner shall jointly own (as provided for below in Section 5.1(d)) the Joint Inventions and Joint Patents.
(d)
U.S. Patent Law Nature of Joint Ownership.
(i)
The joint ownership of Joint Inventions and Joint Patents under Section 5.1(c) shall be, on a worldwide basis with respect to each
jurisdiction in which such a jointly owned Patent exists, joint ownership in accordance with and bearing with it the same rights as the joint ownership interests would
have under U.S. patent laws in the absence of a written agreement (including the right to practice the invention without having to obtain consent from and without
having any duty of accounting to the other Party; and including the right to license others to do the same, without having to obtain consent from and without having
any duty of accounting to the other Party), except solely to the extent explicitly provided to the contrary in this Agreement (including Article 3). Without limiting the
generality of the foregoing, if under applicable law a separate written agreement is still required to formalize the joint ownership, the parties shall in good faith
negotiate and execute such an agreement on terms consistent with this Agreement.
(ii)
To implement the rights of joint ownership throughout the world as provided for in clause (i) above, each Party hereby assigns to the
other, and hereby grants to the other all consents, licenses and waivers, in each case that are necessary to achieve such joint ownership and the rights associated with
such joint ownership (as described in clause (i) above) worldwide, and agrees to provide documents evidencing or that may be required to record such assignments,
consents, licenses and waivers promptly upon the other Party’s request. Each of the foregoing assignments and other grants is coupled with an interest. Promptly after
being requested in writing, each Party shall provide to the other all documents and instruments required to evidence or record any such assignments, consents,
licenses or waivers, or (to the extent otherwise consistent with this Agreement) to enforce rights in the assigned Patents. This Section 5.1(d)(ii) shall not be deemed,
read, or used to contradict or undermine the Parties’ rights and obligations as set forth in Articles 3 and 4.
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(e)
Invention Disclosure. Without modifying or limiting the ownership and rights as provided for in Sections 5.1(a)-(d), each Party shall promptly
disclose to the other Party any Partner Program Invention, AVEO Program Invention and Joint Invention, as applicable, prior to any public disclosure or filing of a
patent application and allow sufficient time for comment and review by the other Party as to whether such other Party would recommend for a Patent to be filed (by
the Party or Parties who is or are entitled to do so in accordance with Section 5.2).
5.2
Prosecution of Patents.
(a)
Listed AVEO Patents and AVEO Program Invention Patents.
Subject to Section 5.8:
(i)
As between AVEO and Partner, AVEO shall be responsible for the filing, prosecution and maintenance of the Listed AVEO Patents and
AVEO Program Invention Patents on a worldwide basis, including in the Partner Territory; provided that, Partner shall be responsible for paying one hundred percent
(100%) of the prosecution and maintenance costs with respect to Listed AVEO Patents and AVEO Program Invention Patents in the Partner Territory (so long as such
costs are reasonably and properly incurred and do not exceed an amount agreed to by the Parties acting in good faith).
(ii)
Partner shall have the right to review and comment upon AVEO’s prosecution of the AVEO Program Invention Patents and Listed
AVEO Patents, in each case in the Partner Territory. AVEO shall provide (or have provided by its patent attorney) to Partner, a copy of each substantive
communication received from any patent authority, and a copy of each proposed submission to a patent authority in the Partner Territory regarding an AVEO
Program Invention Patent reasonably in advance (but no less than thirty (30) days for Partner’s review) of making such filing. Furthermore, with respect to the
preparation, filing, prosecution and maintenance of Listed AVEO Patents and AVEO Program Invention Patents in the Partner Territory, AVEO agrees to: (A) keep
Partner reasonably informed with respect to such activities; (B) consult with Partner regarding such matters, including the final abandonment of any AVEO Program
Invention Patent and Listed AVEO Patents claims; and (C) reasonably consider Partner’s comments.
(iii)
If AVEO determines to abandon or not maintain any Patent that is a Listed AVEO Patent or an AVEO Program Invention Patent in each
case in the Partner Territory, then AVEO shall provide Partner with at least thirty (30) days’ prior written notice of such determination. If Partner requests, and
confirms its commitment to pay one hundred percent (100%) of the prosecution and maintenance costs with respect to such Patents, then AVEO shall not abandon
and shall continue to maintain such Patents.
(b)
Partner Patents.
Subject to Section 5.8:
(i)
Partner shall be responsible for filing, prosecution and maintenance of the Partner Patents on a worldwide basis. Partner shall be
responsible for paying one hundred percent (100%) of the prosecution and maintenance costs with respect to Partner Patents worldwide.
(ii)
AVEO shall have the right to review and comment upon Partner’s prosecution of the Partner Patents in the AVEO Territory. Partner
shall provide (or have
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provided by its patent attorney) to AVEO, a copy of each substantive communication received from any patent authority in the AVEO Territory, and a copy of each
proposed submission to a patent authority regarding an Partner Patent reasonably in advance (but no less than thirty (30) days for AVEO’s review) of making such
filing. Furthermore, with respect to the preparation, filing, prosecution and maintenance of Partner Patents in the AVEO Territory, Partner agrees to: (A) keep AVEO
reasonably informed with respect to such activities; (B) consult with AVEO regarding such matters, including the final abandonment of any Partner Patent claims;
and (C) reasonably consider AVEO’s comments.
(iii)
If Partner determines to abandon or not maintain any Partner Patent in the AVEO Territory, then Partner shall provide AVEO with at
least thirty (30) days’ prior written notice of such determination (or such other period of time reasonably necessary to allow AVEO to assume such responsibilities).
If AVEO requests, AVEO may assume control, at its own expense, for the filing, prosecution and maintenance of any such Partner Patent solely owned by Partner
that would otherwise have gone abandoned (but not, for clarity, any Partner Patent that is in-licensed or jointly-owned), without affecting any of the other financial
terms set forth in this Agreement.
(c)
Joint Patents.
Subject to Section 5.8:
(i)
With respect to each Joint Invention, as between AVEO and Partner, Partner shall prepare, file, prosecute and maintain the
corresponding Joint Patents in the Partner Territory, and AVEO shall prepare, file, prosecute and maintain the corresponding Joint Patents in the AVEO Territory and
KHK Territory provided that the Parties shall mutually agree on which Party shall file the initial patent application disclosing any Joint Invention and shall mutually
agree as to the content and scope of such first filing and shall share the costs equally. Partner shall be responsible for paying one hundred percent (100%) of the
prosecution and maintenance costs with respect to Joint Patents in the Partner Territory and AVEO shall be responsible for paying one hundred percent (100%) of the
prosecution and maintenance costs with respect to Joint Patents in the AVEO Territory and KHK Territory.
(ii)
AVEO shall have the right to review and comment upon Partner’s prosecution and maintenance of Joint Patents in the Partner Territory,
and Partner shall have the right to review and comment upon AVEO’s prosecution and maintenance of Joint Patents in the AVEO Territory and KHK Territory. The
Party responsible for prosecution and maintenance (the “Prosecuting Party”) of Joint Patents shall provide (or have provided by its patent attorney) to the other
Party, a copy of each substantive communication received from any patent authority, and a copy of each proposed submission to a patent authority regarding a Joint
Patent reasonably in advance (but no less than thirty (30) days for the other Party’s review) of making such filing. Furthermore, the Prosecuting Party agrees to: (A)
keep the other Party reasonably informed with respect to such activities; (B) consult with the other Party regarding such matters, including the final abandonment of
any Joint Patent claims; and (C) reasonably consider the other Party’s comments.
(iii)
If the Prosecuting Party determines to abandon or not maintain any Joint Patent, then such Prosecuting Party shall provide the other
Party with at least sixty (60) days’ prior written notice of such determination (or such other period of time reasonably necessary to allow the other Party to assume
such responsibilities). If the other Party requests, the other Party shall have the right, at its expense, to control the filing, prosecution and maintenance of the Patent
that would otherwise have gone abandoned, without affecting any of the other financial terms set forth in this Agreement.
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(d)
Certain Proceedings. For the purposes of this Section 5.2, “prosecution” shall include defending the applicable Patents in proceedings such as
oppositions, reexaminations, interferences, nullities or other administrative actions in which a Third Party contests the inventorship, validity, title or enforceability of
a Patent; provided, however, in the event there is conflict between this Section 5.2 and Section 5.4, or conflict between Sections 5.2 and 5.5, then Section 5.4 or
Section 5.5 shall control.
(e)
Affiliates/Sublicensees. Partner may grant to its Affiliates or Sublicensees all or certain of its rights with respect to the preparation, filing,
prosecution and maintenance of Partner Patents, set forth in this Section 5.2, and AVEO may grant to its Affiliates and Other Licensees all or certain of its rights with
respect to the preparation, filing and prosecution of the Listed AVEO Patents and AVEO Program Invention Patents set forth in this Section 5.2.
5.3
Patent Term Extensions. Unless the Parties agree otherwise (and subject to the terms of the KHK Agreement), AVEO and Partner agree that, in each
country where one or more of the Licensed Patents is eligible for extension of the patent term, the composition of matter patent, designated as KRN 1 in Exhibit B to
this Agreement (the “Composition Patent”), shall be extended. If the Composition Patent has not issued, has expired, or is otherwise not eligible for extension in a
country in the Partner Territory, then AVEO and Partner shall discuss (with each other and, subject to Section 3.3(a), with KHK) and seek to reach mutual agreement
for which, if any, of the Patents within the Licensed Patents, Partner shall apply to extend the patent term with respect to Licensed Products, pursuant to patent term
extension laws or regulations or supplemental protection certificate laws and regulations in the Partner Territory. If AVEO and Partner cannot reach agreement as to
whether to apply to extend the term of a particular Patent in the Partner Territory, then Partner shall have the right to make the final decision.Partner acknowledges
that, KHK’s consent is required (in KHK’s sole discretion) for the extension of any Licensed Patent (as defined in the KHK Agreement) other than a License-Specific
Licensed Patent (as defined in the KHK Agreement).
5.4
Infringement of Patents by Third Parties.
(a)
Notification. Each Party shall promptly notify the other Party in writing if the notifying Party reasonably believes that any Licensed Patent or
Partner Patent is being or has been infringed or misappropriated in the Partner Territory, AVEO Territory and KHK Territory by a Third Party (such infringement,
together with any that may be imminently threatened to occur by any potential generic version of a Licensed Product arising under the implementing procedures of
35 U.S.C. 271(e)(2) or ex-U.S. equivalent, “Infringement,” and “Infringe” shall be interpreted accordingly). In addition, AVEO shall promptly notify Partner in
writing if AVEO receives any notice from KHK that any Partner Patent is Infringed in the KHK Territory.
(b)
Competitive Infringement of Listed AVEO Patents, AVEO Program Invention Patents and Joint Patents.
(i)
First Right. With respect to activities or conduct of a Third Party that compete with, or are expected to compete with, or otherwise
materially affect the market for, Licensed Products in Partner Territory and in the Field (“Competitive Infringement”), Partner (or its Affiliate) shall have the first
right, but not the obligation, to enforce the Listed AVEO Patents, AVEO Program Invention Patents and Joint Patents with respect to any such Competitive
Infringement at its own expense. Partner shall reasonably consider AVEO’s comments on any such enforcement activities.
(ii)
Back-up Right. If Partner does not bring action to prevent or abate the Competitive Infringement within [**] days after notification
thereof to or by Partner pursuant
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to Section 5.4(a), then AVEO (or its Affiliate) shall have the right, but not the obligation, to bring an appropriate action against any Third Party engaged in such
Competitive Infringement, whether direct or contributory, at its own expense; provided, however, that AVEO shall not initiate legal action without first conferring
with Partner and considering in good faith Partner’s reasons for not bringing any such action.
(c)
Competitive Infringement of Partner Patents. For purposes of clarity, Partner or its Affiliates shall have the sole right, but not the
obligation, to enforce the Partner Patents with respect to any Competitive Infringement in the Partner Territory. Partner and its Affiliates shall keep AVEO reasonably
informed with respect to any such enforcement activities, and shall reasonably consider AVEO’s comments on any such enforcement activities, including conferring
with AVEO with respect to any decision by Partner or the applicable Affiliate for not bringing any action to prevent or abate the Competitive Infringement.
(d)
Infringement Outside of the Field. As between AVEO and Partner, AVEO or its Affiliates shall have the sole right, but not the obligation, to
enforce the Licensed Patents with respect to any Infringement outside of the Field, provided that AVEO shall not, and shall procure that its Affiliates, licensees,
assignees or any other party that acquires rights in the Licensed Patents from AVEO do not, enforce any Licensed Patents outside the Field without Partner’s prior
written consent, which shall not be unreasonably withheld. Without otherwise limiting Partner’s ability to withhold its consent, the Parties agree that it shall be
reasonable for Partner to withhold such consent if Partner reasonably believes that (i) such enforcement presents a risk of the loss in whole or in part (directly or
indirectly) of any of the Licensed Patents in the Partner Territory and (ii) that the total worldwide Net Sales of Licensed Product in the Partner Territory for the
previous calendar year was more than $[**] . If Partner does consent to such enforcement action, AVEO and its Affiliates shall keep Partner reasonably informed
with respect to any such enforcement activities to the extent reasonably likely to impact Partner’s rights in the Field. In situations of Infringement that is both in the
Field and outside of the Field, or that is taking place in both the Partner Territory and the AVEO Territory, the Parties shall confer with each other and take such
action in such manner as they shall agree, provided that each Party shall have the right to make decisions about enforcing Licensed Patents in its respective territory.
(e)
KHK Right to Enforce Certain Infringements. Partner acknowledges that KHK has certain rights (but not the obligation) under the KHK
Agreement to enforce certain Licensed Patents with respect to activities or conduct of a Third Party in or for the Field in the KHK Territory or outside the Field
worldwide, and that each of the Party’s rights and obligations with respect to enforcement of Licensed Patents hereunder shall be subject to such KHK rights.
(f)
Third Party Infringement of Joint Patents. With respect to any Third Party Infringement of Joint Patents in the Partner Territory outside of
the Field, the Parties shall confer with each other and take such action in such manner as they shall agree. If the Parties are unable after a reasonable period of time to
agree on how to proceed, then each Party may, at its own cost and expense, exercise its rights as joint owner of the affected Joint Patent in accordance with the
allocation of joint ownership rights as expressed in Section 5.1.
(g)
Participation of the Other Party with Respect to Infringement Suits. If a Party brings an action against Infringement under Section 5.4(b)
or Section 5.4(f), the other Party shall be entitled to separate representation in such matter by counsel of its own choice and at its own expense, and such Party shall
cooperate fully with the Party bringing such action including by being joined as a party plaintiff if necessary to obtain standing for such action (all at the expense of
the prosecuting Party). Partner acknowledges that KHK has the right under the KHK Agreement to participate in any such action in accordance with the terms
thereof.
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(h)
Settlement.
(i)
AVEO shall not settle a claim brought under Section 5.4(b) or Section 5.4(f) involving AVEO Program Invention Patents or Joint
Patents in a manner that would limit or restrict the ability of Partner to research, develop, make, have made, use, sell, offer for sale and import Licensed Products for
use in the Field in the Partner Territory or impair the exclusivity of Partner’s rights hereunder without the prior written consent of Partner (which consent shall not be
unreasonably withheld, conditioned or delayed) and, if applicable, KHK.
(ii)
Partner shall not settle a claim brought under Section 5.4(b), Section 5.4(c) or Section 5.4(f) involving AVEO Program Invention
Patents and Joint Patents or Partner Patents, as applicable, that would limit or restrict the ability of AVEO to research, develop, make, have made, use, sell, offer for
sale and import Licensed Products in the AVEO Territory or for use outside of the Field worldwide, or that would limit or restrict the ability of KHK to sell Licensed
Products in the KHK Territory or for use outside the Field worldwide, or impair the exclusivity of KHK’s rights under the KHK Agreement, in each case without the
prior written consent of AVEO (which consent shall not be unreasonably withheld, conditioned or delayed) and, if applicable, KHK.
(i)
Allocation of Proceeds. If monetary damages are recovered from any Third Party in an action brought by a Party under this Section 5.4, such
recovery shall be allocated as set forth below:
(i)
first, to reimburse the Parties for any costs and expenses incurred by such Parties in such litigation (including, for this purpose, a
reasonable allocation of expenses of internal counsel or other personnel acting in such capacity (i.e., coordination of litigation matters and the like)) to the extent not
previously reimbursed and, solely to the extent required under Section 5.5(g) of the KHK Agreement, to reimburse KHK for costs and expenses incurred by KHK in
such litigation; and
(ii)
second, with respect to actions brought by Partner under Section 5.4(b)(i) or 5.4(f) that claims an AVEO Product Invention (as defined
in the KHK Agreement), the portion of any remaining amounts after the allocation in clause (i) above that represents recovery for Infringement in the Partner
Territory shall be applied to KHK as follows:
(A)
the portion of any such remaining amounts that represents recovery for [**] on any action brought under Section 5.4(b)(i) above
(1) to the extent [**], with the remaining portion of the [**] that does not represent treble or punitive damages being allocated to AVEO and Partner in
accordance with clause (iii) below; and (2) [**] percent ([**]%) of any [**] representing [**] shall be allocated to KHK with the remaining [**] percent
([**]%) allocated to AVEO and Partner in accordance with clause (iii) below;
(B)
the [**] on any action brought by KHK after exercising its back-up enforcement rights under Section 6.5(b)(ii) of the KHK
Agreement shall be allocated to KHK in the same amount as under subclause (A) above;
(C)
the portion of any such remaining amounts that represents recoveries in relation to lost sales of Licensed Products in the AVEO
Territory or outside of the Field (as such term is defined in the KHK Agreement) in the Partner Territory shall be allocated to KHK; and
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(D)
the portion of any such remaining amounts that represents recovery for Infringement in an action brought with respect to any
Licensed Patents that fall within the definition of Jointly Owned Product Patents (as defined in the KHK Agreement) or Joint Other Invention Patents (as
defined in the KHK Agreement) pursuant to Section 6.5(d) of the KHK Agreement shall be [**] percent ([**]%) to KHK and [**] percent ([**]%) to Partner
unless KHK and AVEO agree in writing to a different allocation (which agreement AVEO shall not provide to KHK without Partner’s agreement on such
terms); and
(iii)
with respect to actions brought by Partner under Section 5.4(b)(i), or 5.4(f), any remaining amounts after the allocation in clauses (i)
and (ii) above shall be allocated [**] percent ([**]%) to AVEO and [**] percent ([**]%) to Partner ; and
(iv)
with respect to actions brought by AVEO under Section 5.4(b)(ii), 5.4(d) or 5.4(f), any remaining amounts after the allocation in clause
(i) above shall, as between AVEO and Partner, be retained by AVEO.
(j)    Affiliates/Sublicensees. Partner may grant to its Affiliates or Sublicensees its rights to enforce Licensed Patents as set forth in this Section 5.4,
and vice versa for AVEO and its Affiliates and its Other Licensees.
5.5
Infringement of Third-Party Rights. If any Licensed Product manufactured, used or sold by Partner, its Affiliates or Sublicensees for use in the
Field becomes the subject of a Third Party’s claim or assertion of Infringement of a Patent granted by a jurisdiction within the Partner Territory, the Party first having
notice of the claim or assertion shall promptly notify the other Party, and the Parties shall promptly confer to consider the claim or assertion and the appropriate
course of action. Unless the Parties otherwise agree in writing, each Party shall have the right to defend itself against a suit that names it as a defendant, subject to the
indemnification provisions of Article 8. Neither Party shall enter into any settlement of any claim described in this Section 5.5 that affects the other Party’s rights or
interests (or the rights or interests of KHK under the KHK Agreement) without such other Party’s (or KHK’s, if applicable) written consent, which consent shall not
be unreasonably withheld or delayed. In any event, the Parties shall reasonably assist one another and cooperate in any such litigation at the other Party’s request and
expense.
5.6
Patent Marking. Partner (or its Affiliate, Sublicensee or Distributor) shall mark Licensed Products marketed and sold by Partner (or its Affiliate,
Sublicensee or Distributor) hereunder with appropriate Licensed Patent numbers or indicia at AVEO’s request to the extent permitted by applicable law, in those
countries in which such notices affect recoveries of damages or equitable remedies available with respect to infringements of patents.
5.7
Patent Oppositions and Other Proceedings. If either Party desires to bring an opposition, action for declaratory judgment, nullity action,
interference, reexamination or other attack upon the validity, title or enforceability of a Patent owned or controlled by a Third Party that covers or may cover the
manufacture, use for the Field or sale of any Licensed Product, such Party shall so notify the other Party. The Parties shall discuss in good faith the rationale for, and
proposed actions to be taken, with respect to such opposition or other action.
5.8
In-Licensed Patents.
(a)
Partner acknowledges that:
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(i)
pursuant to Section 6.2(a) of the KHK Agreement, KHK shall have the first right and responsibility for filing, prosecution and
maintenance of the Listed AVEO Patents and any other Licensed Patents that fall within the definition of Kirin Product Invention Patents (as defined in the KHK
Agreement) on a worldwide basis, with AVEO having step-in rights on prosecution and maintenance if KHK determines to abandon or not maintain any such Listed
AVEO Patent and also under Section 6.2(a) of the KHK Agreement AVEO has the right to inter alia review and comment on such prosecution. In relation to such
Patents in the Partner Territory in the Field, AVEO shall provide Partner with the same rights as AVEO has under Section 6.2(a) of the KHK Agreement (except as to
the assumption of abandoned Patents) and shall promptly pass all comments of Partner to KHK;
(ii)
pursuant to Section 6.2(c) of the KHK Agreement, KHK shall have the first right and responsibility for filing, prosecution and
maintenance of any Licensed Patents that fall within the definition of Jointly Owned Product Patents (as defined in the KHK Agreement) in the KHK Territory, and,
as between KHK and AVEO, AVEO shall have the first right and responsibility for filing, prosecution and maintenance of such Licensed Patents in the Partner
Territory, subject to (A) keeping the other party reasonably informed with respect to such activities, consulting with the other party on such matters (including with
respect to final abandonment of any claims), and reasonably considering the other party’s comments, (B) reasonable cooperation and mutual agreement on (and
sharing costs equally with respect to) filings that are applicable to both the KHK Territory and the Partner Territory, and (C) the other party having the right to step-in
on prosecution and maintenance if the original prosecuting party determines to abandon or not maintain any such Licensed Patent in the would-be-abandoning party’s
territory;
(iii)
pursuant to Section 6.2(d) of the KHK Agreement, KHK and AVEO have agreed to confer and agree upon which party shall prosecute
and/or maintain any Joint Other Invention Patent (as defined in the KHK Agreement). AVEO shall not undertake such conference or agreement with KHK with
respect to any Licensed Patent without the Parties’ mutual agreement (which agreement shall not be unreasonably withheld, conditioned or delayed by either Party);
(iv)
if AVEO or Partner, as applicable, does not bring action to prevent or abate Competitive Infringement of any Licensed Patents within
[**] days (or [**] days in the case of an action brought under the Hatch-Waxman Act or any ex-U.S. equivalent of the Hatch-Waxman Act) after notification thereof
to or by such Party pursuant to Section 5.4(a) above, then KHK shall have a back-up right under Section 6.5(b)(ii) of the KHK Agreement to bring, at its own
expense, an appropriate action in the Partner Territory against any person or entity engaged in any such Competitive Infringement directly or contributorily. The
Parties acknowledge that KHK has agreed under the KHK Agreement not to initiate legal action without first conferring with AVEO (and AVEO shall not undertake
such conference without Partner to the extent related to any Competitive Infringement in the Partner Territory, unless otherwise mutually agreed by the Parties) and
considering in good faith AVEO’s (and Partner’s, if applicable) reasons for not bringing any such action;
(v)
KHK shall have the sole right under Section 6.5(b)(iii) of the KHK Agreement to enforce the Listed AVEO Patents and Licensed
Patents that fall within the definition of Kirin Product Invention Patents (as defined in the KHK Agreement) and/or Jointly Owned Product Patents (as defined in the
KHK Agreement) with respect to activities or conduct of a Third Party in or for the Field in the KHK Territory or outside the Field (as defined in the KHK
Agreement) worldwide;
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(vi)
KHK shall have the exclusive right under Section 6.5(c) of the KHK Agreement to prevent or abate any Infringement of any Listed
AVEO Patents or Licensed Patents that fall within the definition of Kirin Product Invention Patents (as defined in the KHK Agreement) anywhere in the world
(including in the Partner Territory) other than Competitive Infringement in the Partner Territory or Infringement in the AVEO Territory resulting from activities or
conduct of a Third Party in the KHK Territory that compete with, or are expected to compete with, or otherwise materially affect the market for, Licensed Products in
the AVEO Territory. In such event, the Parties acknowledge that KHK has agreed to notify AVEO of such Infringement (in which event, AVEO shall notify Partner)
and to keep AVEO reasonably informed with respect to the disposition of any action taken in connection therewith (in which event, AVEO shall pass along such
information to Partner);
(vii)
With respect to any Third Party Infringement of any Licensed Patents that fall within the definition of Jointly Owned Product Patents
(as defined in the KHK Agreement) anywhere in the world (including in the Partner Territory) other than a Competitive Infringement in the Partner Territory or an
Infringement in the KHK Territory that competes with, or is expected to compete with, or otherwise materially affect the market for, Licensed Products in the KHK
Territory, AVEO (and Partner, with respect to any Competitive Infringement in the Partner Territory) shall confer with KHK pursuant to Section 6.5(d) of the KHK
Agreement and take such action in such manner as all parties agree. If the parties are unable after a reasonable period of time to agree on how to proceed, then KHK
and AVEO may exercise their rights as joint owners of the affected Licensed Patent in accordance with the allocation of joint ownership rights as expressed in
Section 6.1 of the KHK Agreement; and
(viii)
Pursuant to Section 6.5(e) of the KHK Agreement, if either AVEO or Partner brings an action against Infringement related to any of the
Licensed Patents under Section 5.4 above for which KHK has back-up enforcement rights, the Parties acknowledge that KHK shall be entitled to separate
representation in such matter by counsel of its own choice and at its own expense.
(b)    Subject to Section 3.7, without limiting the generality of clause (a) above, if there are at any time any Licensed Patents that are in-licensed by
AVEO instead of owned by AVEO (or any AVEO Affiliate) and that are made known to Partner by AVEO in writing, then Sections 5.2, 5.3 and 5.4 shall apply to the
prosecution or enforcement of such Patents, as the case may be, in the same way as if they were Licensed Patents owned by AVEO, to the full extent AVEO has
prosecution and enforcement rights under the agreement by which AVEO received its license rights to such Patents that are in-licensed by AVEO instead of owned by
AVEO (or any AVEO Affiliate), and subject to the rights of the Third Party licensor under such agreement.
(c)    If there are at any time any Partner Patents that are in-licensed by Partner instead of owned by Partner (or a Partner Affiliate) and that are made
known to AVEO by Partner in writing, then Sections 5.2, 5.3 and 5.4 shall apply to the prosecution and enforcement of such Patents, as the case may be, in the same
way as if they were Partner Patents owned by Partner, to the full extent Partner has prosecution and enforcement rights under the agreement by which Partner
received its license rights to such Partner Patents that are in-licensed by Partner instead of owned by Partner (or an Partner Affiliate), and subject to the rights of the
Third Party licensor under such agreement.
5.9
Trademarks.
(a)
Trademark Cross License. Partner may select and own one or more trademarks of its choice for the packaging, promotion, marketing and
sale of the Licensed
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Products in the Partner Territory.Each of the Parties agrees to grant to the other Party an exclusive, fully paid-up, royalty-free, sublicenseable license to use the
granting Party’s trademark(s) for packaging, promotion, marketing and sale of the Licensed Products (or AVEO’s products in the AVEO Territory) in each Party’s
respective territory; provided, however, (i) the good will associated with each trademark shall remain with the granting Party, (ii) the granting Party shall have the
right to review in advance and consent (such consent not to be unreasonably withheld or delayed) to each proposed use of the granting Party’s trademark by the other
Party, and (iii) each Party agrees that it will not use the granting Party’s trademarks in a manner that may harm the goodwill or reputation of the granting Party in
relation to the Licensed Product or otherwise.
(b)
Compensation. Each of the Parties agrees to reimburse the granting Party for all costs of filing, obtaining and maintaining registration of the
trademarks in the grantee Party’s territory.
(c)
Termination. Upon the expiration or termination of this Agreement, each Party shall immediately discontinue (except for a reasonable period
not to exceed 180 days to sell existing inventory) all use of the other Party’s trademarks at no cost whatsoever to the granting Party, and each Party shall immediately
return to the granting Party all material relating to the granting Party’s trademarks.
ARTICLE 6.
CONFIDENTIALITY
6.1
Core Confidential Information. Each Party shall, and shall cause its Affiliates and contractors and their respective officers, directors, employees and
agents to, keep confidential, and not publish or otherwise disclose, and not use directly or indirectly for any purpose, any confidential and proprietary information of
such Party relating to any Licensed Compounds or Licensed Products (the “Core Information”); except to the extent (i) the Core Information is in the public domain
through no fault of such Party, its Affiliates or any of their respective officers, directors, employees or agents, (ii) such disclosure or use would be expressly permitted
under Section 6.3 as if such information was Confidential Information, (iii) such information is of the type customarily disclosed in the ordinary course of business,
including in scientific journals or in scientific, industry or investor meetings, and such disclosure would not materially and adversely affect the rights of the other
Party under this Agreement, or (iv) such disclosure or use is otherwise expressly permitted by the terms of this Agreement. For clarification, the disclosure by AVEO
to Partner or by Partner to AVEO of Core Information shall not cause such information to cease to be subject to the provisions of this Section 6. In the event this
Agreement is terminated in its entirety this Section 6.1 shall have no continuing force or effect and Core Information shall be deemed to be Confidential Information
of AVEO or Partner, as applicable, for purposes of the surviving provisions of this Agreement.
6.2
Treatment of Confidential Information. The Parties agree that during the Term, and for a period of five (5) years after the Term expires in the last
country in which it expires or is terminated, a Party receiving Confidential Information of the other Party shall (a) maintain in confidence such Confidential
Information to the same extent such Party maintains its own most highly confidential proprietary information (but at a minimum each Party shall use Commercially
Reasonable Efforts), (b) not disclose such Confidential Information to any Third Party without prior written consent of the other Party, and (c) not use such
Confidential Information for any purpose except those permitted by this Agreement or the KHK Agreement.
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6.3
Authorized Disclosure. Notwithstanding Section 6.1 or Section 6.2, a Party may disclose Confidential Information of the other Party to the extent
such disclosure is reasonably necessary in the following instances:
(a)
filing for, prosecuting or maintaining Patents;
(b)
regulatory filings;
(c)
prosecuting or defending litigation;
(d)
complying with applicable governmental regulations and/or submitting information to tax or other governmental authorities, provided that if
the receiving Party is required by law to make any public disclosures of Confidential Information of the disclosing Party, to the extent it may legally do so, it will
give reasonable advance notice to the disclosing Party of such disclosure and will use its reasonable efforts to secure confidential treatment of Confidential
Information prior to its disclosure (whether through protective orders or otherwise);
(e)
to (i) its Affiliates, and to prospective and actual licensees, sublicensees, employees, consultants, agents, accountants, lawyers, advisors and
investors, and (ii) others in order to (and solely to the extent required to) exercise such Party’s rights or fulfill its obligations under this Agreement and the KHK
Agreement (including commercialization and/or sublicensing of Licensed Patents, Licensed Know-How or Licensed Products) on a need to know basis, each of
whom in (i) and (ii) prior to disclosure must be bound by similar obligations of confidentiality and non-use substantially equivalent in scope to those set forth in this
Article 6 and that are of reasonable duration in view of the circumstances of the disclosure; and
(f)
to the extent mutually agreed to in writing by the Parties.
6.4
Termination of Prior Agreements. This Agreement supersedes the Prior Agreement. All information exchanged between the Parties under or
otherwise subject to the Prior Agreement shall be deemed Confidential Information (in accordance with and to the extent set forth in the definition of such term in
Article 1), and shall be subject to the terms of this Article 6.
6.5
Publicity.
(a)
The Parties have agreed to issue a joint press release in the form and with the content set forth in Exhibit D for the initial public announcement
of the execution of this Agreement. Any other publication, news release or other public announcement regarding the execution or terms of this Agreement, shall first
be reviewed and approved by both Parties, which approval shall not be unreasonably withheld, conditioned or delayed.
(b)
In addition, Partner shall notify AVEO in advance of any public announcement regarding Licensed Products’ performance and achievements
hereunder. AVEO shall have the right to review and comment upon such public announcement and Partner agrees to reasonably consider AVEO’s comments.
(c)
The terms of this Agreement shall be treated as Confidential Information of both Parties.
(i)
Such terms may be disclosed by a Party to individuals or entities covered by Section 6.3(e)(i) (but not Section 6.3(e)(ii), except for
KHK) above, each of whom
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prior to disclosure must be bound by similar obligations of confidentiality and non-use substantially equivalent in scope to those set forth in this Article 6.
(ii)
Disclosure of the terms of this Agreement (but not other Confidential Information received from the other Party) may also be made, to
actual or potential bankers, lenders, and investors of the disclosing Party, who are bound to obligations of confidentiality and non-use substantially equivalent in
scope to those set forth in this Article 6; provided, however, that Partner shall not be permitted to disclose the terms of the KHK Agreement.
(iii)
In addition, if AVEO is legally required to file a copy of this Agreement with the U.S. Securities and Exchange Commission (“SEC”)
in connection with such Party’s regular reporting obligations as a public company, AVEO shall attempt to obtain confidential treatment of economic and trade secret
information for which such treatment is reasonably available in accordance with applicable laws and regulations and SEC practice.
(iv)
The Parties acknowledge that AVEO is required under Section 7.4 of the KHK Agreement to obtain KHK’s prior approval (not to be
unreasonably withheld, conditioned or delayed) with respect to any publication, news release or public announcement regarding the terms of the KHK Agreement, to
use good faith efforts to notify KHK in advance of any significant public announcement regarding Licensed Products’ performance and achievement and, if either
Party is required to file a copy of this Agreement with the SEC, to provide KHK, at least thirty (30) days in advance of such filing, with a draft set of redactions to
this Agreement (as it relates to the KHK Agreement) for which any confidential treatment will be sought, and to incorporate KHK’s comments as to additional terms
KHK would like to see redacted, and seek confidential treatment for such additional terms (except only in the limited circumstances where confidential treatment is
manifestly unavailable). Partner shall reasonably cooperate with AVEO with respect to AVEO’s efforts to comply with the foregoing obligations to KHK under the
KHK Agreement.
6.6
Publications. The Parties acknowledge that AVEO is required under Section 7.5 of the KHK Agreement to provide KHK with an opportunity to
review any proposed abstracts, manuscripts or scientific presentations (including verbal presentations) which relate to development or commercialization activities
for any Licensed Product, at least thirty (30) days prior to their intended submission for publication, and to not submit any such abstract or manuscript for publication
until KHK is given a reasonable period of time to secure patent protection for any material in such publication which it believes to be patentable. Partner shall
reasonably cooperate with AVEO with respect to AVEO’s efforts to comply with the foregoing obligation to KHK under the KHK Agreement.
ARTICLE 7.
REPRESENTATIONS AND WARRANTIES
7.1
General Representations and Warranties. Each Party represents, warrants and covenants to the other that:
(a)
It is duly organized and validly existing under the laws of its state or country of incorporation, and has full corporate power and authority to
enter into this Agreement and to carry out the provisions hereof.
(b)
It is duly authorized to execute and deliver this Agreement and to perform its obligations hereunder, and the person or persons executing this
Agreement on its behalf has and have been duly authorized to do so by all requisite corporate action.
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(c)
This Agreement is legally binding upon it and enforceable in accordance with its terms. The execution, delivery and performance of this
Agreement by it does not conflict with any agreement, instrument or understanding, oral or written, to which it is a party or by which it may be bound, nor violate
any material law or regulation of any court, governmental body or administrative or other agency having jurisdiction over it.
(d)
It has not granted, and shall not grant during the Term of the Agreement, any right to any Third Party which would conflict with the rights
granted to the other Party hereunder. It has (or shall have at the time performance is due) maintained and shall maintain and keep in full force and effect all
agreements necessary to perform its obligations hereunder.
(e)
It is not aware of any action, suit or inquiry or investigation instituted by any governmental agency which questions or threatens the validity of
this Agreement.
7.2
AVEO’s Warranties. AVEO represents and warrants to Partner that, as of the Effective Date:
(a)
It has supplied Partner with a true, correct and complete copy of the KHK Agreement and the Pharmstandard Agreement and Ophthotech
Agreement.
(b)
The KHK Agreement is in full force and effect and is legally binding upon AVEO and KHK.
(c)
To AVEO’s Knowledge, KHK does not have cause to terminate the KHK Agreement and AVEO is not in default under any material provision
of the KHK Agreement.
(d)
The Listed AVEO Patents are owned or Controlled solely and exclusively by AVEO in the Field, free and clear of any liens, charges and
encumbrances, and AVEO has the right to grant to Partner the rights and licenses set forth hereunder.
(e)
Except as may be provided in the KHK Agreement, Ophthotech Agreement and the Pharmstandard Agreement, neither AVEO nor its
Affiliates, nor to AVEO’s Knowledge KHK or its Affiliates, has granted expressly or otherwise any assignment, license or other extension of right, covenant not to
sue or other similar interest or benefit, exclusive or otherwise, to, under or in the Licensed Patents or the Licensed Know-How with respect to the Licensed
Compound and or the Licensed Products in the Field for the Partner Territory, and no Third Party other than KHK has retained any right or other similar interest or
benefit, exclusive or otherwise to under or in the Licensed Patents in the Field in the Partner Territory,
(f)
The Listed AVEO Patents set out on Exhibit B is a complete and accurate list of all Patents Controlled by AVEO anywhere in the Partner
Territory that claim the composition of the Licensed Compound, the current Licensed Product formulation, any method that is specific to manufacturing the Licensed
Compound or currently used by or on behalf of AVEO or its Affiliates to manufacture the Licensed Compound or the use of the Licensed Compound in the Field or
that are otherwise necessary or required for Partner to fully exercise its rights under this Agreement.
(g)
To AVEO’s Knowledge, prior to the Effective Date, the Licensed Patents are being diligently procured from the respective patent offices in
accordance with applicable law and the Licensed Patents have been filed and maintained properly and correctly and all applicable fees have been paid on or before
the due date for payment.
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(h)
Neither AVEO nor its Affiliates nor, to AVEO’s Knowledge, KHK, has received any written notice of any claim, and does not know of any
grounds for such a claim, that any Patent or trade secret right owned or controlled by a Third Party would be infringed or misappropriated by the use, sale, offer for
sale or importation of Licensed Compounds or Licensed Products as contemplated by this Agreement.
(i)
Neither AVEO nor its Affiliates, or to AVEO’s Knowledge KHK nor its Affiliates, is aware of the existence of any documentation or
publication or conduct by or on behalf of KHK or AVEO or their Affiliates that would bring into question the validity or enforceability of the Listed AVEO Patents.
(j)
To AVEO’s Knowledge, (i) no proceeding is pending or threatened that challenges AVEO’s or KHK’s ownership or Control, as applicable, of
the Licensed Patents, and (ii) the Licensed Patents are not subject to any pending or threatened re-examination, opposition, interference or litigation proceedings, and
AVEO does not know of any grounds for any such foregoing proceedings.
(k)
To AVEO’s Knowledge, apart from those companies selling the Licensed Compound for research use, the Licensed Technology is not being
infringed or misappropriated by any Third Party..
(l)
Other than matters which have been disclosed in AVEO’s filings with the United States Securities and Exchange Commission, there is no
action, claim, demand, suit, proceeding, arbitration, grievance, citation, summons, or subpoena of any nature (civil, criminal, regulatory or otherwise), in law or in
equity, pending or, to AVEO’s Knowledge, threatened, or any grounds for any, against AVEO or its Affiliates relating to the Licensed Patents, the Licensed Know-
How or the transaction contemplated by this Agreement.
(m)
Other than payments to AVEO’s Third Party contractors in connection with Section 1.49 of this Agreement, none of the Licensed Patents
Controlled by AVEO at the Effective Date or the Licensed Know-How require the payment of consideration by AVEO or its Affiliates, or by Partner or its Affiliates,
to any Third Party (excluding KHK) in connection with the grant of rights to Partner and its Affiliates under this Agreement, or the exercise of such rights by Partner
or its Affiliates.
(n)
To AVEO’s Knowledge, each of the Listed AVEO Patents properly identifies each and every inventor of the claims thereof as determined in
accordance with the laws of the jurisdiction in which such Listed AVEO Patent is issued or such application is pending.
(o)
To AVEO’s Knowledge, each person who has or has had any rights in or to any Listed AVEO Patents has assigned and has executed an
agreement assigning its entire right, title and interest in and to such Listed AVEO Patents to AVEO or KHK as appropriate. To AVEO’s Knowledge, no current
officer, employee, agent or consultant of AVEO or any of its Affiliates or KHK or any of its Affiliates is in violation of any term of any assignment or other
agreement regarding the protection of Licensed Patents.
(p)
To AVEO’s Knowledge, the inventions claimed or covered by the Listed AVEO Patents (a) were not conceived, discovered, developed or
otherwise made in connection with any research activities funded, in whole or in part, by the federal government of the United States or any agency thereof and (b)
are not a “subject invention” as that term is described in 35 U.S.C. Section 201(e) and (c) are not otherwise subject to the provisions of the Patent and Trademark
Law Amendments Act of 1980, as amended, codified at 35 U.S.C. §§ 200-212, as
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amended, as well as any regulations promulgated pursuant thereto, including in 37 C.F.R. Part 401.
(q)
AVEO has made (or will make as provided in this Agreement) available to Partner all Regulatory Documentation and Licensed Know-How
listed in Exhibit C in its possession or Control related to the Licensed Compound or the Licensed Products. All such Regulatory Documentation is (and if made
available after the Effective Date, will be) true, complete and correct.
(r)
[Intentionally omitted].
(s)
Neither AVEO nor to AVEO’s Knowledge any licensee (including KHK), nor any of its or their respective officers or employees has (a)
committed (or after the Effective Date, will commit) an act, (b) made (or after the Effective Date, will make) a statement or (c) failed (or after the Effective Date, will
fail) to act or make a statement that, in any case ((a), (b) and (c)), that (i) would be or create an untrue statement of material fact or fraudulent statement to the FDA
or any other Regulatory Authority with respect to the development of the Licensed Compound or the Licensed Products or (ii) could reasonably be expected to
provide a basis for the FDA to invoke its policy respecting “Fraud, Untrue Statements of Material Facts, Bribery and Illegal Gratuities”, set forth in 56 Fed. Reg.
46191 (September 10, 1991) and any amendments thereto or any analogous laws or policies in the Partner Territory, with respect the exploitation of the Licensed
Compound or the Licensed Products.
(t)
AVEO and to AVEO’s Knowledge, KHK and AVEO’s Other Licensees, have conducted, all exploitation of the Licensed Compound and the
Licensed Products, and the Regulatory Documentation has been prepared and maintained, in accordance with applicable good laboratory and clinical practice and
law.
(u)
True, complete and correct copies (as of the Effective Date) of all material adverse information with respect to the safety and efficacy of the
Licensed Compound known to AVEO have been provided to Partner at least two (2) days prior to the Effective Date.
(v)
To AVEO’s Knowledge, the representations and warranties of AVEO in this Agreement and the information, documents and materials
furnished to Partner in connection with its period of diligence prior to the Effective Date, do not, taken as a whole and in light of the nature of such information,
documents and materials and taking into consideration the information that Partner has learned prior to the Effective Date during its diligence process, (a) contain any
untrue statement of a material fact or (b) omit to state any material fact necessary to make the statements or facts contained therein, in light of the circumstances of
Partner’s decision to enter into this Agreement, not misleading.
(w)
To AVEO’s Knowledge (which for clarity shall not require any additional investigation by AVEO’s external intellectual property counsel) the
license grant of the Licensed Technology to Partner pursuant to the terms of this Agreement provides Partner with all intellectual property rights necessary to
manufacture and exploit the Licensed Compound for the RCC Indication in the Field in the Partner Territory.
7.3
AVEO’s Covenants
(a)
Except for the development and manufacture of Licensed Products pursuant to, and in accordance with, the terms and conditions set forth in
Sections 3.3(e)(i) and 3.5 of this Agreement, during the Term neither AVEO nor any of its Affiliates (i) shall develop or commercialize any Competing Product in the
Partner Territory, (ii) shall collaborate with any
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Third Party, shall grant to any Third Party the right, or shall engage in activities on behalf of any Third Party, to develop or commercialize any Competing Product, in
each case in the Partner Territory or (iii) shall grant to any Third Party any license or other right under any Licensed Technology to develop or commercialize any
Competing Product in the Partner Territory.
(b)
AVEO agrees that any amendments to the KHK Agreement that adversely affect Partner’s rights or obligations under this Agreement shall be
agreed by AVEO only with the prior written consent of Partner, not to be unreasonably withheld or delayed.
7.4
Partner’s Warranties and Covenants.
(a)
Except for the development and commercialization of Licensed Products pursuant to, and in accordance with, the terms and conditions set
forth in this Agreement, during the Term neither Partner nor any of its Affiliates (i) shall develop or commercialize any Competing Product in the Partner Territory or
the AVEO Territory, (ii) shall collaborate with any Third Party, shall grant to any Third Party the right, or shall engage in activities on behalf of any Third Party, to
develop or commercialize any Competing Product, in each case in the Partner Territory or the AVEO Territory, or (iii) shall grant to any Third Party any license or
other right under any Licensed Technology to develop or commercialize any Competing Product in the Partner Territory or the AVEO Territory.
(b)
Partner represents and warrants to AVEO that as of the Effective Date it does not have any VEGF Receptor Inhibitor at any stage of
development or commercialization for the diagnosis, prevention or treatment of any form of cancer. Partner further covenants and agrees, that in case it or an Affiliate
or Sublicensee proposes to develop or commercialize any VEGF Receptor Inhibitor in the Field in the Partner Territory, Partner shall:
(i)
provide an overall clinical development plan for the Licensed Compound (if Partner is conducting any development) (at the same level
of detail as the AVEO Overall Clinical Development Plan as defined in the KHK Agreement) to AVEO;
(ii)
to exert at least Commercially Reasonable Efforts to develop and commercialize Licensed Products (without any lowering of such
standard on account of any other VEGF Receptor Inhibitor);
(iii)
to exert efforts on Licensed Products at least as great as any other VEGF Receptor Inhibitor, taking into account all relevant factors
such as the relative stage of development of the products, unique development issues related to each of the products, and potential uses for the products;
(iv)
Promptly (within no more than [**] days after requested by KHK) meet with the KHK Development Committee (as defined in the
KHK Agreement) and AVEO through a representative of the Partner at the level of at least Vice President or above.
(c)
Partner represents, warrants and covenants that in the course of the development of Licensed Products, it shall not during the Term use, any
employee or consultant who has been debarred by the applicable Regulatory Authorities, or, to the best of Partner’s knowledge, who was or is the subject of
debarment proceedings by the applicable Regulatory Authorities. Partner further covenants that Partner and its Sublicensees, and their respective officers, agents and
employees, will not commit or fail to commit any act, or make or fail to make any statement that would be or create an untrue statement of material fact or fraudulent
statement to any Regulatory Authority with respect to the development or commercialization of the Licensed Compound or the Licensed Products or could
reasonably be expected to provide a
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basis for the FDA to invoke its policy respecting “Fraud, Untrue Statements of Material Facts, Bribery and Illegal Gratuities”, set forth in 56 Fed. Reg. 46191
(September 10, 1991) and any amendments thereto or any analogous laws or policies in the Partner Territory, with respect the exploitation of the Licensed Compound
or the Licensed Products.
7.5
Disclaimer Concerning Technology. EXCEPT AS OTHERWISE EXPRESSLY PROVIDED HEREIN, THE PATENTS AND KNOW-HOW
PROVIDED BY EACH PARTY HEREUNDER ARE PROVIDED “AS IS” AND EACH PARTY EXPRESSLY DISCLAIMS ANY AND ALL WARRANTIES OF
ANY KIND, EXPRESS OR IMPLIED, INCLUDING WITHOUT LIMITATION THE WARRANTIES OF DESIGN, MERCHANTABILITY, FITNESS FOR A
PARTICULAR PURPOSE, NONINFRINGEMENT OF THE INTELLECTUAL PROPERTY RIGHTS OF THIRD PARTIES OR ARISING FROM A COURSE OF
DEALING, USAGE OR TRADE PRACTICES, IN ALL CASES WITH RESPECT THERETO. Without limiting the generality of the foregoing, each Party
expressly does not warrant (a) the success of activities performed pursuant to this Agreement or (b) the safety, efficacy or usefulness for any purpose of the Patents or
Know-How it provides under this Agreement or the subject matter of them.
ARTICLE 8.
INDEMNIFICATION
8.1
Indemnification by Partner.
(a)
Partner shall indemnify, hold harmless and defend AVEO and each of its Affiliates, all of their respective officers, directors, employees and
agents, and each of their respective successors, heirs and assigns (collectively, the “AVEO Indemnitees”) from and against any and all losses, damages, liabilities,
judgments, fines, amounts paid in settlement, expenses and costs of defense (including reasonable attorneys’ fees and witness fees) (collectively, “Losses”) resulting
from any demand, claim, action or proceeding brought or initiated by a Third Party (each, a “Third-Party Claim”) against any AVEO Indemnitees(s) to the extent
that such Third-Party Claim arises out of:
(i)
the breach or alleged breach of any representation, warranty or covenant by Partner in Article 7 of this Agreement;
(ii)
any breach of any term of this Agreement by a Partner Indemnitee;
(iii)
the negligence or willful misconduct of any Partner Indemnitee (defined in Section 8.2); or
(iv)
the research, development, manufacture, storage, handling, use, sale, offer for sale or importation of Licensed Products by or for the
Partner Indemnitees, provided that such Third Party Claim results from negligence or willful misconduct of Partner Indemnitees;
provided in each case that (x) the AVEO Indemnitees comply with the procedure set forth in Section 8.3; and (y) such indemnity shall not apply to the extent AVEO
has an indemnification obligation pursuant to Section 8.2 for such Loss or such Loss was caused by a breach of any term of this Agreement by any AVEO
Indemnitee. Partner shall require equivalent indemnification of the AVEO Indemnitees as in clause (iii) of the foregoing sentence from each Sublicensee as to such
Sublicensee’s activities described in such clause (iii).
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(b)
Partner shall indemnify, hold harmless and defend KHK, KHK’s Affiliates, KHK’s and its Affiliates’ sublicensees and all of the respective
officers, directors, employees and agents of each of the foregoing entities (collectively, the “KHK Indemnitees”) from and against any and all Losses resulting from
any Third-Party Claim against any KHK Indemnitees(s) to the extent that such Third-Party Claim arises out of the research, development, manufacture, storage,
handling, use, sale, offer for sale or importation of Licensed Compounds or Licensed Products; provided that (i) the KHK Indemnitees comply with the procedure set
forth in Section 8.3 of the KHK Agreement; and (ii) such indemnity shall not apply to the extent KHK has an indemnification obligation pursuant to Section 9.2 of
the KHK Agreement for such Loss.
8.2
Indemnification by AVEO.
(a)
AVEO shall indemnify, hold harmless and defend Partner, Partner’s Affiliates, Partner’s and its Affiliates’ Sublicensees and all of the
respective officers, directors, employees and agents of each of the foregoing entities (collectively, the “Partner Indemnitees”) from and against any and all Losses
resulting from any Third-Party Claim against them to the extent that such Third-Party Claim arises out of:
(i)
the breach or alleged breach of any representation, warranty or covenant by AVEO in Article 7 of this Agreement; or
(ii)
any breach of any term of this Agreement by an AVEO Indemnitee; or
(iii)
the negligence or willful misconduct of any AVEO Indemnitee;
provided in each case that (y) the Partner Indemnitees comply with the procedure set forth in Section 8.3; and (z) such indemnity shall not apply to the extent Partner
has an indemnification obligation pursuant to Section 8.1 for such Loss or such Loss was caused by a breach of any term of this Agreement by any Partner
Indemnitee.
(b)
In addition, the Parties acknowledge that, pursuant to Section 9.2 of the KHK Agreement, KHK has agreed to indemnify, hold harmless and
defend AVEO and its sublicensees and all of the respective officers, directors, employees and agents of the foregoing entities from and against any and all Losses
resulting from any Third-Party Claim against AVEO or its sublicensees to the extent that such Third-Party Claim arises out of:
(i)
the breach or alleged breach of any representation, warranty or covenant by KHK in Article 8 of the KHK Agreement; or
(ii)
the negligence or willful misconduct of any Kirin Indemnitee (as defined in the KHK Agreement);
provided in each case that (x) AVEO and the applicable sublicensee(s) comply with the procedure set forth in Section 9.3 of the KHK Agreement, and (y) such
indemnity shall not apply to the extent that AVEO has an indemnification obligation to KHK for such Loss pursuant to Section 9.1 of the KHK Agreement.
(c)
If Partner, as a sublicensee of AVEO, seeks to be indemnified by KHK with respect to a Third-Party Claim as set forth in Section 8.2(b) above
and pursuant to Section 9.2 of the KHK Agreement (“Partner Third-Party Claim”), Partner shall promptly notify
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AVEO thereof and, in order to ensure compliance with the procedure set forth in Section 9.3 of the KHK Agreement, each Party shall comply with the procedures set
forth below:
(i)
To the extent that AVEO receives prompt notice from Partner of any Partner Third-Party Claim, AVEO shall provide KHK with prompt
notice of such Partner Third-Party Claim giving rise to KHK’s indemnification obligation pursuant to Section 9.2 of the KHK Agreement and the exclusive ability to
defend (with the reasonable cooperation of AVEO and Partner, at KHK’s expense on a pass-through basis) or settle any such claim. The Parties acknowledge that,
pursuant to Section 9.3 of the KHK Agreement, KHK has agreed not to enter into any settlement for damages other than monetary damages without AVEO’s written
consent (which consent shall not be given by AVEO unless and until the Parties mutually agree to do so, such agreement not to be unreasonably withheld, delayed or
conditioned by either Party).
(ii)
The Parties acknowledge that, pursuant to Section 9.3 of the KHK Agreement, AVEO has the right to participate in the defense of any
claim or suit that has been assumed by KHK under Section 9.2 of the KHK Agreement. If requested by Partner, AVEO shall use its reasonable efforts to obtain
KHK’s consent to Partner’s participation, along with AVEO, in the defense of any claim or suit with respect to any Partner Third-Party Claim that has been assumed
by KHK under Section 9.2 of the KHK Agreement; it being understood that any participation by Partner in such suit or claim shall be conducted at Partner’s own
expense and with counsel of Partner’s own choice
(iii)
The Parties acknowledge that, pursuant to Section 9.3 of the KHK Agreement, if AVEO and KHK cannot agree as to the application of
Section 9.1 or Section 9.2 of the KHK Agreement as to any particular Partner Third-Party Claim (which agreement shall not be given or withheld by AVEO unless
and until the Parties mutually agree to do so, such agreement not to be unreasonably withheld, delayed or conditioned by either Party), AVEO and KHK may conduct
separate defenses of such Partner Third-Party Claim. In such case, as between AVEO and Partner, AVEO shall have the exclusive right to assume the defense of such
Partner Third-Party Claim, including any settlement thereof (provided that AVEO shall not enter into any settlement for damages other than monetary damages
without Partner’s written consent, which shall not be unreasonably withheld, delayed or conditioned), and Partner shall have the right to participate in such defense,
at Partner’s own expense and using counsel of Partner’s own choice. The Parties acknowledge that AVEO reserves the right, and shall use its best efforts, to claim
indemnity from KHK in accordance with Section 9.2 of the KHK Agreement upon resolution of the underlying Partner Third-Party Claim.
8.3
Procedure. To be eligible for its AVEO Indemnitees or Partner Indemnitees (as applicable) to be indemnified hereunder, a Party shall provide the
indemnifying Party with prompt notice of the Third-Party Claim giving rise to the indemnification obligation pursuant to this Article 8 and the exclusive ability to
defend (with the reasonable cooperation of the indemnified Party, at the defending Party’s expense on a pass-through basis) or settle any such claim; provided,
however, that the indemnifying Party shall not enter into any settlement other than by the payment of monetary damages without the indemnified Party’s written
consent, such consent not to be unreasonably withheld, delayed or conditioned. The indemnified Party shall have the right to participate, at its own expense and with
counsel of its choice, in the defense of any claim or suit that has been assumed by the indemnifying Party. If the Parties cannot agree as to the application of Sections
8.1 and 8.2 to any particular Third Party Claim, the Parties may conduct separate defenses of such Third Party Claim. Each Party reserves the right to claim
indemnity from the other in accordance with Sections 8.1 and 8.2 above upon resolution of the underlying claim, notwithstanding the provisions of this Section 8.3
requiring the indemnified Party to tender to the indemnifying Party the exclusive ability to defend such claim or suit.
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8.4
Insurance. Partner shall procure and maintain insurance or self- insurance, including product liability insurance, adequate to cover its obligations
hereunder and which are consistent with normal business practices of prudent companies similarly situated, at all times during which any Licensed Product is being
clinically tested in human subjects or commercially distributed or sold by or on behalf of Partner. At a minimum, prior to the first Marketing Approval of a Licensed
Product in the Partner Territory, Partner shall be insured for [**] Dollars ($[**]) to cover its obligations under this Agreement. After receipt of such Marketing
Approval, Partner shall be insured for a minimum of [**] Dollars ($[**]) to cover its obligations under this Agreement. It is understood that such insurance or self-
insurance shall not be construed to create a limit of Partner’s liability with respect to its indemnification obligations under this Article 8. Partner shall provide AVEO
with written evidence of such insurance or self-insurance upon request. Partner shall provide AVEO with written notice at least thirty (30) days prior to the
cancellation, non-renewal or material change in such insurance or self-insurance which materially adversely affects the rights of AVEO hereunder.
8.5
Limitation of Liability. EXCEPT TO THE EXTENT SUCH PARTY MAY BE REQUIRED TO INDEMNIFY THE OTHER PARTY UNDER THIS
ARTICLE 8 OR IN RESPECT OF A BREACH OF ARTICLE 6, NEITHER PARTY NOR ITS RESPECTIVE AFFILIATES AND LICENSEES (INCLUDING
SUBLICENSEES AND OTHER LICENSEES) SHALL BE LIABLE FOR SPECIAL, INCIDENTAL, EXEMPLARY, CONSEQUENTIAL OR PUNITIVE
DAMAGES, INCLUDING LOST PROFITS, ARISING OUT OF OR IN CONNECTION WITH THIS AGREEMENT, WHETHER IN CONTRACT, WARRANTY,
TORT (INCLUDING NEGLIGENCE), STRICT LIABILITY OR OTHERWISE.
ARTICLE 9.
TERM AND TERMINATION
9.1
Term. This Agreement shall become effective on the Effective Date and, unless it is earlier terminated pursuant to this Article 9, shall continue on a
Licensed Product-by-Licensed Product and country by country basis in the Partner Territory until the expiration of the Royalty Term in a country (the “Term”), at
which time Partner shall have an irrevocable, perpetual, fully paid-up, fully sublicensable, exclusive license to the Licensed Technology in respect of such Licensed
Product in such country.
9.2
Termination for Breach.
(a)
Notice. If either Party believes that the other is in material breach of this Agreement, then the non-breaching Party may deliver written notice
of such breach to the other Party. To be an effective notice under this Section 9.2(a), the written notice must (i) explicitly reference this Section 9.2, and (ii) explicitly
state that if the breach is not cured, the notifying Party will have the right to terminate this Agreement as follows: in the event of a material breach of this Agreement,
the non-breaching Party shall have the right to terminate this Agreement in its entirety (if the breach is material to the Agreement as a whole) or, if the breach is
material to the Agreement in a Partner Region, with respect to such Partner Region (according to where the breach occurs). The allegedly breaching Party shall have
ninety (90) days from receipt of such notice to cure such breach; provided that the cure period shall be thirty (30) days for breaches involving nonpayment of any
amount due hereunder.
(b)
Failure to Cure. If the Party receiving notice of breach fails to cure such breach within such ninety (90) day period (or thirty (30) day period
in the case of non-payment breaches), the Party originally delivering the notice may terminate this Agreement effective immediately upon delivery of a second
written notice to the allegedly breaching Party. Notwithstanding the foregoing: (a) except in the event the basis of the alleged material breach is
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a failure to make payment(s) under this Agreement, such ninety (90)-day cure period shall be extended for an additional ninety (90) days or such longer period as is
reasonably required to cure such breach if the breaching Party is employing ongoing, good faith efforts to cure such alleged material breach; (b) in the event the basis
of the alleged material breach is a failure to make payment(s) under this Agreement and the alleged breaching Party (i) notifies the non-breaching Party, during such
thirty (30)-day cure period, of a bona fide dispute regarding whether such payment(s) are due and (ii) pays the undisputed portion of such payment(s) on or before
providing such notice, such thirty (30)-day cure period shall be tolled pending resolution of such dispute pursuant to Section 10, and in the event the dispute is finally
resolved against the Party allegedly in material breach, the applicable cure period shall commence upon such final resolution; and (c) in the event the basis of the
alleged material breach is other than a failure to make payment(s) under this Agreement and the alleged breaching Party notifies the non-breaching Party, during such
ninety (90)-day cure period, of a bona fide dispute regarding the alleged breach, such ninety (90)-day cure period shall be tolled pending resolution of such dispute
pursuant to Section 10, and in the event the dispute is finally resolved against the Party allegedly in material breach, the applicable cure period shall commence upon
such final resolution.
9.3
Termination for Bankruptcy. This Agreement may be terminated by either Party immediately upon written notice to the other Party and to the extent
permitted under applicable laws, rules, or regulations, upon the filing or institution of bankruptcy, reorganization, liquidation or receivership proceedings, or upon an
assignment of a substantial portion of the assets for the benefit of creditors by the other Party; provided, however, that in the case of any involuntary bankruptcy
proceeding such right to terminate shall only become effective if the other Party consents to the involuntary bankruptcy or such proceeding is not dismissed within
ninety (90) days after the filing thereof.
9.4
Termination for Patent Challenge. If Partner or any of its Affiliates or Sublicensees (a) initiates or requests an interference, post-grant review, inter-
partes review, reexamination, protest, opposition, nullity or similar proceeding with respect to any Licensed Patent, (b) makes, files or maintains any claim, demand
lawsuit, or cause of action to challenge the validity or enforceability of any Licensed Patent, (c) opposes any extension of, or the grant of a supplementary protection
certificate with respect to, any Licensed Patent, or (d) funds or otherwise provides material assistance to any other Person with respect to any of the foregoing, AVEO
shall have the right to terminate this Agreement upon thirty (30) days’ prior written notice to Partner. Any such termination shall only become effective if Partner or
its Affiliate or Sublicensee, as applicable, has not withdrawn such action before the end of the above notice period.
9.5
Elective Termination. Partner shall have the right, in its sole discretion, to terminate this Agreement on a Partner Region by Partner Region basis or
in its entirety by providing not less than one hundred eighty (180) days’ prior written notice to AVEO; provided, however, that Partner shall be obligated to continue
to share in any costs of development previously agreed and committed to in writing as part of a Joint Development Plan (i.e., costs for ongoing clinical trials agreed
to prior to such termination as part of a Joint Development Plan, even where such trials continue beyond termination).
9.6
AVEO’s Rights upon Certain Terminations. Upon termination of this Agreement by AVEO under Section 9.2, 9.3 or 9.4 or by Partner under Section
9.5 (but not expiration of this Agreement):
(a)
License Termination. The licenses granted by AVEO to Partner under Article 3 shall terminate.
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(b)
Regulatory Filings. To the extent permitted by applicable law, Partner shall transfer to AVEO all filings made with a Regulatory Agency in
any jurisdiction that must be made prior to commencing clinical testing in humans, applications for Marketing Approval, Marketing Approvals, Pricing Approvals,
drug dossiers, master files and other regulatory filings and regulatory correspondence related to any Licensed Compounds or Licensed Products that it Controls as of
the effective date of such termination. If Partner is restricted under applicable law from transferring ownership of any of the foregoing items to AVEO, Partner shall
grant AVEO (or its designee) a right of reference or use to such item. Partner shall take all permitted actions reasonably necessary to effect such transfer or grant of
right of reference or use to AVEO.
(c)
Data. Partner shall transfer to AVEO its entire right, title, and interest in and to all preclinical and clinical data, Clinical Regulatory Filings,
Safety Data and all other supporting data, including pharmacology, toxicology, chemistry and biology data, in Partner’s Control as of the effective date of such
termination related to, and to the extent necessary or reasonably useful for AVEO to continue the development, manufacture or commercialization of, Licensed
Compounds and Licensed Products.
(d)
No Further Representations. Partner shall discontinue making any representation regarding its status as a licensee of AVEO in the Partner
Territory and in the Field for Licensed Compounds and Licensed Products and shall cease conducting all activities with respect to the marketing, promotion, sale or
distribution of all of the foregoing.
(e)
Transition Assistance. To the extent requested by AVEO, for a period of [**] months following the effective date of termination, Partner shall
also provide such assistance as may be reasonably necessary to transfer and/or transition over a reasonable period of time to AVEO any licenses and other contracts
specific to Licensed Compounds and Licensed Products (including clinical trial and manufacturing agreements with respect thereto), to the extent such agreements
are in effect as of the effective date of termination and such assignment is permitted.
(f)
Remaining Inventories. AVEO shall have the right to purchase from Partner all of the inventory of Licensed Products held by Partner as of
the effective date of termination at a price equal to Partner’s fully burdened manufacturing cost, determined in accordance with GAAP. AVEO shall notify Partner
within [**] months after termination whether AVEO elects to exercise such right.
(g)
Transfer of Contracts. To the extent requested by AVEO, for a period of six (6) months following the effective date of termination, Partner
shall provide, at a reasonable cost to AVEO, such assistance as may be reasonably necessary to transfer or transition over such period of time to AVEO any license
agreements or other contracts specific to Licensed Compounds and Licensed Products (including clinical trial and manufacturing agreements), to the extent such
agreements are in effect as of the effective date of termination and such assignment or transfer is permitted.
(h)
Prosecution and Enforcement. The provisions of Article 5 (other than Section 5.1) shall be terminated; provided that, as between the Parties,
AVEO shall have the sole right (but not the obligation) to prosecute, maintain and enforce all Licensed Patents and Joint Patents, and Partner shall provide such
assistance and cooperation as may be reasonably necessary in connection with the transition of prosecution and enforcement responsibilities to AVEO with respect to
any Licensed Patents and Joint Patents with respect to which Partner (or its Affiliate or Sublicensee) had prosecution, maintenance or enforcement responsibility
prior to the effective date of termination, including execution of such documents as may be necessary to effect such transition.
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(i)
Transfer of Marketing-Related Materials. Partner shall transfer to AVEO all promotional materials, customer data, competitive intelligence
data, market research and other materials, information or data related to the marketing, promotion or sale of Licensed Compounds and Licensed Products Controlled
by Partner as of the effective date of such termination, to the extent necessary or reasonably useful for the commercialization of Licensed Compounds and Licensed
Products.
(j)
Affiliates and Sublicensees.    Partner shall cause its Affiliates and Sublicensees to comply with Section 9.6 as if they were Partner.
9.7
Grant Back. Upon termination of this Agreement for any reason, Partner shall grant to AVEO, and hereby does grant, an irrevocable, perpetual,
royalty bearing, worldwide, non-exclusive license, with the right to grant sublicenses, under the Partner Patents, Partner Know-How Controlled by Partner, Joint
Inventions and Joint Patents to develop, make, have made, use, sell, offer for sale or import Licensed Compounds and Licensed Products. Royalties shall be payable
by AVEO to Partner only if AVEO uses the license to Partner Patents in the AVEO Territory, and shall be at a reasonable royalty rate to be established by an expert in
such determinations agreed to by both Parties, and otherwise on the same terms as set out herein in relation to Licensed Products and the terms of Sections 4.3.4, 4.4,
4.7, 4.8, 4.9, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15 and 4.17 shall apply mutatis mutandis.
9.8
Partner’s Rights upon Certain Terminations. Upon termination of this Agreement by Partner under Sections 9.2, 9.3 or 9.5, (a) the licenses granted
by AVEO to Partner under Article 3 shall terminate and (b) Partner shall discontinue making any representation regarding its status as a licensee of AVEO in the
Partner Territory and in the Field for Licensed Compounds and Licensed Products and shall cease conducting all activities with respect to the marketing, promotion,
sale or distribution of all of the foregoing.
9.9
Survival.
(a)
The following provisions shall survive any expiration or termination of this Agreement in its entirety: Articles 6, 8 and 10, and Sections 2.6,
2.8, 3.3(e), 4.15, 4.16 (for a period of one year post termination or expiry), 7.5, 9.1, 9.6, 9.7, 9.8, 11.2, 11.3, 11.5, 11.6, 11.7, 11.8, 11.12, 11.13, 11.14 and 11.15.
(b)
Expiration and termination of this Agreement shall not relieve the Parties of any liability which accrued hereunder prior to the effective date of
such termination nor preclude either Party from pursuing all rights and remedies it may have hereunder or at law or in equity with respect to any breach of this
Agreement nor prejudice either Party’s right to obtain performance of any obligation.
ARTICLE 10.
DISPUTE RESOLUTION
10.1
Seeking Consensus. If any dispute, controversy or claim arising out of or relating to the validity, construction, enforceability, performance or breach
of this Agreement arises between the Parties (a “Dispute”), then upon the written request of either Party, the Parties shall have senior executives with decision-
making authority of each Party meet and discuss the matter in good faith. The written request shall explain the nature of the Dispute and refer to the relevant
provisions of the Agreement upon which the Dispute is based. The complaining Party shall also set forth a proposed solution to the problem, including a suggested
time frame within which the Parties must act. The non-complaining Party must respond in writing within [**] days of receiving the notice with an explanation,
including references to the relevant provisions of the
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Agreement and a response to the proposed solution and suggested time frame for action. The complaining Party must initiate the scheduling of this resolution
meeting. The Parties shall have such senior executives, and other personnel as necessary, meet within [**] days after the initial request in writing by either Party. The
Parties shall discuss possible options for resolving the Dispute, including a discussion of whether mediation may be a useful mechanism for resolving the Dispute;
provided that neither Party shall be obligated to enter into or participate in mediation. If the matter is not resolved within [**] following the request for discussions,
and the Parties have not agreed upon mediation, then either Party may then invoke arbitration in accordance with this Article 10. If mediation takes place and is
unsuccessful, then either Party may then invoke arbitration in accordance with this Article 10.
10.2
Arbitration.
(a)
Notice of Arbitration. Any Dispute which may arise between the Parties that is not resolved pursuant to Section 10.1 shall be settled by
binding arbitration as set forth in this Section 10.2, excluding any Patent Disputes as specified in Section 10.5 (which shall be resolved pursuant to Section 10.5).
Either Party, following the end of the [**] day period referenced in Section 10.1, may refer such issue to arbitration by submitting a written notice of such request to
the other Party.
(b)
Selection of Arbitrators. The number of arbitrators to resolve any Dispute submitted to arbitration under Section 10.2(a) shall be three (3).
Each Party shall select one (1) arbitrator within [**] days following receipt of notice under Section 10.2(a), and the two arbitrators selected by the Parties shall be
responsible for selecting the third arbitrator. Each arbitrator shall be neutral and independent of both Parties and all of their respective Affiliates, shall have
significant experience and expertise in licensing and partnering agreements in the pharmaceutical and biotechnology industries. If the two arbitrators selected by the
Parties cannot agree on a third arbitrator within [**] days following either Party’s request for arbitration hereunder, then such third arbitrator shall be appointed by
JAMS, Inc. which arbitrator must meet the foregoing criteria.
(c)
Location; Proceedings. The place of arbitration shall be New York, New York. The proceedings shall be conducted pursuant to the rules set
forth by JAMS, Inc. for streamlined arbitration proceedings. All proceedings and communications shall be in English. Each Party shall have the right to be
represented by counsel of its own choosing.
(d)
Discovery. The Parties agree that discovery appropriate to the issues in the dispute shall be permitted in the arbitration, including reasonable
document requests, pre-hearing exchanges of information, expert witness disclosures, limited depositions of important witnesses and other appropriate discovery;
provided that such discovery shall be limited to the narrower of (i) the scope of discovery agreed to by the Parties, or if none can be agreed, established by the
arbitrators, and (ii) such discovery as would be permitted by the Federal Rules of Civil Procedure and is approved by the arbitrators, keeping in mind the goal of an
expedited and efficient proceeding.
(e)
Procedural Rules; Statute of Limitations. The arbitration shall be governed by the procedural and substantive law set forth in Section 10.3.
The statute of limitations of the State of New York applicable to the commencement of a lawsuit shall apply to the commencement of arbitration under this Article
11; provided that such statute of limitations shall be tolled with respect to the subject matter of any Dispute upon delivery of a Party’s written request under
Section 10.1 relating to such Dispute; provided, further, that if the senior executives are unable to resolve such Dispute within the [**] day period specified in
Section 10.1, the Parties agree to file the notice of arbitration within [**] days thereafter.
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(f)
Costs. Each Party shall bear its own costs and expenses and attorneys’ fees in the arbitration, except that the arbitrators may order the non-
prevailing Party to bear all or an appropriate part (reflective of the relative success on the issues) of the costs and expenses and reasonable attorneys’ fees incurred by
the prevailing Party based on the relative merits of each Party’s positions on the issues in the Dispute. The Party that substantially prevails in the arbitration
proceeding shall be reimbursed any payments it has made in respect of the arbitrators’ fees and expenses and any administrative fees of arbitration.
(g)
Award. Any award rendered by the arbitrators shall be final and binding on the Parties, and shall be governed by the terms and conditions
hereof, including the limitation on damages set forth in Section 8.5. Any award to be paid by one Party to the other Party as determined by the arbitrators shall be
promptly paid in Dollars free of any tax, deduction or offset; and any costs, fees or taxes incident to enforcing the award shall, to the maximum extent permitted by
applicable law, be charged against the Party resisting enforcement. Each Party agrees to abide by the award rendered in any arbitration conducted pursuant to this
Article 10, judgment may be entered upon the final award in any court of competent jurisdiction, including any court of competent jurisdiction in the United States or
in Japan. The award shall include interest from the date of any damages incurred for breach of the Agreement, and from the date of the award until paid in full, at the
rate set forth in Section 4.17.
(h)
Confidentiality. All proceedings and decisions of the arbitrator shall be deemed Confidential Information of each of the Parties, and shall be
subject to Article 6. Except as required by applicable law, neither Party shall make (or instruct the arbitrator to make) any public announcement with respect to the
proceedings or decision of the arbitrators without prior written consent of the other Party. The existence of any dispute submitted to arbitration, and the award, shall
be kept in confidence by the Parties and the arbitrators, except as required in connection with the enforcement of such award or as otherwise required by applicable
law.
(i)
Survivability. Any duty to arbitrate under this Agreement shall remain in effect and be enforceable after termination of this Agreement for any
reason.
10.3
Governing Law. This Agreement shall be governed by and construed under the substantive laws of the State of New York, excluding any conflicts or
choice of law rule or principle that might otherwise refer construction or interpretation of this Agreement to the substantive law of another jurisdiction.
10.4
Injunctive Relief; Remedy for Breach of Exclusivity. Nothing in this Article 10 will preclude either Party from seeking equitable relief or interim or
provisional relief from a court of competent jurisdiction, including a temporary restraining order, preliminary injunction or other interim equitable relief, concerning a
dispute either prior to or during any arbitration if necessary to protect the interests of such Party or to preserve the status quo pending the arbitration proceeding.
Specifically, the Parties agree that a material breach by either Party of its obligations in Article 6 of this Agreement may cause irreparable harm to the other Party, for
which damages may not be an adequate remedy. For the avoidance of doubt, nothing in this Section 10.4 shall otherwise limit a breaching Party’s opportunity to cure
a material breach as permitted in accordance with Section 9.2.
10.5
Patent Disputes. Notwithstanding Section 10.2, any Dispute relating to the scope, validity, enforceability or infringement of any Licensed Patents,
Partner Patents or Joint Patents shall be submitted to a court of competent jurisdiction in the country in which such Patent rights were granted or arose.
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ARTICLE 11.
MISCELLANEOUS
11.1
Export Control. This Agreement is made subject to any restrictions concerning the export of products or technical information from the United States
or other countries which may be imposed upon or related to AVEO or Partner from time to time. Each Party agrees that it shall not export, directly or indirectly, any
technical information acquired from the other Party under this Agreement or any products using such technical information to a location or in a manner that at the
time of export requires an export license or other governmental approval, without first obtaining the written consent to do so from the appropriate agency or other
governmental entity.
11.2
Entire Agreement; Amendment. This Agreement (including the Exhibits hereto) sets forth the complete, final and exclusive agreement and all the
covenants, promises, agreements, warranties, representations, conditions and understandings between the Parties hereto and supersedes and terminates all prior
agreements and understandings between the Parties (including the Prior Agreement with respect to Confidential Information). There are no covenants, promises,
agreements, warranties, representations, conditions or understandings, either oral or written, between the Parties other than as are set forth herein and therein. No
subsequent alteration, amendment, change or addition to this Agreement shall be binding upon the Parties unless reduced to writing and signed by an authorized
officer of each Party.
11.3
Bankruptcy. All rights and licenses granted under or pursuant to this Agreement by either Party to the other are and shall be deemed to be, for
purposes of Section 365(n) of the U.S. Bankruptcy Code, licenses of rights to “intellectual property” as defined under Section 101(52) of the U.S. Bankruptcy Code.
Each Party agrees that the other Party, as a licensee of such rights under this Agreement, shall retain and may fully exercise all of its rights and elections under the
U.S. Bankruptcy Code. Without limiting the foregoing, the Parties further agree that if a bankruptcy proceeding is commenced by or against one Party (the “Debtor”)
then, in the event the Debtor rejects this Agreement pursuant to Section 365 of the U.S. Bankruptcy Code or otherwise applicable law and the other Party elects to
retain its rights hereunder pursuant to Section 365(n) of the U.S. Bankruptcy Code or otherwise applicable law, the other Party shall be entitled to a complete
duplicate of (or complete access to, as appropriate) any such intellectual property and all embodiments of such intellectual property. The Parties further agree,
without limiting the foregoing, that unless and until the Debtor rejects this Agreement pursuant to applicable law, the Debtor shall perform all of its obligations
hereunder or immediately provide to the other Party a complete duplicate of (or complete access to, as appropriate) any such intellectual property and all
embodiments of such intellectual property, and the same, if not already in the other Party’s possession; provided, however, that upon assumption of this Agreement by
the Debtor pursuant to Section 365 of the U.S. Bankruptcy Code or otherwise applicable law, the other Party shall promptly return all such tangible materials,
intellectual property and embodiments thereof that have been provided to it solely as a result of this Section 11.3.
11.4
Force Majeure. Both Parties shall be excused from the performance of their obligations under this Agreement to the extent that such performance is
prevented by a Force Majeure and the nonperforming Party promptly provides notice of the prevention to the other Party. Such excuse shall be continued so long as
the condition constituting Force Majeure continues and the nonperforming Party takes reasonable efforts to remove the condition. For purposes of this Agreement,
“Force Majeure” means conditions beyond a Party’s reasonable control or ability to plan for, including acts of God, war, terrorism, civil commotion, labor strike or
lock-out, epidemic, failure or default of public utilities or common carriers, and destruction of production facilities or materials by fire, earthquake, storm or like
catastrophe; provided,
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however, the payment of invoices due and owing hereunder shall not be excused by reason of a Force Majeure affecting the payor.
11.5
Notices. Any notice required or permitted to be given under this Agreement shall be in writing, shall specifically refer to this Agreement and shall be
deemed to have been sufficiently given for all purposes if mailed by first class certified or registered mail, postage prepaid, express delivery service or personally
delivered. Unless otherwise specified in writing, the mailing addresses of the Parties shall be as described below.
If to Partner:
EUSA Pharma (UK) Limited
Breakspear Park,
Breakspear Way,
Hemel Hempstead, HP24TZ
United Kingdom
Attention: Chief Executive Officer
In the case of AVEO:
AVEO Pharmaceuticals, Inc.
One Broadway, 14  Floor
Cambridge, Massachusetts 02142
Attention: Chief Executive Officer
Copy to: VP Corporate Development and Alliance Management
Facsimile: (617) 995-4995
with a required copy to:
Choate, Hall & Stewart
Two International Place
Boston, MA 02110
Attn: Robert A. Licht, Esq.
11.6
Maintenance of Records. Each Party shall keep and maintain all records required by law or regulation with respect to Licensed Products and shall
make copies of such records available to the other Party upon request.
11.7
Construction. This Agreement has been prepared jointly and shall not be strictly construed against either Party. Any reference in this Agreement to an
Article, Section, subsection, paragraph, clause, or Exhibit shall be deemed to be a reference to any Article, Section, subsection, paragraph, clause, or Exhibit, of or to,
as the case may be, this Agreement. Except where the context otherwise requires, (a) any definition of or reference to any agreement, instrument or other document
refers to such agreement, instrument other document as from time to time amended, supplemented or otherwise modified (subject to any restrictions on such
amendments, supplements or modifications set forth herein or therein), (b) any reference to any laws refers to such laws as from time to time enacted, repealed or
amended, (c) the words “herein,” “hereof” and hereunder,” and words of similar import, refer to this Agreement in its entirety and not to any particular provision
hereof, (d) the words “include,” “includes” and “including” shall be deemed to be followed by the phrase “but not limited to,” “without limitation” or words of
similar import, and (e) the word “or” has the inclusive meaning represented by the phrase “and/or”, (f) the words “date hereof” refers to the Effective Date, (g) the
word “extent” in the phrase “to the extent” means the degree to which a subject or other thing
th
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extends, and such phrase does not mean simply “if”; and (g) definitions contained in this Agreement are applicable to the singular as well as the plural forms of such
terms.
11.8
Ambiguities. Ambiguities, if any, in this Agreement shall not be construed against any Party, irrespective of which Party may be deemed to have
authored the ambiguous provision.
11.9
Assignment. Neither this Agreement nor any right or obligation hereunder may be assigned or otherwise transferred by any Party without the consent
of the other Party; provided, however, that any Party may, without such consent, assign this Agreement, (a) in whole or in part (divided on a geographic basis but not
otherwise), to any of its respective Affiliates; provided that such Party shall remain jointly and severally liable with such Affiliate in respect of all obligations so
assigned; such Affiliate has acknowledged and confirmed this in writing effective as of such assignment or other transfer; and such Affiliate shall be bound by this
Agreement as if it were a party to it as and to the identical extent applicable to the transferor; or (b) as a whole, if either Party merges with, or all or substantially all
of its business or assets are acquired by, another entity (whether by merger, sale of assets, sale of stock, by way of security to a bank or other financial institution, or
otherwise) (an “M&A Event”), to the Party’s merger partner or the acquirer as part of that M&A Event. Each Party agrees that, notwithstanding any provisions of
this Agreement to the contrary, if this Agreement is assigned by a Party in connection with an M&A Event, such assignment shall not provide the non-assigning Party
with rights or access to intellectual property or technology of the acquirer of the assigning Party. Any permitted assignment shall be binding on the successors of the
assigning Party. Any assignment or attempted assignment by either Party in violation of the terms of this Section 11.9 shall be null and void.
11.10 Independent Contractors. It is expressly agreed that AVEO and Partner shall be independent contractors and that the relationship between them shall
not constitute a partnership, joint venture or agency. Neither AVEO nor Partner shall have the authority to make any statements, representations or commitments of
any kind, or to take any action, which shall be binding on the other Party, without the prior written consent of the other Party to do so.
11.11 Counterparts. This Agreement may be executed in two (2) or more counterparts, each of which shall be deemed an original, but all of which together
shall constitute one and the same instrument. Signature pages may be exchanged electronically in portable document format (.pdf) form.
11.12 Severability. If any provision of this Agreement is held to be invalid or unenforceable in the alternative dispute resolution proceedings specified in
Article 10 from which no court appeal can be or is taken, the provision shall be considered severed from this Agreement and shall not serve to invalidate any
remaining provisions hereof. The Parties shall make a good faith effort to replace any invalid or unenforceable provision with a valid and enforceable one such that
the objectives contemplated by the Parties when entering this Agreement may be realized.
11.13 Headings. The headings for each article and section in this Agreement have been inserted for convenience of reference only and are not intended to
limit or expand on the meaning of the language contained in the particular article or section.
11.14 No Waiver. Any delay in enforcing a Party’s rights under this Agreement or any waiver as to a particular default or other matter shall not constitute a
waiver of such Party’s rights to the subsequent enforcement of its rights under this Agreement, excepting only as to an
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express written and signed waiver as to a particular matter for a particular period of time executed by an authorized officer of the waiving Party.
11.15 No Third Party Beneficiaries. Except as expressly set forth in this Agreement, no Third Party shall be deemed an intended third party beneficiary
hereunder or have any right to enforce any obligation of this Agreement.
11.16 Costs. Each Party shall bear its own legal costs of and incidental to the preparation, negotiation and execution of this Agreement.
11.17 Further Assurances. Each Party shall perform, or caused to be performed, all further acts and things and execute and deliver such further documents
as may be necessary or as the other Party may reasonably require to implement or give effect to this Agreement
[signature page follows]
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IN WITNESS WHEREOF, Partner and AVEO have caused this Agreement to be executed by their duly authorized officers as of the Effective Date.
EUSA PHARMA (UK) LIMITED     AVEO PHARMACEUTICALS, INC.
By:    /s/ Lee Morley                By:    /s/ Michael Bailey            
Name:    Lee Morley                Name:
Title:    CEO                    Title:    President & Chief Executive Officer
- 61 -


FIRST AMENDMENT TO SUBLEASE AGREEMENT
30 WINTER STREET
Boston, Massachusetts
This First Amendment to Sublease Agreement (this “Agreement”) is dated as of November 17, 2021 (“Effective Date”) by and between Commonwealth
Care Alliance, Inc., a Massachusetts not-for-profit corporation (“Sublandlord”; sometimes also referred to as “Tenant”), and AVEO Pharmaceuticals, Inc., a
Delaware corporation (“Subtenant”).
Background
A.
Sublandlord and Subtenant have entered into that certain Sublease Agreement (the “Sublease”) dated as of March 5, 2020, covering the Sublease
Premises, more specifically described in the Sublease consisting of 6,465 square feet of the third (3rd) floor area (the “Third Floor Space”) and 3,693 square feet of
the sixth (6th) floor area (the “Sixth Floor Space” and together with the Third Floor Space, the “Sublease Premises”), of the building located at 30 Winter Street,
Boston, Massachusetts (the “Building”), as more particularly described in the Master Lease (as defined below), upon the terms and conditions contained therein.
B.
TFC 30 Winter LLC, a Massachusetts limited liability company (“Landlord”) and Tenant are parties to that certain Lease dated as of January 26,
2007 (the “Original Lease”), as amended by (i) that certain First Amendment to Lease dated as of September 2008; (ii) that certain Second Amendment to Lease
dated December 2010; (iii) that certain Third Amendment to Lease dated as of January 23, 2013; (iv) that certain Fourth Amendment to Lease dated as of March
26, 2014; (v) that certain Fifth Amendment to Lease dated as of October 1, 2014; (vi) that certain Sixth Amendment to Lease dated as of July, 2017 and (vii) that
certain Seventh Amendment to Lease of even date herewith (the Original Lease, as amended, collectively referred to as the “Master Lease”) whereby Landlord
leased to Sublandlord certain master premises consisting of approximately 55,636 square feet of rentable area (the “Master Premises”).
C.
Reference is made to that certain Consent to Sublease dated April 2, 2020 by and among Landlord, Tenant and Subtenant (the “Original Landlord
Consent”).
D.
Provided Landlord enters into a written lease for the entire sixth floor of the Building (the “Replacement Lease”) by November 15, 2021,
Sublandlord and Subtenant agree to amend the Sublease to terminate the Sublease with respect to the Sixth Floor Space prior to the scheduled expiration date
thereof, and the Sublease shall remain in effect as to the Third Floor Space. Pursuant to the Master Lease, Tenant must obtain Landlord’s consent to any
amendment to the Sublease. Tenant has requested Landlord’s consent to this Agreement.
Agreement

NOW THEREFORE, in consideration of the mutual covenants herein contained and other good and valuable consideration, the receipt and
sufficiency of which is hereby acknowledged, Sublandlord and Subtenant hereby agree as follows:
1.
Partial Termination. Subject to the terms and conditions contained herein, (A) the Sublease with respect to the Sixth Floor Space, shall terminate at
11:59 p.m. on December 1, 2021 (the “Early Termination Date”), as though such date were the initially scheduled Expiration Date under the Sublease for the Sixth
Floor Space, and (B) from and after the Early Termination Date, Subtenant shall not be responsible for base rent, additional rent (including any charges for HVAC
or electricity supplied to the Sixth Floor Space) or other amounts coming due under the Sublease from and after the Early Termination Date with respect to the
Sixth Floor Space. Except as expressly set forth herein, the Sublease shall continue in full force and effect with respect to the Third Floor Space; provided,
however that the Security Deposit currently being held by Sublandlord in the amount of $327,132.90 pursuant to the terms of the Sublease shall be retained by
Sublandlord and applied toward the remaining base rent payable to Sublandlord for the Third Floor Space in accordance with Section 5(a) of the Sublease, and
shall be deemed to satisfy in full the amounts due to Sublandlord for the base rent obligations for the Third Floor Space through the Expiration Date and shall be
deemed to satisfy charges to be paid by Subtenant to Sublandlord for HVAC or electricity supplied to the Third Floor Space through the Expiration Date. As of the
Early Termination Date, Subtenant shall have no right or claim to its Security Deposit and Sections 5(d) and 5(e) of the Sublease shall be deleted.
2.
Surrender. Subtenant shall vacate and surrender the Sixth Floor Space to Sublandlord on or before the Early Termination Date, free and clear of all
personal property and equipment and shall leave the Sixth Floor Space in broom clean condition on or before the Early Termination Date and otherwise in
accordance with the terms of the Sublease. If Subtenant fails so to vacate and surrender the Premises as of such date, Subtenant shall be a tenant at sufferance
therein pursuant to the terms of the Sublease, as amended.
3.
Replacement Lease. Sublandlord and Subtenant acknowledge and agree that the early termination of the Sublease as to the Sixth Floor Space as
described herein is conditioned upon the full execution and delivery of the Replacement Lease (and Landlord is under no obligation to Sublandlord or Subtenant to
enter into the Replacement Lease). In the event the Replacement Lease is not fully executed by November 15, 2021, this Agreement shall be automatically deemed
null and void. Subtenant and Sublandlord acknowledge and agree that Landlord shall, at its cost, perform or cause to be performed certain work in the Sixth Floor
Space and the Third Floor Space in accordance with Section 1 of the Seventh Amendment to Lease of even date herewith (amending the Master Lease) by and
between Sublandlord and Landlord (the “Reduction Work”). The Reduction Work shall not impose any cost or increase the obligations of Sublandlord or
Subtenant. Neither the submission of this instrument for signature, nor any draft thereof, shall constitute an offer by Sublandlord to terminate the Sublease with
respect to the Sixth Floor Space.
4.
Brokers. Sublandlord and Subtenant each represent and warrant to the other that they have not dealt with any broker in connection with this
Agreement. Sublandlord and Subtenant each agree to defend, indemnify and hold the other harmless from and against all claims by any broker for fees,
commissions or other compensation to the extent such broker

alleges to have been retained by the indemnifying party in connection with the execution of this Agreement. The provisions of this paragraph shall survive the
expiration or sooner termination of the Sublease.
5.
Ratification. Except as set forth herein, the terms of the Sublease are hereby ratified and confirmed. This Agreement may not be orally changed or
terminated, nor any of its provisions waived, except by an agreement in writing signed by the party against whom enforcement of any changes, termination or
waiver is sought. All references in the Sublease to the "Sublease" shall refer to the Sublease as modified by this Agreement. Defined terms not otherwise defined
in this Agreement shall have the definitions ascribed to them in the Sublease.
6.
Counterparts. This Agreement may be executed in two (2) or more counterparts, each of which shall be an original but together shall constitute one
and the same instrument. Without limiting the generality of the foregoing, the parties agree that counterparts may be exchanged by electronic “.pdf” signature and
when both Landlord and Tenant have signed and delivered at least one such electronic counterpart, each shall be deemed an original and, when taken together
with the other, shall constitute one and the same Agreement which shall be binding upon and effective as to Sublandlord and Subtenant. This Agreement when
executed and delivered by both parties shall be binding upon, and inure to the benefit of the parties hereto and their respective legal representatives, successors,
and assigns.
[signature page follows]

Executed to take effect as a sealed Massachusetts instrument as of the date first written above.
SUBLANDLORD:    Commonwealth Care Alliance, Inc.,
a Massachusetts not-for-profit corporation
By:         Name:         Title:         
SUBTENANT:    AVEO Pharmaceuticals, Inc.,
a Delaware corporation
By:         Name:         Title:         

LANDLORD’S CONSENT
The undersigned Landlord does hereby consent to the foregoing First Amendment to Sublease, provided that the terms and conditions of the Original
Landlord Consent are hereby incorporated by reference and Landlord, by signing below, and Sublandlord and Subtenant by signing above, hereby ratify and agree
to the provisions of the Original Landlord Consent as applied to the Sublease as amended by the foregoing First Amendment to Sublease; provided, however, the
last two sentences of Section 1(n) of the Original Landlord Consent shall not apply to the base rent payable by Subtenant to Sublandlord pursuant to Section 1 of
the foregoing First Amendment to Sublease. In the event Subtenant and Landlord execute a temporary license agreement granting Subtenant use of the Sixth Floor
Space following the Early Termination Date, then, as between Sublandlord and Landlord, such use of the Sixth Floor Space by Subtenant shall not constitute a
holdover in the Sixth Floor Space by Sublandlord or Subtenant under the Master Lease.
LANDLORD:    TFC 30 Winter LLC,
a Massachusetts limited liability company
By: Fallon Management Company LLC, its Manager
By:     Name:     Title:     

REVOCABLE TEMPORARY LICENSE AGREEMENT
THIS REVOCABLE TEMPORARY LICENSE AGREEMENT (this “License”)
dated as of November 17, 2021 is entered into between TFC 30 Winter LLC, a Massachusetts limited liability company (“Licensor”), and AVEO
Pharmaceuticals, Inc., a Delaware corporation (“Licensee”).
BACKGROUND
A.
Licensor is the owner of that certain building located at 30 Winter Street, Boston, Massachusetts (the “Building”).
B.
Licensee currently subleases approximately 3,693 square feet of rentable space on the 6th floor (the “Sixth Floor Space”) from
Commonwealth Care Alliance, Inc., a Massachusetts not-for-profit corporation, a tenant of Licensor, which sublease expires December 1, 2021 with
respect to such space. In consideration of the covenants of Licensee hereunder, Licensor has agreed to grant Licensee, and Licensee has agreed to
accept from Licensor, a direct, temporary license to use such Sixth Floor Space for office use, which license shall be upon the terms and conditions
hereinafter set forth.
AGREEMENT
FOR VALUE RECEIVED, Licensor and Licensee agree as follows:
1.
License. Licensor hereby grants to Licensee and Licensee hereby accepts from Licensor a license to enter into and use the that
rentable space containing approximately 3,693 square feet of rentable space on the 6th floor and shown on the plan attached hereto as Exhibit A
(the “Licensed Premises”) solely for the Permitted Uses (hereinafter defined) and otherwise subject to the terms of this License. As used herein, the
term “Permitted Uses” shall mean general office use in compliance with applicable laws, codes and ordinances.
2.
License Term. The term of this License (the “Term”) shall commence at 12:01 a.m. on December 2, 2021 (the “Term Commencement
Date”) and shall end on the date (the “Expiration Date”) that is the earlier of (a) December 31, 2021 or (b) the date on which Licensor substantially
completes certain refurbishment work on the third (3 ) floor of the Building (the “Third Floor Work”) as determined by Licensor; provided that
Licensor shall notify Licensee of the anticipated date of the substantial completion of the Third Floor Work at least two (2) business days in advance
of such date. Either party may terminate this License by at least five (5) days’ prior written notice to the other, without cause, in which case the date
set forth in such notice shall be the Term Expiration Date.
3.
Licensed Premises. Licensee acknowledges and agrees that it is currently in possession of the Licensed Premises, that it has inspected
the Licensed Premises and
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accepts the same on an “AS IS, WHERE IS” basis, it being expressly agreed that Licensor shall have no obligation, liability or risk whatsoever with
respect to the Building, the Licensed Premises or their condition. Licensee further acknowledges and agrees that neither Licensor nor any agent or
employee of Licensor has made any representations or warranties, express or implied, concerning the Building, the Licensed Premises or their
condition. Licensee shall make no alterations or improvements to the Licensed Premises without Licensor's prior written consent, which consent
may be granted or withheld in Licensor’s sole discretion. Licensor and its agents or designees reserve the right to enter and examine and show the
Licensed Premises, and to perform work therein, at any time and from time to time upon reasonable prior notice to Licensee.
4.
License Fee/Additional Charges/Utilities.
(a)
License Fee. Licensee shall not be obligated to pay a license fee in connection with the use of the Licensed Premises.
(b)
Additional Charges. Licensee shall pay to Licensor for any special or non-customary services performed at Licensee’s request,
or additional costs incurred in the Licensed Premises or on account of Licensee, for which Licensor is normally compensated a separate
reimbursement, at reasonable rates established by Licensor. Notwithstanding the foregoing, Licensee shall not be charged for HVAC or electricity
costs on account of the Licensed Premises during the Term.
5.
Licensor's Services. Licensor shall provide Licensee with reasonable access to the Licensed Premises and shall otherwise have no other
obligation to provide Licensee with any services, utilities, facilities or supplies for the Licensed Premises except the utilities and systems serving the
Licensed Premises as of the commencement date of this License. If Licensor is prevented or delayed from providing any such service, or perform any
other obligation under this License, by reason of any cause, then Licensor shall not be liable to Licensee therefor, and Licensee shall not be entitled to
any reduction or abatement of amounts due hereunder.
6.
Signage. No sign, advertisement or notice (“Signage”) shall be exhibited, painted or affixed by Licensee on any part of the exterior
façade or windows of the Licensed Premises or any part of the interior of the Licensed Premises, if visible from the exterior of the Licensed
Premises, without Licensor’s prior written consent, which consent may be withheld in Licensor’s sole discretion. Licensor reserves the right to
require that Licensee remove, relocate or shield any Signage that is exhibited, painted or affixed by Licensee on the interior portions of the Licensed
Premises or that is visible from the exterior of the Licensed Premises.
7. Licensee's Personnel and Building/Insurance.

(a)
Licensee, its personnel and visitors, and their property, from time to time in the Licensed Premises or elsewhere in the Building
(or in transit thereto or therefrom) shall be at Licensee's risk, and to the maximum extent permitted by law Licensor shall not be liable for any
damage or injury to such parties or their property. If any claim is brought against Licensor (or any affiliate of Licensor) by Licensee, or any of its
personnel or visitors, on account of any injury, loss, theft or damage to any person or property while on or in the Licensed Premises, or in connection
with any condition within the Licensed Premises, then Licensee shall indemnify, defend, hold harmless and reimburse Licensor (and its affiliates) for
any loss, cost, damage or expense (including reasonable attorneys' fees) arising from such claim except to the extent that such claim results from
Licensor's negligence or willful misconduct, which obligations of Licensee shall survive the expiration or earlier termination of this License.
(b)
Until this License is revoked or terminated, Licensee shall maintain commercial general liability insurance coverage insuring
Licensor (and Licensor’s designated affiliates, managing agent and mortgagee), against all claims, demands or actions for injury, death and property
damage in the minimum amount of $1,000,000 per occurrence and $2,000,000 in the aggregate. Any insurance carried by either party with respect to
the Licensed Premises or property therein or occurrences thereon shall include a clause or endorsement denying to the insurer rights of subrogation
against the other party to the extent rights have been waived by the insured hereunder prior to the occurrence of injury or loss. Each party,
notwithstanding any provisions of this License to the contrary, hereby waives any rights of recovery against the other for injury or loss due to
hazards covered by such insurance to the extent of indemnification received hereunder. Evidence that Licensee has obtained such insurance shall be
provided to Licensor prior to occupying the Licensed Premises and thereafter upon Licensor’s request.
8.
Revocation and Termination. This License is at the pleasure and discretion of Licensor and, in addition to the termination rights
provided elsewhere in this License, is revocable at any time upon five (5) days prior written notice from Licensor to Licensee in the event that
Licensee is in breach of any of the covenants herein. Licensee waives any statutory notices and other legal process relating to tenancies and
acknowledges that Licensee is not a tenant and has no property or possessory rights in or to the Licensed Premises, but only a revocable license to
enter onto the Licensed Premises for temporary use. Licensee shall vacate the Licensed Premises to Licensor on the date of revocation or termination
of this License in as good condition as on the Term Commencement Date or in such better condition as the Licensed Premises may be put hereafter
(reasonable wear and tear excepted). Upon revocation or termination of this License, Licensee shall have no further rights in or access to the
Licensed Premises and Licensor shall continue to have possession of the Licensed Premises with the right to lease or license the same to any party. If
Licensee fails to vacate the Licensed Premises upon revocation or termination of this License, at Licensor’s election, Licensee shall pay to Licensor a
holdover license fee equal to 200% of the market license fee for the Licensed Premises (as determined by Licensor) for any month or partial month
during which such holdover continues. Upon

revocation or termination of this License, Licensee shall remove all of Licensee’s goods, effects and property that Licensee is directed to remove,
and if Licensee fails to remove such items, then Licensor may have them removed and stored in a public warehouse, all at the expense and risk of
Licensee. If such items are not removed from storage within thirty
(30) days, such items may be sold by any customary methods in order to pay storage costs and other expenses of Licensee. Licensee acknowledges
that time is of the essence in vacating the Licensed Premises at the expiration of the Term.
9.
Compliance with Legal Requirements. Licensee shall not cause or permit the Licensed Premises or the Building to be used in any
way that violates any law, code, ordinance, restrictive covenant, encumbrance, governmental regulation, order, permit, or approval (each a “Legal
Requirement”), annoys or interferes with the rights of tenants of the Building, or constitutes a nuisance or waste. Licensee shall obtain and pay for
all permits, including any requisite certificates of occupancy, and shall promptly take all actions necessary to comply with all Legal Requirements
regulating Licensee's use of the Licensed Premises or the Building. Licensee shall maintain in full force and effect all certifications or permissions
to provide its services required by any authority having jurisdiction to authorize, franchise or regulate such services.
10.
Successors and Assigns; Licensor's Liability. Licensee's rights under this License are for the benefit only of the Licensee named herein.
Licensee shall not assign, sublicense, or transfer any of its rights under this License, and shall not permit any other party to use or occupy the
Licensed Premises. Licensor may transfer its rights and obligations under this License to a successor owner of the Building. Licensee agrees to look
only to Licensor's interest in the Building for satisfaction of any claim against Licensor, or its successors, and not to any other property or assets of
Licensor, or its successors. If the Building is transferred, then from and after such transfer Licensee shall look solely to the interests in the Building of
each transferee for the performance of Licensor's obligations under this License. If the Building is transferred to an institutional lender providing
financing for the Building, then Licensee agrees such lender shall have no liability under this License for any breaches occurring prior to the date it
acquires title to and possession of the Building. The obligations of Licensor shall not be binding on any partners (or trustees or beneficiaries) of
Licensor or of any successor, individually, but only upon Licensor's or such successor's interest described above. In no event shall Licensor, or its
successors, be liable for any indirect or consequential damages.
11.
Brokers. Licensee warrants that it has had no dealings with any broker or agent in connection with this License or any other space in
the Building. Licensee covenants to pay, hold harmless and indemnify Licensor from and against any and all costs, expense or liability for any
compensation, commissions and charges claimed by any broker or agent with respect to this License or the negotiation thereof arising from a breach
of the foregoing warranty.

12.
Miscellaneous. Any notice given under or in connection with this License shall be effective only if given in writing and shall be
deemed duly served if and when hand delivered or if and when mailed prepaid certified mail (in either case, whether or not accepted for delivery) to
the following addresses:
If to Licensor:
TFC 30 WINTER LLC
c/o The Fallon Company One Marina Park Drive Boston, MA 02210
and
DLA Piper LLP (US)
33 Arch Street, 26th Floor Boston, MA 02110
Attention: Geoff A. Howell, Esq. If to Licensee:
Aveo Pharmaceuticals, Inc. 30 Winter Street, 3  Floor Boston, Massachusetts 02108
Attention: Michael Bailey
Either party may from time to time designate other addresses within the continental United States by notice to the other. If Licensee shall breach any
of the terms or conditions of this License, Licensee shall reimburse Licensor for any expenses, including reasonable attorneys' fees, incurred in
enforcing any obligations of Licensee under this License with which Licensee has failed to comply. This License shall be construed as a sealed
Massachusetts instrument, contains all of the agreements between the parties with respect to the Licensed Premises, and may be amended only in
writing by an instrument signed by all of the parties hereto. No provision of this License shall be deemed to have been waived by either party unless
such waiver is in writing and is signed by the party to be charged.
This License may be executed in two (2) or more counterparts, each of which shall be an original but together shall constitute one and the same
instrument. Without limiting the generality of the foregoing, the parties agree that counterparts may be exchanged by electronic “.pdf” signature and
when both Licensor and Licensee have signed and delivered at least one such electronic counterpart, each shall be deemed an original and, when
taken together with the other, shall constitute one and the same License which shall be binding upon and effective as to Licensee and Licensor. This
License when executed
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and delivered by both parties shall be binding upon, and inure to the benefit of the parties hereto and their respective legal representatives,
successors, and assigns.
[Remainder of page left intentionally blank; signature page follows]

EXECUTED to take effect as a sealed instrument.
LICENSOR:
TFC 30 WINTER LLC, a Massachusetts limited liability company
By: Fallon Management Company LLC, its Manager
By:     Name:     Title:     
LICENSEE:
AVEO Pharmaceuticals, Inc., a Delaware corporation
By:     Name:     Title:     

Exhibit A
Plan of Licensed Premises [to be attached]

    
SUBSIDIARIES OF THE REGISTRANT
Name             Jurisdiction of Organization             Percentage Ownership    
AVEO Pharma Limited    United Kingdom    100%
AVEO Securities Corporation    Massachusetts    100%
AVEO Pharma (Ireland) Limited    Ireland    100%

Exhibit 23.1
Consent of Independent Registered Public Accounting Firm
We consent to the incorporation by reference in the following Registration Statements:
a.
Registration Statement (Form S-8 Nos. 333-221838, 333-189565, 333-175390, 333-165530, 333-250276, and 333-256993) of AVEO Pharmaceuticals, Inc., and
a.
Registration Statement (Form S-3 No. 333-212051 and No. 333-249982) of AVEO Pharmaceuticals, Inc.;
of our reports dated March 14, 2022, with respect to the consolidated financial statements of AVEO Pharmaceuticals, Inc and the effectiveness of internal control over financial reporting of Aveo
Pharmaceuticals, Inc. included in this Annual Report (Form 10-K) for the year ended December 31, 2021.
/s/ Ernst & Young LLP
Boston, Massachusetts
March 14, 2022
    

Exhibit 31.1
CERTIFICATION
I, Michael Bailey, certify that:
1.
I have reviewed this Annual Report on Form 10-K of AVEO Pharmaceuticals, Inc.;
2.
Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the
circumstances under which such statements were made, not misleading with respect to the period covered by this report;
3.
Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the financial condition, results of
operations and cash flows of the registrant as of, and for, the periods presented in this report;
4.
The registrant’s other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in Exchange Act Rules 13a-15(e) and
15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have:
a.
Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material
information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those entities, particularly during the period in
which this report is being prepared;
b.
Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our supervision, to provide
reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally
accepted accounting principles;
c.
Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the effectiveness of the
disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and
d.
Disclosed in this report any change in the registrant’s internal control over financial reporting that occurred during the registrant’s most recent fiscal quarter (the
registrant’s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to materially affect, the registrant’s internal
control over financial reporting; and
5.
The registrant’s other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the registrant’s auditors and the audit
committee of the registrant’s board of directors (or persons performing the equivalent functions):
a.
All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are reasonably likely to adversely
affect the registrant’s ability to record, process, summarize and report financial information; and
b.
Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal control over financial
reporting.
Date: March 14, 2022
/s/ Michael Bailey
Michael Bailey
Chief Executive Officer
(Principal Executive Officer)

Exhibit 31.2
CERTIFICATION
I, Erick Lucera, certify that:
1.
I have reviewed this Annual Report on Form 10-K of AVEO Pharmaceuticals, Inc.;
2.
Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make the statements made, in light of the
circumstances under which such statements were made, not misleading with respect to the period covered by this report;
3.
Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects the financial condition, results of
operations and cash flows of the registrant as of, and for, the periods presented in this report;
4.
The registrant’s other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in Exchange Act Rules 13a-15(e) and
15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and 15d-15(f)) for the registrant and have:
a.
Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our supervision, to ensure that material
information relating to the registrant, including its consolidated subsidiaries, is made known to us by others within those entities, particularly during the period in
which this report is being prepared;
b.
Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under our supervision, to provide
reasonable assurance regarding the reliability of financial reporting and the preparation of financial statements for external purposes in accordance with generally
accepted accounting principles;
c.
Evaluated the effectiveness of the registrant’s disclosure controls and procedures and presented in this report our conclusions about the effectiveness of the
disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and
d.
Disclosed in this report any change in the registrant’s internal control over financial reporting that occurred during the registrant’s most recent fiscal quarter (the
registrant’s fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably likely to materially affect, the registrant’s internal
control over financial reporting; and
5.
The registrant’s other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting, to the registrant’s auditors and the audit
committee of the registrant’s board of directors (or persons performing the equivalent functions):
a.
All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are reasonably likely to adversely
affect the registrant’s ability to record, process, summarize and report financial information; and
b.
Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant’s internal control over financial
reporting.
Date: March 14, 2022
/s/ Erick Lucera
Erick Lucera
Chief Financial Officer
(Principal Financial Officer)

Exhibit 32.1
CERTIFICATION PURSUANT TO 18 U.S.C. SECTION 1350,
AS ADOPTED PURSUANT TO
SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002
In connection with the Annual Report on Form 10-K of AVEO Pharmaceuticals, Inc. (the “Company”) for the fiscal year ended December 31, 2021 as filed with the Securities and Exchange
Commission on the date hereof (the “Report”), the undersigned, Michael Bailey, Chief Executive Officer of the Company, hereby certifies, pursuant to 18 U.S.C. Section 1350, that, to his knowledge
on the date hereof:
(1) The Report fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934; and
(2) The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.
Date: March 14, 2022
/s/ Michael Bailey
Michael Bailey
Chief Executive Officer
(Principal Executive Officer)

Exhibit 32.2
CERTIFICATION PURSUANT TO 18 U.S.C. SECTION 1350,
AS ADOPTED PURSUANT TO
SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002
In connection with the Annual Report on Form 10-K of AVEO Pharmaceuticals, Inc. (the “Company”) for the fiscal year ended December 31, 2021 as filed with the Securities and Exchange
Commission on the date hereof (the “Report”), the undersigned, Erick Lucera, Chief Financial Officer of the Company, hereby certifies, pursuant to 18 U.S.C. Section 1350, that, to his knowledge on
the date hereof:
(1) The Report fully complies with the requirements of Section 13(a) or 15(d) of the Securities Exchange Act of 1934; and
(2) The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the Company.
Date: March 14, 2022
/s/ Erick Lucera
Erick Lucera
Chief Financial Officer
(Principal Financial Officer)