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2023 ReportPeers and competitors of Kamada Ltd.:
Albireo PharmaUNITED STATES
SECURITIES AND EXCHANGE COMMISSION
WASHINGTON, D.C. 20549
FORM 20-F
(Mark One)
☐ REGISTRATION STATEMENT PURSUANT TO SECTION 12(b) OR (g) OF THE SECURITIES EXCHANGE ACT OF 1934
☒ ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
OR
For the fiscal year ended December 31, 2022
OR
☐ TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
OR
☐ SHELL COMPANY REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
Date of event requiring this shell company report: Not applicable
For the transition period from ____ to _____
Commission file number 001-35948
Kamada Ltd.
(Exact name of registrant as specified in its charter)
N/A
(Translation of Registrant’s name into English)
State of Israel
(Jurisdiction of incorporation or organization)
2 Holzman St.
Science Park
P.O Box 4081
Rehovot 7670402
Israel
(Address of principal executive offices)
Amir London, Chief Executive Officer
2 Holzman St., Science Park
Rehovot 7670402, Israel
+972 8 9406472
(Name, Telephone, E-mail and/or Facsimile number and Address of Company Contact Person)
Securities registered or to be registered pursuant to Section 12(b) of the Act.
Title of Each Class
Ordinary Shares, par value NIS 1.00 each
Trading Symbol
KMDA
Name of Each Exchange on which Registered
The Nasdaq Stock Market LLC
Securities registered or to be registered pursuant to Section 12(g) of the Act. None
Securities for which there is a reporting obligation pursuant to Section 15(d) of the Act. None
Indicate the number of outstanding shares of each of the issuer’s classes of capital or common stock as of the close of the period covered by the annual
report.
As of December 31, 2022, the Registrant had 44,832,843 Ordinary Shares outstanding.
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act.
☐ Yes ☒ No
If this report is an annual or transition report, indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the
Securities Exchange Act of 1934.
☐ 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.
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
☒ Yes ☐ No
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or an emerging growth company. See
definition of “large accelerated filer”, “accelerated filer”, and “emerging growth company” in Rule 12b-2 of the Exchange Act.
Large accelerated filer ☐ Accelerated filer ☒ Non-accelerated filer ☐ Emerging growth company ☐
If an emerging growth company that prepares its financial statements in accordance with U.S. GAAP, 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. ☐
† The term “new or revised financial accounting standard” refers to any update issued by the Financial Accounting Standards Board to its Accounting
Standards Codification after April 5, 2012.
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. ☒
If securities are registered pursuant to Section 12(b) of the Act, indicate by check mark whether the financial statements of the registrant included in the
filing reflect the correction of an error to previously issued financial statements. ☐
Indicate by check mark whether any of those error corrections are restatements that required a recovery analysis of incentive-based compensation received
by any of the registrant’s executive officers during the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark which basis of accounting the registrant has used to prepare the financial statements included in this filing:
U.S. GAAP ☐
International Financial Reporting Standards as issued by the International
Accounting Standards Board ☒
Other ☐
If “Other” has been checked in response to the previous question, indicate by check mark which financial statement item the registrant has elected to
follow.
If this is an annual report, indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Exchange Act).
Item 17 ☐ Item 18 ☐
☐ Yes ☒ No
PART I
Item 1.
Item 2.
Item 3.
Item 4.
Item 4A.
Item 5.
Item 6.
Item 7.
Item 8.
Item 9.
Item 10.
Item 11.
Item 12.
Item 13.
Item 14.
Item 15.
Item 16.
Item 16A.
Item 16B.
Item 16C.
Item 16D.
Item 16E.
Item 16F.
Item 16G.
Item 16H.
Item 16I.
Item 17.
Item 18.
Item 19.
TABLE OF CONTENTS
Identity of Directors, Senior Management and Advisers
Offer Statistics and Expected Timetable
Key Information
Information on the Company
Unresolved Staff Comments
Operating and Financial Review and Prospects
Directors, Senior Management and Employees
Major Shareholders and Related Party Transactions
Financial Information
The Offer and Listing
Additional Information
Quantitative and Qualitative Disclosures About Market Risk
Description of Securities Other Than Equity Securities
Defaults, Dividend Arrearages and Delinquencies
Material Modifications to the Rights of Security Holders and Use of Proceeds
Controls and Procedures
[Reserved]
Audit Committee Financial Expert
Code of Ethics
Principal Accountant Fees and Services
Exemptions from the Listing Standards for Audit Committees
Purchase of Equity Securities by the Issuer and Affiliated Purchasers
Change in Registrant’s Certifying Accountant
Corporate Governance
Mine Safety Disclosure
Disclosure Regarding Foreign Jurisdictions That Prevent Inspections
Financial Statements
Financial Statements
Exhibits
i
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139
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142
In this Annual Report on Form 20-F (this “Annual Report”), unless the context indicates otherwise, references to “NIS” are to the legal currency
of Israel, “U.S. dollars,” “$” or “dollars” are to United States dollars, and the terms “we”, “us”, the “Company”, “our company”, “our”, and
“Kamada” refer to Kamada Ltd., along with its consolidated subsidiaries.
This Annual Report contains forward-looking statements that relate to future events or our future financial performance, which express the current
beliefs and expectations of our management in light of the information currently available to it. Such statements involve a number of known and unknown
risks, uncertainties and other factors that could cause our actual future results, performance or achievements to differ materially from any future results,
performance or achievements expressed or implied by such forward-looking statements. Forward-looking statements include all statements that are not
historical facts and can be identified by words such as, but without limitation, “believe”, “expect”, “anticipate”, “estimate”, “intend”, “plan”, “target”,
“likely”, “may”, “will”, “would”, or “could”, or other words, expressions or phrases of similar substance or the negative thereof. We have based these
forward-looking statements largely on our management’s current expectations and future events and financial trends that we believe may affect our
financial condition, results of operation, business strategy and financial needs. Forward-looking statements include, but are not limited to, statements
about:
● our continued focus on driving profitable growth through expanding our growth catalysts which include: investment in the commercialization
and life cycle management of our commercial Proprietary products led by CYTOGAM and KEDRAB sales in the U.S. market; continue
growing our Proprietary hyper-immune – portfolio’s revenues in existing and new geographic markets through registration and launch of the
products in new territories; expanding sales of GLASSIA in ex-U.S. markets; generating royalties from GLASSIA sales by Takeda; expanding
our plasma collection capabilities in support of our growing demand for hyper-immune specialty plasma as well as sales of normal source
plasma to the market; continued increase of our Distribution segment revenues specifically through launching the eleven biosimilar products
in Israel; and leveraging our U.S. Food and Drug Administration (“FDA”)-approved hyperimmune immunoglobulins (“IgG”) platform
technology, manufacturing, research and development expertise to advance development and commercialization of additional product
candidates including our Inhaled Alpha-1 antitrypsin (“AAT”) product candidate and identify potential commercial partners for this product;
● our current exception to generate fiscal year 2023 total revenues at a range of $138 million to $146 million and EBITDA in the range of $22
million to $26 million; and that the mid- range points of the projected 2023 revenue and EBITDA forecast would represent a 10% and 35%
growth over fiscal year 2022, respectively;
● our belief that sales of CYTGOM and KEDRAB in the U.S. market will continue to increase in the coming years and will be a major growth
catalyst for the foreseeable future;
● our expectation to receive FDA approval for manufacturing of CYTOGAM and initiate commercial manufacturing of the product in our
manufacturing facility in Beit Kama, Israel by mid 2023;
● our expectation to receive the Canadian health authorities' approval for manufacturing of CYTOGAM in our manufacturing facility in Beit
Kama, Israel by the third quarter of 2023;
● our expectation that based on current GLASSIA sales in the U.S. and forecasted future growth, we will receive royalties from Takeda in the
range of $10 million to $20 million per year for 2023 to 2040;
● our expectation to supply CYTOGAM, HEPAGAM, VARIZIG and WINRHO SDF to Canadian Blood Services (CBS) for an additional three
years, commencing on April 1, 2023, for an approximate total value of $22 million;
● our expectation that VARIZIG's supply to Pan American Health Organization (“PAHO”) will continue through the first half of 2023;
● our expectation to continue manufacturing HEPAGAM B, VARIZIG and WINRHO SDF at Emergent BioSolutions Inc. (“Emergent”) in the
foreseeable future, and, upon decision to do so, initiate in parallel a technology transfer project for transitioning the manufacturing of these
products to our manufacturing facility in Beit Kama, Israel, subject to executing a new amended manufacturing services agreement with
Emergent covering operational aspects and the technology transfer related services and scope, and our anticipation that if initiated, such a
technology transfer may be completed within four to five years;
● our intention to expand our Proprietary plasma-derived products business, including that of CYTOGAM, HEPGAM B, VARIZIG and
WINRHO SDF, by maximizing the market potential of our existing Proprietary products portfolio;
ii
● our expectation that, subject to European Medicines Agency (“EMA”) and subsequently the Israeli Ministry of Health (“IMOH”) approvals,
we will launch in Israel eleven biosimilar products through 2028 and that sales generated by the launch of the biosimilar products portfolio
will become a major growth catalyst, and our estimate that the potential aggregate peak revenues, achievable within several years of launch,
generated by the distribution of all eleven biosimilar products will be approximately $40 million annually;
● our ability to procure adequate quantities of plasma and fraction IV from our suppliers, which are acceptable for use in our manufacturing
processes;
● our plans to significantly expand our hyperimmune plasma collection capacity by investing in our plasma collection center in Beaumont,
Texas, and leveraging our FDA license to establish a network of new plasma collection centers in the United States, with the intention to
collect normal source as well as hyperimmune specialty plasma required for manufacturing of some of our other Proprietary products
including KEDRAB/KAMRAB during 2023; and our expectation that the expansion of our plasma collection capabilities will allow us to
better support our plasma needs as well as generate additional revenues through sales of collected normal source plasma;
● our intention to seek new long-term supply agreements for hyper-immune plasma with additional plasma-collection companies;
● our intention to enhance our current manufacturing capabilities;
● our intention to implement staff reductions when needed in order to adjust to lower plant utilization;
● our expectations regarding the potential market opportunities for our products and product candidates;
● our belief that the acquired inventory of CYTOGAM which we acquired from Saol is sufficient to meet market demand through the second part
of 2023;
● our belief that the administration of CYTOGAM together with the available antivirals may provide additional protection in preventing
cytomegalovirus (“CMV”) disease for certain high-risk transplant populations, such as lung and heart transplant;
● our belief that there is an under-utilization of CYTOGAM as prophylaxis to CMV in high risk populations within Solid Organ Transplants
("SOT") due to a lack of new data and awareness regarding the benefits of combination CYTOGAM and antiviral therapy, and by addressing
these deficits, higher usage rates can be supported;
● our intention to seek registration of CYTOGAM in various other territories as well as explore label expansion of CYTOGAM to be used in
other indication;
● our belief that anti-rabies products based on equine serum are inferior to products made from human plasma;
● our belief that the exit of Sanofi S.A. from the U.S anti-Rabies IgG market, as well as some additional international markets, creates an
opportunity for us to expand KEDRAB’s U.S. market share;
● our belief that as WINRHO SDF is the only Rho (D) product positioned in the U.S. for ITP, and that maintaining awareness of the product
will continue to support ongoing usage rates;
● our belief that given the expected continued increase in liver transplants in ex-U.S. countries, and with our planned direct marketing efforts
HEPAGAM usage may grow;
● our expectation to launch and sell GLASSIA in some of the additional countries where it is currently registered during 2023-2024;
● our belief that our relationships with our strategic partners, including with Kedrion, Takeda and PARI, will continue without disruption;
iii
● our belief that we will be able to register our proprietary products, including CYTOGAM, HEPGAM B, VARIZIG and WINRHO SDF, in
additional countries where they are not currently registered, and our belief that this would lead to additional sales worldwide;
● our belief that we will be able to continue to meet our customers demand for our proprietary products;
● our expectations regarding the potential actions or inactions of existing and potential competitors of our products, including our belief that
there will be no new supplier of AAT by infusion in the U.S. market in the near future;
● our expectation that key U.S. physicians will publish new clinical data related to our portfolio, and our belief that the educational
symposiums that they conduct will have a positive impact on the understanding of our portfolio and thereby contributing to continued growth
in demand;
● the legislation or regulation in countries where we sell our products that affect product pricing, reimbursement, market access or distribution
channels may affect our sales and profitability;
● our projection that changes in the product sales mix and geographic sales mix may have an effect on our sales and profitability;
● our expectation of launching one of Alvotech's biosimilar products in Israel during 2023 and two others during 2024, and that following
receipt of the EMA marketing approval by Alvotech, and subject to subsequent approval by the IMOH, the remaining Alvotech products will
be launched in Israel through 2028;
● our expectation of launching three additional biosimilar products of two undisclosed international pharmaceutical companies in Israel
through 2026;
● our ability to identify growth opportunities for existing products and our ability to identify and develop new product candidates;
● our belief that the market opportunity for AAT products for the treatment of AATD will continue to grow;
● our expectation that the AATD's diagnosis will continue to increase going forward as awareness of AATD increases;
● our plan to continue to develop our pipeline, primarily focusing on the pivotal Phase 3 InnovAATe clinical trial of Inhaled AAT for the
treatment of Alpha-1 Deficiency (AATD) and to explore new strategic business development opportunities;
● our ability to attract partners for development programs for Inhaled AAT for AATD in the United States and the European Union, and to
maintain such partnerships, if we decide to pursue such direction, as well as the impact on our business resulting from such partnerships, or
from a failure to form such partnerships or fully realize the benefits of such partnerships;
● our intention to meet with the FDA and EMA during the first half of 2023 to discuss the InnovAATe clinical trial progress and potential
opportunities to shorten the regulatory pathway;
● our belief that Inhaled AAT for AATD will increase patient convenience and reduce the need for patients to use intravenous infusions of AAT
products, thereby decreasing the need for clinic visits or nurse home visits and reducing medical costs;
● our belief that Inhaled AAT for AATD will enable us to treat significantly more patients from the same amount of fraction IV and production
capacity and therefore increase our profitability;
● our belief that the inhaled formulation of AAT would be more effective in reducing inflammation of the lung tissue and inhibiting the
uncontrolled neutrophil elastase that causes the breakdown of the lung tissue and emphysema;
iv
● our intention to conduct a sub-study in North America in which approximately 30 patients will be evaluated for the effect of ADA on AAT
levels in plasma with Inhaled AAT and IV AAT treatments;
● our ability to obtain and/or maintain regulatory approvals for our products and new product candidates, the rate and degree of market
acceptance, and the clinical utility of our products;
● our ability to maintain compliance with government regulations and licenses;
● our intention to vigorously defend ourselves against any claims if and when they arise from the matters of the termination of the distribution
agreement in Russia and Ukraine;
● our belief that our current cash and cash equivalents and expected future cash to be generated by our operational activities will be sufficient
to satisfy our liquidity requirements for at least the next 12 months;
● our expectation that our capital expenditures will increase in the coming years mainly due to the planned expansion of our plasma collection
operations as well as potentially to facilitate the transition of manufacturing of HEPGAM B, VARIZIG and WINRHO SDF to our
manufacturing facility in Beit Kama, Israel;
● our expectations to pay approximately $24.9 million on account of contingent consideration, inventory related liability and the assumed
liabilities, during the next 12 months;
● our ability to obtain and maintain protection for the intellectual property, trade secrets and know-how relating to or incorporated into our
technology and products;
● our expectations regarding our ability to utilize Israeli tax incentives against future income; and
● our expectations regarding taxation, including that we will not be classified as a passive foreign investment company for the taxable year
ending December 31, 2023.
All forward-looking statements involve risks, assumptions and uncertainties. You should not rely upon forward-looking statements as predictors of
future events. The occurrence of the events described, and the achievement of the expected results, depend on many events and factors, some or all of which
may not be predictable or within our control. Actual results may differ materially from expected results. See the sections “Item 3. Key Information — D.
Risk Factors” and “Item 5. Operating and Financial Review and Prospectus,” as well as elsewhere in this Annual Report, for a more complete discussion
of these risks, assumptions and uncertainties and for other risks, assumptions and uncertainties. These risks, assumptions and uncertainties are not
necessarily all of the important factors that could cause actual results to differ materially from those expressed in any of our forward-looking statements.
Other unknown or unpredictable factors also could harm our results.
All of the forward-looking statements we have included in this Annual Report are based on information available to us as of the date of this
Annual Report and speak only as of the date hereof. We undertake no obligation, and specifically decline any obligation, to update publicly or revise any
forward-looking statements, whether as a result of new information, future events or otherwise. In light of these risks, uncertainties and assumptions, the
forward-looking events discussed in this Annual Report might not occur.
The audited consolidated financial statements for the years ended December 31, 2022, 2021 and 2020 included in this Annual Report have been
prepared in accordance with the international financial reporting standards (“IFRS”) as issued by the international accounting standards board (“IASB”).
None of the financial information in this Annual Report has been prepared in accordance with accounting principles generally accepted in the United
States (“U.S. GAAP”).
Unless otherwise noted, NIS amounts presented in this Annual Report are translated at the rate of $1.00 = NIS 3.519, the exchange rate published
by the Bank of Israel as of December 31, 2022.
v
Item 1. Identity of Directors, Senior Management and Advisers
Not applicable.
Item 2. Offer Statistics and Expected Timetable
PART I
Not applicable.
Item 3. Key Information
A. [Reserved]
B. Capitalization and Indebtedness
Not applicable.
C. Reasons for the Offer and Use of Proceeds
Not applicable.
D. Risk Factors
Our business, liquidity, financial condition, and results of operations could be adversely affected, and even materially so, if any of the risks
described below occur. As a result, the trading price of our securities could decline, and investors could lose all or part of their investment. This Annual
Report including the consolidated financial statements contains forward-looking statements that involve risks and uncertainties. Our actual results could
differ materially and adversely from those anticipated, as a result of certain factors, including the risks facing the Company as described below and
elsewhere in the Annual Report. You should carefully consider the risks and uncertainties included herewith. The risks and uncertainties described below
are not the only ones we face. Additional risks and uncertainties that we are unaware of, or that we currently believe are not material, may also become
important factors that adversely affect our business. Material risks that may affect our business, operating results and financial condition include, but are
not necessarily limited to, those relating to:
● Our business is currently highly concentrated on our two leading products, CYTOGAM and KEDRAB, as well as on royalty income generated
from GLASSIA sales by Takeda. Any adverse market event with respect to such products and income would have a material adverse effect on
our business and financial condition.
● A significant portion of our net revenue has been and will continue to be driven from sales of our proprietary products, and in our largest
geographic region, the United States. Any adverse market event with respect to some of our proprietary products or the United States would
have a material adverse effect on our business.
● Our ability to maintain and expand sales of our commercial products portfolio in the U.S. and ex-U.S. markets is critical to our profitability
and financial stability
● We have excess manufacturing plant capacity in our manufacturing facility, which may result in reduction in operating profits, if not
effectively managed.
● We recently established our U.S. plasma collection operations and have invested and intend to continue to invest in expanding this activity in
order to reduce our dependency on third-party suppliers in terms of plasma supply needs as well as to generate sales from commercialization
of collected normal source plasma, and our ability to successfully expand this operation is important to support our future growth and
profitability.
● We have several product development candidates, including our Inhaled AAT for AATD, as well as several other early-stage development
projects. There can be no assurance that the development activities associated with these products will materialize and result in the FDA,
EMA or any other relevant agencies granting us marketing authorization for any of these products.
● In our Proprietary Products segment, continued availability of CYTOGAM is dependent on FDA approval of the technology transfer of its
manufacturing to our manufacturing facility in Beit Kama, Israel as well as our ability to maintain continuous plasma supply.
● In our Proprietary Products segment, we rely on Kedrion for the sales of our KEDRAB product in the United States, and any disruption to our
relationships with Kedrion would have an adverse effect on our future results of operations and profitability.
● We rely in large part on third parties for the sale, distribution and delivery of our products, and any disruption to our relationships with these
third-party distributors would have an adverse effect on our future results of operations and profitability.
1
● In our Proprietary Product segment, we rely on Contract Manufacturing Organizations (“CMO”) to manufacture some of our products and
any disruption to our relationship with such manufacturers would have an adverse effect on the availability of products, our future results of
operations and profitability.
● Our Proprietary Product segment operates in a highly competitive market.
● We would become supply-constrained and our financial performance would suffer if we were unable to obtain adequate quantities of source
plasma or plasma derivatives or specialty ancillary products that meet the regulatory requirement of the FDA, EMA, Health Canada or the
regulatory authorities in Israel, or if our suppliers were to fail to modify their operations to meet regulatory requirements or if prices of the
source plasma or plasma derivatives were to raise significantly.
● Our Distribution segment is dependent on a few suppliers, and any disruption to our relationship with these suppliers, or their inability to
supply us with the products we sell, in a timely manner, in adequate quantities and/or at a reasonable cost, would have a material adverse
effect on our business, financial condition and results of operations.
● Laws and regulations governing the conduct of international operations may negatively impact our development, manufacture and sale of
products outside of the United States and require us to develop and implement costly compliance programs.
● If our manufacturing facility in Beit Kama, Israel were to suffer a serious accident, contamination, force majeure event (including, but not
limited to, a war, terrorist attack, earthquake, major fire or explosion etc.) materially affecting our ability to operate and produce saleable
plasma-derived protein therapeutics, all of our manufacturing capacity could be shut down for an extended period.
● Our business and operations would suffer in the event of computer system failures, cyber-attacks on our systems or deficiency in our cyber
security measures.
● Our success depends in part on our ability to obtain and maintain protection in the United States and other countries for the intellectual
property relating to or incorporated into our technology and products, including the patents protecting our manufacturing process.
● We have incurred significant losses since our inception and while we were profitable in the three years ended December 31, 2020, we
incurred operating losses in the last two fiscal years and may not be able to achieve or sustain profitability.
● Our business requires substantial capital, including potential investments in large capital projects, to operate and grow and to achieve our
strategy of realizing increased operating leverage. Despite our indebtedness, we may still incur significantly more debt.
● Our share price may be volatile.
● Conditions in Israel could adversely affect our business.
Risks Related to Our Business
Our business is currently highly concentrated on our two leading products, CYTOGAM and KEDRAB, as well as on royalty income generated from
GLASSIA sales by Takeda. Any adverse market event with respect to such products and income would have a material adverse effect on our business
and financial condition.
Our business currently relies on the sales of CYTOGAM, our Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV), and
KEDRAB, our Human Rabies Immune Globulin (HRIG), as well as royalty income on sales of GLASSIA, our intravenous AAT product, by Takeda.
Revenue from sales of these products and royalties comprised approximately 17%, 13% and 9%, respectively (39% in total), of our total revenues for the
year ended December 31, 2022.
2
In the event that CYTOGAM or KEDRAB were to lose significant sales or were to be substantially or completely displaced in the market, we
would lose a significant and material source of our total revenues. Similarly, if these products were to become the subject of litigation and/or an adverse
governmental action or ruling causing us to cease the manufacturing, export or sales of these products, our business and financial condition would be
adversely affected.
We are entitled to royalty payments from Takeda on GLASSIA sales in the United States (as well as in Canada, Australia and New Zealand to the
extent GLASSIA will be approved and sales will be generated in these other markets) at a rate of 12% on net sales through August 2025, and at a rate of
6% thereafter until 2040, with a minimum of $5 million annually, for each of the years from 2022 to 2040. For the period between March and December
2022, we accounted for $12.2 million of sales-based royalty income from Takeda, and based on forecasted future growth, we project receiving royalties
from Takeda in the range of $10 million to $20 million per year from 2023 to 2040. However, any reduction in sales of GLASSIA by Takeda or should
Takeda reduce its manufacturing and marketing of GLASSIA for any reason (including but not limited to inability to adequately or sufficiently manufacture
GLASSIA, regulatory limitations, difficulties in marketing, reduction in market size, or changes in corporate focus), our future expected royalty income
from Takeda’s sales of GLASSIA would be adversely impacted, which would have an adverse effect on our revenues and profitability.
A significant portion of our net revenue has been and will continue to be driven from sales of our proprietary products, and in our largest geographic
region, the United States. Any adverse market event with respect to some of our proprietary products or the United States would have a material adverse
effect on our business.
A significant portion of our revenues has been, and will continue to be, derived from sales of our proprietary products, including those of
CYTOGAM, KEDRAB, HEPGAM B, VARIZIG, WINRHO SDF and GLASSIA, as well as royalty income from GLASSIA sales by Takeda. Revenue
from our Proprietary products comprised approximately 79%, 73% and 76% of our total revenues for the years ended December 31, 2022, 2021 and 2020,
respectively. If some of our proprietary products were to lose significant sales or were to be substantially or completely displaced in the market, we would
lose a significant and material source of our total revenues. Similarly, if these products were to become the subject of litigation and/or an adverse
governmental action or ruling causing us to cease the manufacturing, export or sales of these products, our business and financial condition would be
adversely affected.
A significant portion of our sales and income are generated in the United States and comprised approximately 51%, 48% and 63% of our total
revenues for the years ended December 31, 2022, 2021 and 2020, respectively. If our sales or income generated in the United States were significantly
impacted by material changes to government or private payor reimbursement, other regulatory developments, competition or other factors, then our
business and financial condition would be adversely affected.
Our ability to maintain and expand sales of our commercial products portfolio in the U.S. and ex-U.S. markets is critical to our profitability and
financial stability.
Our Proprietary commercial products portfolio, comprising of CYTOGAM, KEDRAB, WINRHO SDF, VARIZIG, HEPGAM B and GLASSIA,
as well as KAMRAB, KAMRHO (D) and two types of equine-based anti-snake venom (ASV) products, are currently distributed in the U.S. market, where
we market and distribute some of these products directly based on our sales and marketing personnel, and in approximately 30 additional ex-U.S.
international markets, including the Middle East and North Africa (“MENA”) region, where we had little to no prior sales and operational experience.
While we intend to leverage our existing strong international distribution network to grow our commercial revenue in the existing markets in which we sell
our products, we also plan to expand to geographic markets in which these products are not currently sold, and we may not be successful in developing
additional markets for these products.
Our ability to successfully maintain and expand our recently established U.S. based commercial and distribution infrastructure, maintain and
expand ex-U.S. commercialization, is critical for our future growth, profitability and financial stability. Given our limited prior experience in some of the
required activities and responsibilities, including operation of direct sales in the U.S. market, knowledge and experience in the MENA region, as well as
other operational, technical, regulatory, financial and compliance challenges, we may not be able to continue to expand our existing commercial operation,
which may materially adversely affect the operating results of our business as well as our financial condition.
3
We have excess manufacturing plant capacity in our manufacturing facility, which may result in a reduction in operating profits, if not effectively
managed.
Following the transition of GLASSIA manufacturing to Takeda in 2021, we have been and may continue to be affected by reduced efficiency of
our manufacturing facility, which resulted and may continue to result in increased manufacturing costs per vial, reduced gross profitability and potential
operating losses. We plan to utilize the excess manufacturing capacity in our manufacturing plant to manufacture our proprietary products, including
KEDRAB/KAMRAB and GLASSIA (which are currently manufactured in our facility) and CYTOGAM (subject to obtaining required regulatory
approval). We are also currently manufacturing at our plant small quantities of KAMRHO and anti-snake venom products as well as clinical lots needed for
the Inhaled AAT clinical study. We might also potentially in the future use the existing capacity for the manufacturing of HEPGAM B, VARIZIG and
WINRHO SDF, which would be subject to a technology transfer and regulatory approvals and the execution of a new revised contract manufacturing
agreement with Emergent. We may also consider utilizing our plant in the future for the manufacturing of products for other companies as a contract
manufacturing organization (CMO). While we have the knowhow and expertise to support the manufacturing of additional products in our facility, we may
not be able to complete required technology transfers or obtain required regulatory approvals in the expected timeline, or at all. Further, while we are
capable of increasing the manufacturing capacity at our facility, there is no assurance that there will be increased market demand for these products at a
profitable market price in the markets in which we distribute our products or other markets. The manufacturing of excess quantities of products, which may
not be sold due to lower demands, may result in the need to write-down the value of inventories, which may result in significant operating losses. See also
“—Manufacturing of new plasma-derived products in our manufacturing facility requires a lengthy and challenging development project and/or technology
transfer project as well as regulatory approvals, all of which may not materialize.”
While we would expect to implement staff reductions when needed in order to adjust to lower plant utilization, the risk of not adequately adjusting
to lower plant utilization could result in inefficiencies, reduced profitability or operating losses. Staff reductions have in the past, and may in the future,
require us to pay excess severance compensation and may lead to labor disputes and strikes, which could affect our ability to continue to manufacture
products and may lead to increased costs, reduced profitability and operating losses. For labor related risk see “—We have entered into a collective
bargaining agreement with the employees’ committee and the Histadrut (General Federation of Labor in Israel), and we have incurred and could in the
future incur labor costs or experience work stoppages or labor strikes as a result of any disputes in connection with such agreement.”
Failure to adequately or timely adapt our manufacturing volume or our CMOs supplies as needed may lead to an inability to supply products, may
have an adverse effect on our business and could cause substantial harm to our business reputation and result in breach of our sales agreements and the loss
of future customers and orders.
We recently established our U.S. plasma collection operations and have invested, and intend to continue to invest, in expanding this activity in order to
reduce our dependency on third-party suppliers in terms of plasma supply needs as well as to generate sales from commercialization of collected
normal source plasma, and our ability to successfully expand this operation is important to support our future growth and profitability.
In March 2021, we acquired the plasma collection center of B&PR in Beaumont, Texas, which primarily collects hyper-immune plasma used in
the manufacture of our KAMRHO (D). We are in the process of significantly expanding our hyperimmune plasma collection capacity in this center. We
registered with the FDA the collection of hyper-immune plasma to be used in the manufacture of KEDRAB/KAMRAB and plan to start collections of such
plasma during 2023. We also intend to leverage our experience with plasma collection to establish additional plasma collection centers in the United States,
with the intention of collecting normal source plasma, as well as hyper-immune specialty plasma required for manufacturing of our proprietary products. To
that end, during March 2023, we entered into a lease for a new plasma collection center in Uvalde, Houston, Texas and expect to commence operations at
the new center following the completion of its construction and obtaining the required regulatory approvals.
However, given our limited prior experience in managing plasma collection operations, the operational, technical, and regulatory challenges in
establishing and maintaining plasma collection operations, as well as the challenges in screening locations, in negotiating the lease and other third party
agreements required for the ongoing operations of the centers, the financial investment required to expand our collection capabilities and open new
collection centers and the management of an expanded scope of plasma collection operations, we may not be able to realize our investment and the
anticipated benefits of such activities. Further, we may not be able to adequately collect sufficient quantities of plasma through our plasma collection
operations to support our plasma sourcing needs, which will result in continued dependency on third party suppliers; and even if we are successful in
collection sufficient quantities, there can be no assurance that we will be able to reduce the cost of plasma through our collection operations, as compared
to costs associated with procuring plasma from third parties. In addition, there could be no assurance that we will be able to collect adequate quantities of
normal source plasma as well as secure supply agreements with customers at adequate prices See also “—We would become supply-constrained and our
financial performance would suffer if we were unable to obtain adequate quantities of source plasma or plasma derivatives or specialty ancillary products
approved by the FDA, the EMA, Health Canada or the regulatory authorities in Israel, or if our suppliers were to fail to modify their operations to meet
regulatory requirements or if prices of the source plasma or plasma derivatives were to raise significantly”; and “—We may in the future engage in
additional strategic transactions to acquire or sell assets, businesses, products or technologies or engage in in-license or out-license transactions of
products or technologies or form collaborations that could negatively affect our operating results, dilute our stockholders’ ownership, increase our debt, or
cause us to incur significant expense.”
4
We have several product development candidates, including our Inhaled AAT for AATD as well as several other early stage development projects. There
can be no assurance that the development activities associated with these products will materialize and result in the FDA, EMA or any other relevant
agencies granting us marketing authorization for any of these products.
We are engaged in research and development activities with respect to several pharmaceutical products candidates, including Inhaled AAT for
AATD, which is our lead product development candidate.
During December 2019, the first patient was randomized in Europe into our pivotal Phase 3 InnovAATe clinical trial evaluating the safety and
efficacy of our proprietary Inhaled AAT therapy for the treatment of AATD. The study was initiated following extensive discussions with both the FDA and
EMA regarding the trial’s design as well a thorough analysis of a prior pivotal Phase 2/3 clinical trial for Inhaled AAT for AATD conducted in Europe,
which did not meet its primary or other pre-defined efficacy endpoints, and a prior Phase 2 clinical trial conducted in the U.S which met its
pharmacokinetic endpoint. In addition to the pivotal study and based on feedback received from the FDA regarding anti-drug antibodies (“ADA”) to
Inhaled AAT, we intend to concurrently also conduct a sub-study in North America in which approximately 30 patients will be evaluated for the effect of
ADA on AAT levels in plasma with Inhaled AAT and IV AAT treatments. While a recent routine and planned meeting of the independent Data and Safety
Monitoring Board (“DSMB”) supported an expansion to the inclusion criteria of the trial and recommended it continue without modification, there can be
no assurance that we will be able to complete this trial successfully or that the trial results will be sufficient for obtaining FDA and EMA approval. See also
“As a result of the COVID-19 pandemic we encountered delays in patient recruitment into our pivotal Phase 3 InnovAAT clinical study conducted at a first
study site in Europe and it impacted our ability to open additional study sites in the United States and Europe. COVID-19 may in the future affect our
ability to conduct the study.”
In addition, we are currently engaged in the early stage development of other product candidates, including a recombinant AAT product candidate,
and in 2022, we initiated three additional early-stage development programs, all of which are associated with plasma derived product candidates. There can
be no assurance that the development activities associated with these products will materialize and result in the FDA, EMA or any other relevant agencies
granting us marketing authorization for any of these products. For additional information, see — “Item 4. Information on the Company — Our
Development Product Pipeline.”
There can be no assurance that the development activities associated with these products will materialize and result in the FDA, EMA or any other
relevant agencies granting us marketing authorization for any of these products. See also “—Research and development efforts invested in our pipeline of
specialty and other products may not achieve expected results” and “—If we are unable to successfully introduce new products and indications or fail to
keep pace with advances in technology, our business, financial condition and results of operations may be adversely affected.”
We may in the future engage in additional strategic transactions to acquire or sell assets, businesses, products or technologies or engage in in-license
or out-license transactions of products or technologies or form collaborations that could negatively affect our operating results, dilute our
stockholders’ ownership, increase our debt, or cause us to incur significant expense.
As part of our business development strategy, we have in the past, and may in the future engage in strategic transactions to acquire or sell assets,
businesses, or products; or otherwise engage in in-licensing our out-licensing transactions with respect to products or technologies; or enter into other
strategic alliances or collaborations. We may not identify additional suitable transactions, or complete such transactions in a timely manner, on a cost-
effective basis, or at all. Moreover, we may devote resources to potential opportunities that are never completed, or we may incorrectly judge the value or
worth of such opportunities. Even if we successfully execute a strategic transaction, we may not be able to realize the anticipated benefits of such
transaction, may incur additional debt or assume unknown or contingent liabilities in connection therewith, and may experience losses related to our
investments or dispositions. Integration of an acquired company or assets into our existing business or a transition of an asset to an acquirer or partner may
not be successful and may disrupt ongoing operations, require the hiring of additional personnel and the implementation of additional internal systems and
infrastructure, and require management resources that would otherwise focus on developing our existing business. Even if we are able to achieve the long-
term benefits of a strategic transaction, our expenses and short-term costs may increase materially and adversely affect our liquidity. Any of the foregoing
could have a material effect on our business, results of operations and financial condition.
The COVID-19 pandemic may continue to impact our business, operating results and financial condition.
The outbreak of the COVID-19 pandemic in January 2020 and its spread throughout the world has led to a global health and economic crisis and
had an effect on most of the countries in the world. In response, governments around the world, including Israel, announced defensive measures such as
restrictions on travel between countries, isolation measures and limitations on gatherings and movement, lockdowns, restrictions on operating private
businesses and government and municipal services. Commencing in the second quarter of 2021, the Israeli economy showed an evident trend of recovery
from the COVID-19 crisis as a result of the high vaccination rate of the population, which made it possible to ease travel restrictions at various destinations
around the world and to return to normal business activity. The trend of recovery continued to increase, and it appears that the effect of the COVID-19
pandemic in Israel and in many other places around the world is fading. While we maintained ongoing operations with no material affect during the
pandemic to date and believe that we will be able to continue operating normally in the future, there is still some level of uncertainty regarding the
reinstatement of restrictions as a result of the discovery of additional coronavirus variants and fear of further spread.
5
The COVID-19 pandemic and the volatile global economic conditions stemming from it may precipitate or amplify the other risks described in
this “Risk Factors” section of this Annual Report, which could materially adversely affect our business, operations and financial conditions and results
from operations.
Risks Related to Our Proprietary Products Segment
Sales of CYTOGAM, HEPGAM B, VARIZIG and WINRHO SDF in the U.S. market are critical in order to support future growth, future
results of operations and profitability.
Sales of CYTOGAM, HEPGAM B, VARIZIG and WINRHO SD in the U.S. market represented approximately 30% of our Proprietary Product
segment sales for the year ended December 31, 2022. Following the acquisition of these products in November 2021, we established a U.S. based
commercial and sales team which gradually assumed the U.S. commercial responsibility for these products. Such activities included hiring employees with
relevant U.S. commercial experience, engaging wholesalers, customers, and a U.S. third-party logistics (“3PL”) provider, and understanding market
landscape and trends for these products through market research and discussions with physicians and key opinion leaders, as well as medical affairs
activities which include educating physicians, supporting medical publications and collecting new clinical data associated with these products.
However, given our limited prior experience in directly managing U.S. commercial and medical operations and the operational, technical and
regulatory challenges in maintaining such activity, as well as the significant costs involved in such operations, we may not be able to realize the anticipated
benefits of such activities, and may not be able to adequately maintain or expand market demand and continued product sales, which may result in
significant reduction in sales, increased operating costs and reduced profitability.
See “— Our ability to maintain and expand sales of our commercial products portfolio in the U.S. and ex-U.S. markets is critical to our
profitability and financial stability.” See also – “Item 4. Information on the Company — Proprietary Products Segment.”
Continued availability of CYTOGAM is dependent on FDA approval of the technology transfer of its manufacturing to our manufacturing facility in
Beit Kama, Israel as well as our ability to maintain continuous plasma supply.
As part of the acquisition of the four FDA approved plasma-derived hyperimmune commercial products from Saol, we acquired inventory of
CYTOGAM which is sufficient to meet market demand through the second part of 2023. During 2019, pursuant to an earlier engagement with Saol, we
initiated technology transfer activities for transitioning CYTOGAM manufacturing to our manufacturing facility in Beit Kama, Israel. As a result of the
consummation of the IgG portfolio acquisition, which included the acquisition of all rights relating to CYTOGAM, the previous contract manufacturing
engagement with Saol with respect to this product expired. During December 2022, we submitted a prior approval supplement (“PAS”) to the FDA for
approval to manufacture CYTOGAM at the Beit Kama facility and subject to the results of an FDA audit of our facility, we expect to receive FDA approval
for manufacturing of CYTOGAM and initiate commercial manufacturing of the product by mid-2023. A similar application to the Canadian health
authorities was submitted in January 2023, with approval expected by the third quarter of 2023. Failure to obtain the required regulatory approvals, in a
timely manner, may affect product availability, result in a decrease in sales and a deterioration in our market position, and could have an adverse effect
upon our sales, margins and profitability.
As part of the initiation of the CYTOGAM technology transfer process, we engaged Prothya Biosolutions Belgium (“Prothya”) as a third-party
contract manufacturer to perform certain manufacturing activities required for the manufacturing of CYTOGAM. In addition, we assumed a plasma supply
agreement with CSL for the continued supply of required plasma for the manufacturing of the product. If we fail to maintain our relationship with these
entities, we could face supply shortages, which could adversely impact our ability to manufacture and supply CYTOGAM, and could incur increased costs
in finding replacement vendors. Delays in establishing a relationship with new vendors could lead to a decrease in the product’s sales and a deterioration in
our market position when compared with one or more of our competitors. Any of the foregoing developments could have an adverse effect upon our sales,
margins and profitability.
6
In our Proprietary Products segment, we rely on Kedrion for the sales of our KEDRAB product in the United States, and any disruption to our
relationships with Kedrion would have an adverse effect on our future results of operations and profitability.
Pursuant to the strategic distribution and supply agreement with Kedrion for the clinical development and marketing in the United States of
KEDRAB, Kedrion is the sole distributor of KEDRAB in the United States. Sales to Kedrion accounted for approximately 13%, 12% and 14% of our total
revenues in the years ended December 31, 2022, 2021 and 2020, respectively. We are dependent on Kedrion for its marketing and sales of KEDRAB in the
United States. The term of the agreement is for six years commencing on the date by which KEDRAB U.S. launch was feasible (i.e., until March 2024) and
Kedrion has an option to extend the term by two additional years (i.e., until March 2026).
We currently also purchase from a subsidiary of Kedrion, KedPlasma LLC (“Kedplasma”), a large portion of the hyper-immune plasma which is
used for the production of KEDRAB/KAMRAB. See “—We would become supply-constrained, and our financial performance would suffer if we were
unable to obtain adequate quantities of source plasma or plasma derivatives or specialty ancillary products approved by the FDA, the EMA, Health
Canada or the regulatory authorities in Israel, or if our suppliers were to fail to modify their operations to meet regulatory requirements or if prices of the
source plasma or plasma derivatives were to raise significantly.”
If we do not maintain the distribution relationship with Kedrion, we would be required to assume the sales and marketing activities of KEDRAB,
or we would need to engage a replacement distributor for the product in the United States. Further, if we fail to maintain the plasma supply agreement with
KedPlasma we would need to increase supply from other available sources and/or find a replacement supplier of the hyper-immune plasma which is used to
manufacture KEDRAB/ KAMRAB. Establishing a relationship with a new distributor or supplier or internalizing those activities could lead to a decrease
in KEDRAB/ KAMRAB sales and a deterioration in our market share when compared with one or more of our competitors. Any of the foregoing
developments could have an adverse effect upon our sales, margins and profitability.
In our Proprietary Products segment, we currently earn royalties on GLASSIA sales by Takeda in the United States (and in the future may earn
royalties on GLASSIA sales by Takeda in Canada, Australia and New Zealand, to the extent GLASSIA will be approved for sale and sales will be
generated in these other markets), and any reduction in sales of GLASSIA by Takeda would have an adverse effect on our future expected royalty
income and profitability.
Commencing in March 2022, we are entitled to royalty payments from Takeda on GLASSIA sales in the United States (and in the future we may
earn royalties on GLASSIA sales by Takeda in Canada, Australia and New Zealand, to the extent GLASSIA will be approved and sales will be generated in
these other markets) at a rate of 12% on net sales through August 2025, and at a rate of 6% thereafter until 2040, with a minimum of $5 million annually,
for each of the years from 2022 to 2040. For the period between March and December 2022, we accounted for $12.2 million of sales-based royalty income
from Takeda, and based on forecasted future growth, we project receiving royalties from Takeda in the range of $10 million to $20 million per year for
2023 to 2040. However, any reduction in sales of GLASSIA by Takeda or should Takeda reduce its manufacturing and marketing of GLASSIA for any
reason (including but not limited to inability to adequately or sufficiently manufacture GLASSIA, regulatory limitations, difficulties in marketing,
reduction in market size, or changes in corporate focus), our future expected royalty income from Takeda’s sales of GLASSIA would be adversely
impacted, which would have an adverse effect on our results of operations and profitability.
In our Proprietary Products segment, we rely on Contract Manufacturing Organizations to manufacture some of our products and any disruption to
our relationship with such manufacturers would have an adverse effect on the availability of products, our future results of operations and profitability.
HEPAGAM B, VARIZIG and WINRHO SDF are currently manufactured by Emergent under a contract manufacturing agreement which was
assigned to us from Saol following the consummation of the acquisition. We are dependent on Emergent to secure the supply of adequate quantities of
plasma needed to timely manufacture these products and we rely on their manufacturing, quality and regulatory systems to ensure the manufacturing
process complies with current Good Manufacturing Practice (“cGMP”) standards and any other regulatory requirements and that each product
manufactured meets its specification and is appropriately released for human consumption.
7
If we fail to maintain our relationship with Emergent, or if Emergent fails to operate in compliance with cGMP and other regulatory requirements,
we could face supply shortages and may not be able to supply these products. In addition, such failure may result in increased costs and delays in
transferring the manufacturing of the products to our plant in Beit Kama, Israel, or in finding a replacement manufacturer for these products and we might
be required to identify replacement supplier of the plasma which is used for the production of these products. Delays in internalizing the production or
establishing a relationship with a new manufacturer could lead to a decrease in these products sales and a deterioration in our market share when compared
with one or more of our competitors. Any of the foregoing developments could have an adverse effect upon our sales, margins and profitability.
We have also engaged Prothya as a third-party contract manufacturer to perform certain manufacturing activities required for the manufacturing of
CYTOGAM. If we fail to maintain our relationship with Prothya, or if Prothya fails to operate in compliance with cGMP and other regulatory
requirements, we could face supply shortages, which could adversely impact our ability to manufacture and supply CYTOGAM, and could incur increased
costs in finding a replacement manufacturer for this product. Delays in establishing a relationship with a new manufacturer could lead to a decrease in this
product sales and a deterioration in our market share when compared with one or more of our competitors. Any of the foregoing developments could have
an adverse effect upon our sales, margins and profitability.
Certain of our sales in our Proprietary Products segment rely on our ability to win tender bids based on the price and availability of our products in
public tender processes.
Certain of our sales in our Proprietary Products segment rely on our ability to win tender bids in certain markets, including those of the World
Health Organization (WHO) and other similar health organizations. Our ability to win bids may be materially adversely affected by competitive conditions
in such bid process. Our existing and new competitors may also have significantly greater financial resources than us, which they could use to promote
their products and business. Greater financial resources would also enable our competitors to substantially reduce the price of their products or services. If
our competitors are able to offer prices lower than us, our ability to win tender bids during the tender process will be materially affected and could reduce
our total revenues or decrease our profit margins.
We rely in large part on third parties for the sale, distribution and delivery of our products, and any disruption to our relationships with these third-
party distributors would have an adverse effect on our future results of operations and profitability.
We engage third party distributors to distribute and sell our Proprietary Products in ex-U.S. markets (other than the Israeli market), including the
recently acquired products CYTOGAM, HEPGAM B, VARIZIG and WINRHO SDF. Sales through such distributors accounted for approximately 25%,
17% and 10% of our total revenues in the years ended December 31, 2022, 2021 and 2020, respectively and we expect such sales to increase in 2023 and
beyond. We are dependent on these third parties for successful marketing, distribution and sales of our products in these markets. If such third parties were
to breach, terminate or otherwise fail to perform under our agreements with them, our ability to effectively distribute our products would be impaired and
our business could be adversely affected. Moreover, circumstances outside of our control such as a general economic decline, market saturation or
increased competition may influence the successful renegotiation of our contracts or the securing of to us favorable terms.
In addition to distribution and sales, these third-party distributors are, in some cases, responsible for the regulatory registration of our products in
the local markets in which they operate, as well as responsible for participation in tenders for sale of our products. Failure of these third-party distributors
to obtain and maintain such regulatory approvals and/or win tenders or provide competitive prices to our products may adversely affect our ability to sell
our Proprietary Products in these markets, which in turn will negatively affect our revenues and profitability. In addition, our inability to sell our
Proprietary Products in these markets may reduce our manufacturing plant utilization and effectiveness and may lead to additional reduction of profitability.
In the U.S. market we utilize a 3PL provider in connection with the distribution of CYTOGAM, HEPGAM B, VARIZIG and WINRHO SDF,
which provides complete order to cash services. If such 3PL provider were to breach, terminate or otherwise fail to adequately perform under our
agreement with it, including inadequate inventory management, transportation delays and incorrect temperature control during storage and handling, fails
to issue invoices correctly or on a timely basis and/or fails to collect payments due to us from our U.S. customers, our ability to effectively distribute such
products would be impaired, which could negatively impact our business operations and financial performance.
Disputes with distributors have arisen in the past and disputes may arise in the future that cause the delay or termination of the development,
manufacturing, supply or commercialization of our product candidates, or could result in costly litigation or arbitration that diverts management’s attention
and resources. In May 2022, we terminated a distribution agreement with a third-party engaged to distribute our propriety products in Russia and Ukraine
(the “Distributor”) and a power of attorney granted in connection with such distribution agreement to an affiliate of the Distributor (the “Affiliate”). In July
2022, the Affiliate filed a request for a conciliation hearing with the Court in Geneva relying on the terminated power of attorney and seeking damages for
the alleged inability to sell the remaining product inventory previously acquired from the Company and compensation for the lost customer base. The
conciliation hearing was scheduled for March 17, 2023, and, at this time, it is not possible to assess the prospects and scope of any claims against us and
any potential liabilities and impact on our business. See “Item 4. Information on the Company — Legal Proceedings.”
8
Our Proprietary Products segment operates in a highly competitive market.
Our Proprietary Products compete with products distributed by well-established biopharmaceutical companies, including several large competitors
in the plasma industry. These large competitors include CSL Behring Ltd. (“CSL”), Takeda, and Grifols S.A. (“Grifols”), which acquired a previous
competitor, Talecris Biotherapeutics, Inc. (“Talecris”) in 2011, Octapharma, Kedrion (other than for KEDRAB), Biotest AG and ADMA Biologics Inc.
(“ADMA”). We compete against these companies for, among other things, licenses, expertise, clinical trial patients and investigators, consultants and third-
party strategic partners. We also compete with these companies for market share for certain products in the Proprietary Products segment. Our large
competitors have advantages in the market because of their size, financial resources, markets and the duration of their activities and experience in the
relevant market, especially in the United States and countries of the European Union. As a result, they may be able to devote more funds to research and
development and new production technologies, as well as to the promotion of their products and business. These competitors may also be able to sustain
longer periods of substantial reduction in the price of their products or services. These competitors also have an additional advantage regarding the
availability of raw materials, as they own or control multiple plasma collection centers and/or plasma fractionation facilities.
In addition, our plasma-derived protein therapeutics face, or may face in the future, competition from existing or newly developed non-plasma
products and other courses of treatments. New treatments, such as antivirals, gene therapies, small molecules, correctors, monoclonal or recombinant
products, may also be developed for indications for which our products are now used.
Our products generally do not benefit from patent protection and compete against similar products produced by other providers. Additionally, the
development by a competitor of a similar or superior product or increased pricing competition may result in a reduction in our net sales or a decrease in our
profit margins.
Our hyper-immune IgG products in the Proprietary Products segment face competition from several competing plasma derived products and non-
plasma derived pharmaceuticals, mainly anti-viral.
CYTOGAM. To our knowledge, CYTOGAM is the sole plasma derived CMV IgG product approved for sale in the United States and Canada.
Based on available public information, the FDA approved the following antiviral drugs for the prevention of CMV infection and disease: Letermovir
(Prevymis), developed by Merck & Co., and for treatment of refractory/resistant infection, Maribavir (Livtencity), developed by Takeda, which may result
in the loss of market share for CYTOGAM. Currently, treatment guidelines state that combination therapy with standard antiviral can be considered for
certain solid organ transplant recipients. The most commonly used antivirals are Ganciclovir (Cytovene-IV Roche) and Valganciclovir (Valcyte Roche).
Patients treated with antiviral agents for a long time can develop resistance and will require a second-line treatment such as Foscarnet (Foscavir Pfizer) or
Cidofovir (Gilead Sciences). In rest of the world (“ROW”) markets, Cytotec CP (Biotest), a plasma derived competing product is available.
KEDRAB/KAMRAB. We believe that there are two main competitors for KEDRAB/KAMRAB, our anti-rabies products worldwide: Grifols, whose
product we estimate comprises approximately 70% of the anti-rabies IgG market in the United States, and CSL, which sells its anti-rabies product in
Europe and elsewhere. Sanofi Pasteur, the vaccines division of Sanofi S.A., recently exited the U.S anti-rabies IgG market as well as some additional
international markets, however, may still be competing in other markets or in the future could return to exited markets. Bio Products Laboratories Ltd.
(“BPL”), which has an anti-Rabies IgG product for the UK market, has developed it also for the U.S market, including performing a clinical trial, but to our
knowledge the program is currently paused. There are several local producers in other countries that make anti-rabies IgG products, mostly based on equine
serum. Over the past several years, several companies have made attempts, and some are still in the process of developing monoclonal antibodies for an
anti-rabies treatment. These products, if approved, may be as effective as the currently available plasma derived anti-rabies IgG and may potentially be
significantly cheaper, and as such may result in loss of market share of KEDRAB/KAMRAB.
WINRHO SDF. In the United States, WINRHO SDF competes with corticosteroids (oral prednisone or high-dose dexamethasone) or intravenous
immune globulin (“IVIG”) (Grifols, CSL and Takeda are the main manufacturers and suppliers in the U.S.) as first line treatment of acute ITP, with IVIG
or WINRHO SDF recommended for pediatric patients in whom corticosteroids are contraindicated. IVIG has similar efficacy to WINRHO SDF, and ITP is
its labeled indication for IVIG. Rhophylac (CSL Behring) is also approved for ITP treatment, but we believe it is mostly used for Hemolytic Disease of the
Newborn (“HDN”), due to its comparatively small vial size. For HDN indication, the market is usually led by tenders, where key indicators are registration
status and price, and the main multiple competitors in Canada and ROW countries are RhoGAM (Kedrion), Hyper RHO (Grifols) and Rhophylac (CSL
Behring) and our KAMRHO (D).
HEPAGAM B. To our knowledge, in the United States, HEPAGAM B is the only approved HBIG with an on-label indication for Liver
Transplants. To our understanding, HEPAGAM B holds the majority market share for the indication, while another HBIG (Nabi-HB manufactured and
supplied by ADMA) is being used off-label by some medical centers for the indication. In recent years, duration of treatment has been reduced by
physicians. New generation antivirals are considered effective for preventing HBV reactivation post-transplant, hence limiting HBIG use. Post-exposure
prophylaxis (“PEP”) indication in the United States is covered almost totally by Nabi-HB (ADMA) and HyperHEP (Grifols). In Canada, main competition
in national tenders is HyperHEP. In ROW countries such as Turkey, Saudi-Arabia and Israel, HEPATECT and Zutectra (Biotest AG) represent the primary
competition.
9
VARIZIG. In the United States, incidence of Varicella Zoster Virus (“VZV”) infection has decreased dramatically since the introduction of the
varicella vaccine in 1995. Two vaccines containing varicella virus are licensed for use in the United States. Varivax is the single-antigen varicella vaccine.
ProQuad is a combination measles, mumps, rubella, and varicella (MMRV) vaccine. Although the use of the vaccine has reduced the frequency of
chickenpox, the virus, has not been eradicated. Moreover, incidence of Herpes Zoster, also caused by VZV, is increasing among adults in the United States.
Suboptimal vaccination rates contribute to outbreaks and increased risk of VZV exposure. Immunocompromised population and other patient groups are at
high risk for severe varicella and complications, after being exposed to VZV. In the United States market VARIZIG is the single FDA-approved product
and recommended by the Centers for Disease Control (“CDC”) for post-exposure prophylaxis of varicella for persons at high risk for severe disease who
lack evidence of immunity to varicella. Alternative, CDC recommendations include IVIG if VARIZIG is unavailable and some experts recommend using
Acyclovir, Valacyclovir, although published data on the benefits of acyclovir as post-exposure prophylaxis among immunocompromised people is limited.
In ROW markets, several plasma derived competitor products are available, such as VARITECT (Biotest) and others.
KAMRHO (D). We manufacture and market KAMRHO (D) for HDN in a few markets outside of the US, mainly in Russia, Israel, Argentina and
Brazil. Kedrion is one of our competitors for KAMRHO(D) in some of those international markets. We believe there are currently two additional main
suppliers of competitive products, Grifols and CSL. There are also local producers in other countries that make similar products mostly intended for local
markets.
Our market share of the AAT product could be negatively impacted by new competitors or adoption of new methods of administration.
We believe that our two main competitors in the AAT market are Grifols and CSL. We estimate that Grifols’ AAT by infusion product for the
treatment of AATD, Prolastin A1PI, accounts for at least 50% market share in the United States and more than 70% of sales in the worldwide market for
the treatment of AATD, which also includes sales of Prolastin in different European countries. To the best of our knowledge, since 2018, Grifols sell
Prolastin Liquid, a ready-to-infuse solution of AAT, in the United States. Apart from its sales through Talecris’ historical business, Grifols is also a local
producer of the product in the Spanish market and operates in Brazil. CSL’s intravenous AAT product, Zemaira, is mainly sold in the United States. In
2015, CSL’s intravenous AAT product, Respreeza, was granted centralized marketing authorization in Europe and CSL has launched the product in a few
European countries since 2016. There is another, smaller local producer in the French market, LFB S.A. In addition, we estimate that each of Grifols and
CSL owns more than 300 operating plasma collection centers located across the United States.
Several of our competitors are conducting preclinical and clinical trials for the development of gene therapy, recombinant AAT, small molecule
treatment or correctors for AATD. While these products are not yet in pivotal trial or in late stages of development, they may eventually be successfully
developed and launched, and could adversely impact our revenue and growth of sales of GLASSIA or GLASSIA-related royalties as well as affect our
ability to launch our Inhaled AAT product, if approved.
Similarly, if a new AAT formulation or a new route of administration with significantly improved characteristics is adopted (including, for
example, aerosol inhalation), the market share of our current AAT product, GLASSIA, could be negatively impacted. While we are in the process of
developing Inhaled AAT for AATD, our competitors may also be attempting to develop similar products. For example, several of our competitors may have
completed early-stage clinical trials for the development of an inhaled formulation of AAT for different indications. While these products are in the early
stages of development, they may eventually be successfully developed and launched. Furthermore, even if we are able to commercialize Inhaled AAT for
AATD prior to the development of comparable products by our competitors, sales of Inhaled AAT for AATD, subject to approval of such product by the
applicable regulatory authorities, could adversely impact our revenue and growth of sales of GLASSIA or GLASSIA -related royalties.
Our products involve biological intermediates that are susceptible to contamination and the handling of such intermediates and our final products
throughout the supply chain and manufacturing process requires cold-chain handling, all of which could adversely affect our operating results.
Plasma and its derivatives are raw materials that are susceptible to damage and contamination and may contain microorganisms that cause diseases
in humans, commonly known as human pathogens, any of which would render such materials unsuitable as raw material for further manufacturing. Almost
immediately after collection from a donor, plasma and plasma derivatives must be stored and transported at temperatures that are at least -20 degrees
Celsius (-4 degrees Fahrenheit). Improper storage or transportation of plasma or plasma derivatives by us or third-party suppliers may require us to destroy
some of our raw material. In addition, plasma and plasma derivatives are also suitable for use only for certain periods of time once removed from storage.
If unsuitable plasma or plasma derivatives are not identified and discarded prior to release to our manufacturing processes, it may be necessary to discard
intermediate or finished products made from such plasma or plasma derivatives, or to recall any finished product released to the market, resulting in a
charge to cost of goods sold and harm to our brand and reputation. Furthermore, if we distribute plasma-derived protein therapeutics that are produced from
unsuitable plasma because we have not detected contaminants or impurities, we could be subject to product liability claims and our reputation would be
adversely affected.
10
Despite overlapping safeguards, including the screening of donors and other steps to remove or inactivate viruses and other infectious disease-
causing agents, the risk of transmissible disease through plasma-derived protein therapeutics cannot be entirely eliminated. If a new infectious disease was
to emerge in the human population, the regulatory and public health authorities could impose precautions to limit the transmission of the disease that would
impair our ability to manufacture our products. Such precautionary measures could be taken before there is conclusive medical or scientific evidence that a
disease poses a risk for plasma-derived protein therapeutics. In recent years, new testing and viral inactivation methods have been developed that more
effectively detect and inactivate infectious viruses in collected plasma. There can be no assurance, however, that such new testing and inactivation methods
will adequately screen for, and inactivate, infectious agents in the plasma or plasma derivatives used in the production of our plasma-derived protein
therapeutics. Additionally, this could trigger the need for changes in our existing inactivation and production methods, including the administration of new
detection tests, which could result in delays in production until the new methods are in place, as well as increased costs that may not be readily passed on to
our customers.
Plasma and plasma derivatives can also become contaminated through the manufacturing process itself, such as through our failure to identify and
purify contaminants through our manufacturing process or failure to maintain a high level of sterility within our manufacturing facilities.
Once we have manufactured our plasma-derived therapeutics, they must be handled carefully and kept at appropriate temperatures. Our failure, or
the failure of third parties that supply, ship, store or distribute our products, to properly care for our plasma-derived products, may result in the requirement
that such products be destroyed.
While we expect work-in-process inventories scraps in the ordinary course of business because of the complex nature of plasma and plasma
derivatives, our processes and our plasma-derived therapeutics, unanticipated events may lead to write-offs and other costs in amounts materially higher
than our expectations. We have, in the past, experienced situations that have caused us to write-off the value of inventories. Such write-offs and other costs
could materially adversely affect our operating results. Furthermore, contamination of our plasma-derived protein therapeutics could cause consumers or
other third parties with whom we conduct business to lose confidence in the reliability of our manufacturing procedures, which could materially adversely
affect our sales and operating results.
Our ability to continue manufacturing and distributing our plasma-derived therapeutics depends on continued adherence by us and contract
manufacturers to current Good Manufacturing Practice regulations.
The manufacturing processes for our products are governed by detailed written procedures and regulations that are set forth in cGMP requirements
for blood products, including plasma and plasma derivative products. Failure to adhere to established procedures or regulations, or to meet a specification
set forth in cGMP requirements, could require that a product or material be rejected and destroyed. There are relatively few opportunities for us or contract
manufacturers to rework, reprocess or salvage nonconforming materials or products. Any failure in cGMP inspection will affect marketing in other
territories, including the U.S. and Israel.
The adherence by us and our contract manufacturers to cGMP regulations and the effectiveness of applicable quality control systems are
periodically assessed through inspections of the manufacturing facility, including our manufacturing facility in Beit Kama, Israel, by the FDA, the IMOH
and regulatory authorities of other countries. Such inspections could result in deficiency citations, which would require us or our contract manufacturers to
take action to correct those deficiencies to the satisfaction of the applicable regulatory authorities. If serious deficiencies are noted or if we or our contract
manufacturers are unable to prevent recurrences, we may have to recall products or suspend operations until appropriate measures can be implemented. The
FDA could also stop the import of products into the United States if there are potential deficiencies. Such deficiencies may also affect our ability to obtain
government contracts in the future. We are required to report certain deviations from procedures to the FDA. Even if we determine that the deviations were
not material, the FDA could require us or our contract manufacturers to take certain measures to address the deviations. Since cGMP reflects ever-evolving
standards, we regularly need to update our manufacturing processes and procedures to comply with cGMP. These changes may cause us to incur additional
costs and may adversely impact our profitability. For example, more sensitive testing assays (if and when they become available) may be required or
existing procedures or processes may require revalidation, all of which may be costly and time-consuming and could delay or prevent the manufacturing of
a product or launch of a new product.
We may face manufacturing stoppages and other challenges associated with audits or inspections by regulatory bodies.
The regulatory authorities may, at any time and from time to time, audit the facilities in which the product is manufactured. If any such inspection
or audit of our facilities identifies a failure to comply with applicable regulations, or if a violation of our product specifications or applicable regulations
occurs independently of such an inspection or audit, the relevant regulatory authority may require remedial measures that may be costly or time consuming
for us to implement and that may include the temporary or permanent suspension of commercial sales or the temporary or permanent closure of a facility.
Any such remedial measures imposed upon us with whom we contract could materially harm our business.
Manufacturing of new plasma-derived products in our manufacturing facility requires a lengthy and challenging development project and/or
technology transfer project as well as regulatory approvals, all of which may not materialize.
The manufacturing of newly marketed or investigational plasma-derived products in our plant, including our Proprietary Products currently
manufactured by third parties, requires a lengthy and challenging development project and/or technology transfer project through which we transfer the
know-how and capabilities to manufacture the new product. Such projects are usually complex and involve investment of significant time (approximately
three to four years) and resources. There is no assurance that such development and/or technology transfer projects will be successful and will allow us to
manufacture the new product according to its required specifications.
11
Such development and/or technology transfer projects require regulatory approval by the FDA and/or EMA and/or Health Canada or other
relevant regulatory agencies. Obtaining such regulatory approval may require activities such as the manufacturing of comparable batches and/or performing
comparability non-clinical and/or clinical studies between the product manufactured by its existing manufacturer and the product manufactured at our
manufacturing facility. There is no assurance that we will be able to provide supporting comparability results that meet all regulatory requirements needed
to obtain the regulatory approval required to be able to commence commercial manufacturing of new plasma-derived products in our manufacturing plant.
If we are unable to adequately complete the required development and/or technology transfer projects or subsequently obtain the required
regulatory approvals, we will not be able to meet commercial demand, utilize the excess capacity of our manufacturing plant, incur additional costs and
may suffer reduced profitability or operating losses.
We would become supply-constrained and our financial performance would suffer if we were unable to obtain adequate quantities of source plasma or
plasma derivatives or specialty ancillary products that meet the regulatory requirement of the FDA, EMA, Health Canada or the regulatory authorities
in Israel, or if our suppliers were to fail to modify their operations to meet regulatory requirements or if prices of the source plasma or plasma
derivatives were to raise significantly.
Our proprietary products depend on our access to U.S., European or other territories’ hyper-immune plasma or plasma derivatives, such as fraction
IV. We purchase these plasma products from third-party licensed suppliers, some of which are also responsible for the plasma fractionation process,
pursuant to multiple purchase agreements. We have entered into (and with respect to the recently acquired four FDA approved products, we assumed) a
number of plasma supply agreements with various third parties in the United States and Europe. These agreements contain various termination provisions,
including upon a material breach of either party, force majeure and, with respect to supply agreements with strategic partners, the failure or delay on the
part of either party to obtain the applicable regulatory approvals or the termination of the principal strategic relationship. If we are unable to obtain
adequate quantities of source plasma or fraction IV plasma that meet the regulatory requirements of the FDA, the EMA or the regulatory authorities in
Israel from these providers, we may be unable to find an alternative cost-effective source.
In order for plasma and fraction IV plasma to be used in the manufacturing of our plasma-derived protein therapeutics, the individual centers at
which the plasma is collected must be registered with and meet the regulatory requirements of the relevant regulatory authorities, such as the FDA and
EMA. When a new plasma collection center is opened, and on an ongoing basis after its registration, it must be inspected by the FDA, the EMA or the
regulatory authorities in Israel for compliance with cGMP and other regulatory requirements. An unsatisfactory inspection could prevent a new center from
being established or lead to the suspension or revocation of an existing registration. If relevant regulatory authorities determine that a plasma collection
center did not comply with cGMP in collecting plasma, we may be unable to use and may ultimately destroy plasma collected from that center, which may
impact on our ability to timely meet our manufacturing and supply obligations. Additionally, if noncompliance in the plasma collection process is identified
after the impacted plasma has been pooled with compliant plasma from other sources, entire plasma pools, in-process intermediate materials and final
products could be impacted, such as through product destruction or rework. Consequently, we could experience significant inventory impairment
provisions and write-offs, which could adversely affect our business and financial results.
In addition, the plasma supplier’s fractionation process must also meet standards of the FDA, the EMA or the regulatory authorities in Israel. If a
plasma supplier is unable to meet such standards, we will not be able to use the plasma derivatives provided by such supplier, which may impact on our
ability to timely meet our manufacturing and supply obligations.
If we were unable to obtain adequate quantities of source plasma or plasma derivatives that meet the regulatory standards of the FDA, the EMA or
the regulatory authorities in Israel, we would be limited in our ability to maintain or increase current manufacturing levels of our plasma derivative
products, as well as in our ability to conduct the research required to maintain our product pipeline. As a result, we could experience a substantial decrease
in total revenues or profit margins, a potential breach of distribution agreements, a loss of customers, a negative effect on our reputation as a reliable
supplier of plasma derivative products or a substantial delay in our production and strategic growth plans.
The ability to increase plasma collections may be limited, our supply of plasma and plasma derivatives could be disrupted or the cost of plasma
and plasma derivatives could increase substantially, as a result of numerous factors, including a reduction in the donor pool, increased regulatory
requirements, decreased number of plasma supply sources due to consolidation and new indications for plasma-derived protein therapeutics, which could
increase demand for plasma and plasma derivatives and lead to shortages.
The plasma collection process is dependent on donors arriving in plasma collection centers and agreeing to donate plasma. Factors such as
changes in reimbursement rates, competition for donors, and declining donor loyalty may lead to a decrease in the number of donors, which may negatively
impact our ability to obtain adequate quantities of plasma. During major healthcare events, such as the recent COVID-19 pandemic, the number of donors
attending plasma collection centers decreases, which may adversely affect the availability of plasma and its derivatives. A significant shortage in plasma
supply may adversely affect our ability to continue manufacturing our products, may result in shortages in our products in the market, and may result in
reduced sales and profitability.
12
We are also dependent on a number of suppliers who supply specialty ancillary products used in the production process, such as specific gels and
filters. Each of these specialty ancillary products is provided by a single, exclusive supplier. If these suppliers were unable to provide us with these
specialty ancillary products, if our relationships with these suppliers deteriorate, if these suppliers fail to meet our vendors qualification processes, or these
suppliers’ operations are negatively affected by regulatory enforcement due to noncompliance, the manufacture and distribution of our products would be
materially adversely affected, which would adversely affect our sales and results of operations. See “—If we experience equipment difficulties or if the
suppliers of our equipment or disposable goods fail to deliver key product components or supplies in a timely manner, our manufacturing ability would be
impaired and our product sales could suffer.”
Some of our required specialty ancillary products and other materials used in the manufacturing process are commonly used in the healthcare
industry world-wide. If the global demand for these products increases due to healthcare issues, epidemics or pandemics, such as the coronavirus (COVID-
19) pandemic, our ability to secure adequate supply at reasonable cost of such products may be negatively affected, which would materially adversely
affect our ability to manufacture and distribute our products, which would adversely affect our sales and results of operations.
In addition, regulatory requirements, including cGMP regulations, continually evolve. Failure of our plasma suppliers to adjust their operations to
conform to new standards as established and interpreted by applicable regulatory authorities would create a compliance risk that could impair our ability to
sustain normal operations.
In addition, if the purchase prices of the source plasma or plasma derivatives that we use to manufacture our proprietary products were to rise
significantly, we may not be able to pass along these increased plasma and plasma-derivative prices to our customers. Prices in many of our principal
markets are subject to local regulation and certain pharmaceutical products, such as plasma-derived protein therapeutics, are subject to price controls. Any
inability to pass costs on to our customers due to these factors or others would reduce our profit margins. In addition, most of our competitors have the
ability to collect their own source plasma or produce their own plasma derivatives, and therefore their products’ prices would not be impacted by such a
price rise, and as a result any pricing changes by us in order to pass higher costs on to our customers could render our products noncompetitive in certain
territories.
Disruption of the operations of our current or any future plasma collection center due to regulatory impediments or otherwise would cause us to
become supply constrained and our financial performance would suffer.
In March 2021, we completed the acquisition of the FDA licensed plasma collection center and certain related assets from the privately held
B&PR based in Beaumont, Texas, which currently specializes in the collection of hyper-immune plasma used in the manufacture KAMRHO(D). We are in
the process of significantly expanding our hyperimmune plasma collection capacity in this center. We registered the collection of hyper-immune plasma to
be used in the manufacture of KEDRAB with the FDA and plan to start collections of such plasma during 2023. We also intend to leverage our experience
with plasma collection to establish additional plasma collection centers in the United States, with the intention of collecting normal source plasma, as well
as hyper-immune specialty plasma required for manufacturing of our Proprietary Products. To that end, during March 2023, we entered into a lease for a
new plasma collection center in Uvalde, Houston, Texas and expect to commence operations at the new center following the completion of its construction
and obtaining the required regulatory approvals.
In order for plasma to be used in the manufacturing of our products, the individual centers at which the plasma is collected must be registered with
and meet the regulatory requirements of the regulatory authorities, such as the FDA and the EMA, of those countries in which we sell our products. When a
new plasma collection center is opened, it must be inspected on an ongoing basis after its approval by the FDA and the EMA for compliance with cGMP
and other regulatory requirements, and these regulatory requirements are subject to change. An unsatisfactory inspection could prevent a new center from
being established or risk the suspension or revocation of an existing registration. In order for a plasma collection center to maintain its governmental
registration, its operations must continue to conform to cGMP and other regulatory requirements or recommendations which may be applicable from time
to time (e.g., in January 2022, the FDA issued guidance providing recommendations to blood establishments on collection of convalescent plasma during
the public health emergency).
If it would be determined that our plasma collection center did not comply with cGMP, or other regulatory requirements in collecting plasma, we
may be unable to use and may ultimately be required to destroy plasma collected from that center, which would be recorded as a charge to cost of goods.
Additionally, if noncompliance in the plasma collection process is identified after the impacted plasma has been pooled with compliant plasma from other
sources, entire plasma pools, in-process intermediate materials and final products could be impacted. Consequently, we could experience significant
inventory impairment provisions and write-offs if it was determined that our plasma collection center did not comply with cGMP in collecting plasma.
We plan to increase our supplies of plasma for use in our manufacturing processes through collections at our existing plasma collection center and
through the establishment of new plasma collection centers. This strategy is dependent upon our ability to successfully establish and register new centers,
to maintain compliance with all FDA and other regulatory requirements in all centers and to attract donors to our centers.
Our ability to increase and improve the efficiency of plasma collection at our current or any future plasma collection center may be affected by: (i)
changes in the economic environment and population in selected regions where we operate plasma collection centers; (ii) the entry of competitive centers
into regions where we operate; (iii) our misjudging the demographic potential of individual regions where we expect to increase production and attract new
donors; (iv) unexpected facility related challenges; (v) unexpected management challenges at select plasma collection centers; or (vi) changes to regulatory
requirements.
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The biologic properties of plasma and plasma derivatives are variable, which may impact our ability to consistently manufacture our products in
accordance with the approved specifications.
While our manufacturing processes were developed to meet certain product specifications, variations in the biologic properties of the plasma or
plasma derivatives as well as the manufacturing processes themselves may result in out of specification results during the manufacturing of our products.
While we expect certain work-in-process inventories scraps in the ordinary course of business because of the complex nature of plasma and plasma
derivatives, our processes and our plasma-derived protein therapeutics, unanticipated events may lead to write-offs and other costs in amounts that are
materially higher than our expectations. We have, in the past, experienced situations that have caused us to write-off the value of our products. Such write-
offs and other costs could materially adversely affect our operating results.
The biologic properties of plasma and plasma derivatives are variable, which may adversely impact our levels of product yield from our plasma or
plasma derivative supply.
Due to the nature of plasma, there will be variations in the biologic properties of the plasma or plasma derivatives we purchase that may result in
fluctuations in the obtainable yield of desired fractions, even if cGMP is followed. Lower yields may limit production of our plasma-derived protein
therapeutics because of capacity constraints. If these batches of plasma with lower yields impact production for extended periods, we may not be able to
fulfill orders on a timely basis and the total capacity of product that we are able to market could decline and our cost of goods sold could increase, thus
reducing our profitability.
Usage of our products may lead to serious and unexpected side effects, which could materially adversely affect our business and may, among other
factors, lead to our products being recalled and our reputation being harmed, resulting in an adverse effect on our operating results.
The use of our plasma-derived protein therapeutics may produce undesirable side effects or adverse reactions or events. For the most part, these
side effects are known, are expected to occur at some frequency and are described in the products’ labeling. Known side effects of several plasma-derived
therapeutics include headache, nausea and additional common protein infusion related events, such as flu-like symptoms, dizziness and hypertension. The
occurrence of known side effects on a large scale could adversely affect our reputation and public image, and hence also our operating results.
In addition, the use of our plasma-derived protein therapeutics may be associated with serious and unexpected side effects, or with less serious
reactions at a greater than expected frequency. This may be especially true when our products are used in critically ill patient populations. When these
unexpected events are reported to us, we typically make a thorough investigation to determine causality and implications for product safety. These events
must also be specifically reported to the applicable regulatory authorities, and in some cases, also to the public by media channels. If our evaluation
concludes, or regulatory authorities perceive, that there is an unreasonable risk associated with one of our products, we would be obligated to withdraw the
impacted lot or lots of that product or, in certain cases, to withdraw the product entirely. Furthermore, it is possible that an unexpected side effect caused by
a product could be recognized only after extensive use of the product, which could expose us to product liability risks, enforcement action by regulatory
authorities and damage to our reputation.
We are subject to several existing laws and regulations in multiple jurisdictions, non-compliance with which could adversely affect our business,
financial condition and results of operations, and we are susceptible to a changing regulatory environment, which could increase our compliance costs
or reduce profit margins.
Any new product must undergo lengthy and rigorous testing and other extensive, costly, and time-consuming procedures mandated by the FDA
and similar authorities in other jurisdictions, including the EMA and the regulatory authorities in Israel. Our facilities and those of our contract
manufacturers must be approved and licensed prior to production and remain subject to inspection from time to time thereafter. Failure to comply with the
requirements of the FDA or similar authorities in other jurisdictions, including a failed inspection or a failure in our reporting system for adverse effects of
our products experienced by the users of our products, or any other non-compliance, could result in warning letters, product recalls or seizures, monetary
sanctions, injunctions to halt the manufacture and distribution of products, civil or criminal sanctions, import or export restrictions, refusal or delay of a
regulatory authority to grant approvals or licenses, restrictions on operations or withdrawal of existing approvals and licenses. Furthermore, we may
experience delays or additional costs in obtaining new approvals or licenses, or extensions of existing approvals and licenses, from a regulatory authority
due to reasons that are beyond our control such as changes in regulations or a shutdown of the U.S. federal government, including the FDA, or similar
governing bodies or authorities in other jurisdictions. In addition, while we recently entered the U.S. plasma collection market with our recent acquisition
of a plasma collection center in the United States, we continue to rely on, Kedrion, CSL, Emergent, Takeda and additional plasma suppliers, for plasma
collection required for the manufacturing of KEDRAB, CYTOGAM, HEPGAM B, VARIZIG, WINRHO SDF, GLASSIA and other Proprietary products,
and in the case of Kedrion and Takeda, for the distribution of these products in the United States (and in the case of Takeda, also potentially in Canada,
Australia and New Zealand). In performing such services for us, these plasma suppliers are required to comply with certain regulatory requirements. Any
failure by these plasma suppliers to properly advise us regarding, or properly perform tasks related to, regulatory compliance requirements, could adversely
affect us. Any of these actions could cause direct liabilities, a loss in our ability to market each of KEDRAB, CYTOGAM, HEPGAM B,
VARIZIG,WINRHO SDF, GLASSIA and/or other Proprietary products, or a loss of customer confidence in us or in GLASSIA and/or KEDRAB and/or
other Proprietary products, which could materially adversely affect our sales, future revenues, reputation, and results of operations. Similarly, we rely on
other third-party vendors, for example, in the testing, handling, and distributions of our products. If any of these companies incur enforcement action from
regulatory authorities due to noncompliance, this could negatively affect product sales, our reputation and results of operations. In addition, we rely on
other distributors of our other proprietary products, for purposes of our distribution related regulatory compliance for the products they distribute in the
territories in which they operate. Any failure by such distributors to properly advise us regarding, or properly perform tasks related to, regulatory
compliance requirements, could adversely affect our sales, future revenues, reputation and results of operations.
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Changes in our production processes for our products may require supplemental submissions or prior approval by FDA and/or similar authorities
in other jurisdictions. Failure to comply with any requirements as to production process changes dictated by the FDA or similar authorities in other
jurisdictions could also result in warning letters, product recalls or seizures, monetary sanctions, injunctions to halt the manufacture and distribution of
products, civil or criminal sanctions, refusal or delay of a regulatory authority to grant approvals or licenses, restrictions on operations or withdrawal of
existing approvals and licenses.
Pursuant to the amendment to the GLASSIA license agreement with Takeda, entered into in March 2021, we agreed to transfer the BLA to
Takeda. Following the effectiveness of such transfer, we will rely on Takeda to share with us any relevant information with respect to changes in the
manufacturing of the product or its usage which may be applicable in order to update the products registration file in certain ROW markets in which it is
currently registered and/or distributed or may be registered and/or distributed in the future.
In addition, changes in the regulation of our activities, such as increased regulation affecting quality or safety requirements or new regulations
such as limitations on the prices charged to customers in the United States, Israel or other jurisdictions in which we operate, could materially adversely
affect our business. In addition, the requirements of different jurisdictions in which we operate may become less uniform, creating a greater administrative
burden and generating additional compliance costs, which would have a material adverse effect on our profit margins. See also – “Regulatory approval for
our products is limited by the FDA, EMA, the IMOH and similar authorities in other jurisdictions to those specific indications and conditions for which
clinical safety and efficacy have been demonstrated, and the prescription or promotion of off-label uses could adversely affect our business.”; and “—Laws
and regulations governing the conduct of international operations may negatively impact our development, manufacture, and sale of products outside of
the United States and require us to develop and implement costly compliance programs.” and “—Uncertainty surrounding and future changes to
healthcare law in the United States and other United States Government related mandates may adversely affect our business.”
If we experience equipment difficulties or if the suppliers of our equipment or disposable goods fail to deliver key product components or supplies in a
timely manner, our manufacturing ability would be impaired, and our product sales could suffer.
For certain equipment and supplies, we depend on a limited number of companies that supply and maintain our equipment and provide supplies
such as chromatography resins, filter media, glass bottles and stoppers used in the manufacture of our plasma-derived protein therapeutics. If our equipment
were to malfunction, or if our suppliers stop manufacturing or supplying such machinery, equipment or any key component parts, the repair or replacement
of the machinery may require substantial time and cost and could disrupt our production and other operations. Alternative sources for key component parts
or disposable goods may not be immediately available. In addition, any new equipment or change in supplied materials may require revalidation by us or
review and approval by the FDA, the EMA, the IMOH or other regulatory authorities, which may be time-consuming and require additional capital and
other resources. We may not be able to find an adequate alternative supplier in a reasonable time period, or on commercially acceptable terms, if at all. As a
result, shipments of affected products may be limited or delayed. Our inability to obtain our key source supplies for the manufacture of products may
require us to delay shipments of products, harm customer relationships and force us to curtail operations.
We have been required to conduct post-approval clinical trials of GLASSIA and KEDRAB as a commitment to continuing marketing such products in
the United States, and we may be required to conduct post-approval clinical trials as a condition to licensing or distributing other products.
When a new product is approved, the FDA or other regulatory authorities may require post-approval clinical trials, sometimes called Phase 4
clinical trials. For example, the FDA has required that we conduct Phase 4 clinical trials of GLASSIA and for KEDRAB. Such Phase 4 clinical trials are
aimed at collecting additional safety data, such as the immune response in the body of a human or animal, commonly referred to as immunogenicity, viral
transmission, levels of the protein in the lung, or epithelial lining fluid, and certain efficacy endpoints requested by the FDA. If the results of such trials are
unfavorable and demonstrate a previously undetected risk or provide new information that puts patients at risk, or if we fail to complete such trials as
instructed by the FDA, this could result in receiving a warning letter from the FDA and the loss of the approval to market the product in the United States
and other countries, or the imposition of restrictions, such as additional labeling, with a resulting loss of sales. Furthermore, there can be no assurance that
the FDA will accept the results of any post-marketing commitment study, such as the results of the KEDRAB study, and under certain circumstances the
FDA may require a subsequent study. Other products we develop may face similar requirements, which would require additional resources and which may
not be successful. We may also receive approval that is conditioned on successful additional data or clinical development, and failure in such further
development may require similar changes to our product label or result in revocation of our marketing authorization.
The nature of producing and developing plasma-derived protein therapeutics may prevent us from responding in a timely manner to market forces and
effectively managing our production capacity.
The production of plasma-derived protein therapeutics is a lengthy and complex process. Our ability to match our production of plasma-derived
protein therapeutics to market demand is imprecise and may result in a failure to meet the market demand for our plasma-derived protein therapeutics or
potentially in an oversupply of inventory. Failure to meet market demand for our plasma-derived protein therapeutics may result in customers transitioning
to available competitive products, resulting in a loss of segment share or distributor or customer confidence. In the event of an oversupply in the market, we
may be forced to lower the prices we charge for some of our plasma-derived protein therapeutics, record asset impairment charges or take other action
which may adversely affect our business, financial condition and results of operations.
15
Risks Related to Our Distribution Segment
Our Distribution segment is dependent on a few suppliers, and any disruption to our relationship with these suppliers, or their inability to supply us
with the products we sell, in a timely manner, in adequate quantities and/or at a reasonable cost, would have a material adverse effect on our business,
financial condition and results of operations.
Sales of products supplied by Biotest A.G., Kedrion, Chiesi Farmaceutici S.p.A, BPL and Valneva SE, which are sold in our Distribution segment,
together represented approximately 20%, 26% and 24% of our total revenues for the years ended December 31, 2022, 2021 and 2020, respectively. While
we have distribution agreements with each of our suppliers, these agreements do not obligate these suppliers to provide us with minimum amounts of our
Distribution segment products. Purchases of our Distribution segment products from our suppliers are typically on a purchase order basis. We work closely
with our suppliers to develop annual forecasts, but these forecasts are not obligations or commitments. However, if we fail to submit purchase orders that
meet our annual forecasts or if we fail to meet our minimum purchase obligations, we could lose exclusivity or, in certain cases, the distribution agreement
could be terminated.
These suppliers may experience capacity constraints that result in their being unable to supply us with products in a timely manner, in adequate
quantities and/or at a reasonable cost. Contributing factors to supplier capacity constraints may include, among other things, industry or customer demands
in excess of machine capacity, labor shortages, changes in raw material flows or shortages in raw materials which may result from different market
conditions including, but not limited to, shortages resulting from increased global demand for these raw materials due to global healthcare issues,
epidemics and pandemics, such as the COVID-19 pandemic. These suppliers may also choose not to supply us with products at their discretion or raise
prices to a level that would render our products noncompetitive. Any significant interruption in the supply of these products could result in us being unable
to meet the demands of our customers, which would have a material adverse effect on our business, financial condition and results of operations as a result
of being required to pay of fines or penalties, be subject to claims of reach of contract, loss of reputation or even termination of agreement.
If our relationship with either distributor deteriorated, our distribution sales could be adversely affected. If we fail to maintain our existing
relationships with these suppliers, we could face significant costs in finding a replacement supplier, and delays in establishing a relationship with a new
supplier could lead to a decrease in our sales and a deterioration in our market share when compared with one or more of our competitors.
Additionally, our future growth in the Distribution segment is dependent on our ability to successfully engage other manufacturers for distribution
in Israel of other products. Failure to engage new suppliers may have an adverse effect on our revenue growth and profitability.
Certain of our sales in our Distribution segment rely on our ability to win tender bids based on the price and availability of our products in annual
public tender processes.
Certain of our sales in our Distribution segment rely on our ability to win tender bids during the annual tender process in Israel, as well as on sales
made to Health Maintenance Organizations (HMOs), hospitals and to the IMOH. Our ability to win bids may be materially adversely affected by
competitive conditions in such bid process. Our existing and new competitors may also have significantly greater financial resources than us, which they
could use to promote their products and business. Greater financial resources would also enable our competitors to substantially reduce the price of their
products or services. If our competitors are able to offer prices lower than us, our ability to win tender bids during the annual tender process will be
materially affected and could reduce our total revenues or decrease our profit margins.
Certain of our products in both segments have historically been subject to price fluctuations as a result of changes in the production capacity
available in the industry, the availability and pricing of plasma, development of competing products and the availability of alternative therapies. Higher
prices for plasma-derived protein therapeutics have traditionally spurred increases in plasma production and collection capacity, resulting over time in
increased product supply and lower prices. As demand continues to grow, if plasma supply and manufacturing capacity do not commensurately expand,
prices tend to increase. Additionally, consolidation in plasma companies has led to a decrease in the number of plasma suppliers in the world, as either
manufacturers of plasma-based pharmaceuticals purchase plasma suppliers or plasma suppliers are shut down in response to the number of manufacturers
of plasma-based pharmaceuticals decreasing, which may lead to increased prices. We may not be able to pass along these increased plasma and plasma-
derivative prices to our customers, which would reduce our profit margins.
Sales of our Distribution segment products are made through public tenders of Israeli hospitals and HMOs on an annual basis or in the private
market based on detailing activity made by our medical representatives. The prices we can offer, as well as the availability of products, are key factors in
the tender process. If our suppliers in the Distribution segment cannot sell us products at a competitive price or cannot guarantee sufficient quantities of
products, we may lose the tenders.
Our Distribution segment is dependent on a few customers, and any disruption to our relationship with these customers, or our inability to supply, in a
timely manner, in adequate quantities and/or at a reasonable cost, would have a material adverse effect on our business, financial condition and results
of operations.
The Israeli market for drug products includes a relatively small number of HMOs and several hospitals. Sales to Clalit Health Services, an Israeli
HMO, accounted for approximately 46%, 42% and 41% of our Distribution segment revenues in the years ended December 31, 2022, 2021 and 2020,
respectively.
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If our relationship with any of our Israeli customers deteriorated, our distribution sales could be adversely affected. Failure to maintain our
existing relationships with these customers could lead to a decrease in our revenues and profitability.
Before we may sell products in the Distribution segment, we must register the products with the IMOH and there can be no assurance that such
registration will be obtained.
Before we may sell products in the Distribution segment in Israel, we must register the products, at our own expense, with the IMOH. We cannot
predict how long the registration process of the IMOH may take or whether any such registration ultimately will be obtained. The IMOH has substantial
discretion in the registration process and we can provide no assurance of success of registration. Our business, financial condition or results of operations
could be materially adversely affected if we fail to receive IMOH registration for the products in the Distribution segment.
Our Distribution segment is a low-margin business and our profit margins may be sensitive to various factors, some of which are outside of our
control.
Our Distribution segment is characterized by high volume sales with relatively low profit margins. Volatility in our pricing may have a direct
impact on our profitability. Prolonged periods of product cost inflation may have a negative impact on our profit margins and results of operations to the
extent we are unable to pass on all or a portion of such product cost increases to our customers. In addition, if our product mix changes, we may face
increased risks of compression of our margins, as we may be unable to achieve the same level of profit margins as we are able to capture on our existing
products. Our inability to effectively price our products or to reduce our expenses due to volatility in pricing could have a material adverse impact on our
business, financial condition or results of operations.
We may be subject to milestone payments in connection with our Distribution segment products irrespective of whether the commercialization is
successful.
Certain of our agreements in the Distribution segment, including agreements for distribution of biosimilar product candidates, require us to make
milestone payments in advance of product launch. In some cases, we may not be able to obtain reimbursement for such payments. To the extent that we are
not ultimately able to recoup these payments, our business, financial position and results of operations may be adversely affected.
We face significant competition in our Distribution segment from companies with greater financial resources.
In the Distribution segment, we face competition for our distribution products that are marketed in Israel and compete for market share. We
believe that there are several companies active in the Israeli market distributing the products of several manufacturers whose comparable products compete
with the products we distribute as part of our Distribution segment. In the plasma area, these manufacturers include Grifols, Takeda and CSL. In other
specialties and biosimilar products, we compete with products produced by some of the largest pharmaceutical manufacturers in the world, such as,
Novartis AG, AstraZeneca AB, Sanofi and GlaxoSmithKline. Each of these competitors sells its products through a local subsidiary or a local
representative in Israel. Our existing and new competitors may have significantly greater financial resources than us, which they could use to promote their
products and business or reduce the price of their products or services. If we are unable to maintain or increase our market share, we may need to reduce
prices and may suffer reduced profitability or operating losses, which could have a material adverse impact on our business, financial condition or results of
operations.
We recently entered into agreements for future distribution in Israel of several biosimilar product candidates, and the successful future distribution of
these products is dependent upon several factors some of which are beyond our control.
Over the past several years we entered into agreements with respect to planned distribution in Israel of certain biosimilar product candidates.
Biosimilar products are highly similar to biological products already licensed for distribution by the FDA, EMA or any other relevant regulatory agency,
notwithstanding minor differences in clinically inactive components, and that they have no clinically meaningful differences, as compared to the marketed
biological products in terms of the safety, purity and potency of the products. The similar nature of a biosimilar and a reference product is demonstrated by
comprehensive comparability studies covering quality, biological activity, safety and efficacy.
In order to launch biosimilar products in Israel we would need to obtain IMOH marketing authorization, which will be subject to prior
authorization to be obtained by the manufacturer of the biosimilar product from the FDA or the EMA. Even if an FDA or EMA authorization is provided,
there can be no assurance that the IMOH will accept such authorization as a reference and will grant us the authorization to distribute such biosimilar
products in the Israeli market. In the event we will not be able to obtain the necessary marking authorization to launch the products, we may not generate
the expected sale and profitability from these products, which could have a material adverse impact on our business, financial condition or results of
operations. Delays in the commercialization of such biosimilar products, including due to delays in obtaining marketing authorization, may expose us to
increased competition, such as due to the entry of new competitors into the market, which may adversely impact our potential sales and profitability from
these products.
Innovative pharmaceutical products are generally protected for a defined period by various patents (including those covering drug substance, drug
product, approved indications, methods of administration, methods of manufacturing, formulations and dosages) and/or regulatory exclusivity, which are
intended to provide their holders with exclusive rights to market the products for the life of the patent or duration of the regulatory data protection period.
Biosimilar products are intended to replace such innovative pharmaceutical upon the expiration or termination of their exclusivity period or in such markets
whereby such exclusivity does not exist. The launch of a biosimilar product may potentially result in the infringement of certain IP rights and exclusivity
and be subject to potential legal proceedings and restraining orders effecting its potential launch. Such intellectual property threats may preclude
commercialization of such biosimilar product candidates, may result in incurring significant legal expenses and liabilities and we may not generate the
expected sale and profitability from these products, which could have a material adverse impact on our business, financial condition or results of
operations.
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In addition, the commercialization of biosimilars includes the potential for steeper than anticipated price erosion due to increased competitive
intensity, and lower uptake for biosimilars due to various factors that may vary for different biosimilars (e.g., anti-competitive practices, physician
reluctance to prescribe biosimilars for existing patients taking the originator product, or misaligned financial incentives), all of which may affect our
potential sales and profitability from these products which could have a material adverse impact on our business, financial condition or results of
operations.
Risks Related to Development, Regulatory Approval and Commercialization of Product Candidates
Drug product development including preclinical and clinical trials is a lengthy and expensive process and may not result in receipt of regulatory
approval.
Before obtaining regulatory approval for the sale of our product candidates, including Inhaled AAT for AATD, or for the marketing of existing
products for new indications, we must conduct, at our own expense, extensive preclinical tests to demonstrate the safety of our product candidates in
animals and clinical trials to demonstrate the safety and efficacy of our product candidates in humans. We cannot predict how long the approval processes
of the FDA, the EMA, the regulatory authorities in Israel or any other applicable regulatory authority or agency for any of our product candidates will take
or whether any such approvals ultimately will be granted. The FDA, the EMA, the regulatory authorities in Israel and other regulatory agencies have
substantial discretion in the relevant drug approval process over which they have authority, and positive results in preclinical testing or early phases of
clinical studies offer no assurance of success in later phases of the approval process. The approval process varies from country to country and the
requirements governing the conduct of clinical trials, product manufacturing, product licensing, pricing and reimbursement vary greatly from country to
country.
Preclinical and clinical testing is expensive, is difficult to design and implement, can take many years to complete and is uncertain as to outcome.
A failure of one or more of our clinical trials can occur at any stage of testing. For example, the Phase 2/3 clinical trial in Europe for Inhaled AAT for
AATD did not meet its primary or secondary endpoints and we subsequently withdrew the Marketing Authorization Application (“MAA”) in Europe for
our Inhaled AAT for AATD.
As a result of the COVID-19 pandemic we encountered delays in patient recruitment into our pivotal Phase 3 InnovAAT clinical study conducted at a
first study site in Europe and it impacted our ability to open additional study sites in the United States and Europe. COVID-19 may in the future affect
our ability to conduct the study.
During December 2019, we announced that the first patient was randomized in Europe into our pivotal Phase 3 InnovAATe clinical trial, a
randomized, double-blind, placebo-controlled, pivotal Phase 3 trial designed to assess the efficacy and safety of Inhaled AAT in patients with AATD and
moderate lung disease. Under the study design, up to 220 patients will be randomized 1:1 to receive either Inhaled AAT at a dose of 80mg once daily, or
placebo, over two years of treatment. Enrolment into the trial continued through February 2020, however, thereafter was temporarily halted due to the
impact of COVID-19 pandemic on healthcare systems. Although during 2022, we resumed and accelerated patient recruitment to the study and expanded
the study to additional sites across Europe, the COVID-19 pandemic may continue to slow down the rate of recruitment, and may cause a material delay in
completing this study, or otherwise may require us to halt the study completely or reduce the overall size of the study, which might not be acceptable by the
FDA and/or EMA. These circumstances may affect our ability to complete the study successfully or may prevent us from having sufficient information to
file for and obtain regulatory approval for this product by the FDA, EMA or any other relevant regulatory agency.
Each inhaled formulation of AAT, including Inhaled AAT for AATD, is being developed with a specific nebulizer produced by PARI, and the
occurrence of an adverse market event or PARI’s non-compliance with its obligations would have a material adverse effect on the commercialization of
any inhaled formulation of AAT.
We are dependent upon PARI GmbH (“PARI”) for the development and commercialization of any inhaled formulation of AAT, including our
Inhaled AAT for AATD. We have an agreement with PARI, pursuant to which it is required to obtain the appropriate clearance to market PARI’s proprietary
eFlow® device, which is a device required for the administration of inhaled formulation of AAT, from the EMA and FDA for use with Inhaled AAT for
AATD. See “Item 4. Information on the Company — Strategic Partnerships — PARI.” Failure of PARI to achieve these authorizations, or to maintain
operations in regulatory compliance, will have a material adverse effect on the commercialization of any inhaled formulation of AAT, including Inhaled
AAT for AATD, which would harm our growth strategy.
Additionally, pursuant to the agreement, PARI is obligated to manufacture and supply all of the market demand for the eFlow device for use in
conjunction with any inhaled formulation of AAT and we are required to purchase all of our volume requirements from PARI. Any event that permanently,
or for an extended period, prevents PARI from supplying the required quantity of devices would have an adverse effect on the commercialization of any
inhaled formulation of AAT, including Inhaled AAT for AATD.
Lastly, we rely on PARI to ensure that the eFlow device is not violating or infringing on any third party intellectual property or patents. PARI’s
inability to ensure its freedom to operate may have a significant effect on our ability to continue the development of our Inhaled AAT product candidate as
well as potentially commercializing it.
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We rely on third parties to conduct our preclinical and clinical trials. The failure of these third parties to successfully carry out their contractual duties
or meet expected deadlines could substantially harm our business because we may not obtain regulatory approval for, or commercialize, our product
candidates in a timely manner or at all.
We rely upon third-party contractors, such as university researchers, study sites, physicians and contract research organizations (“CROs”), to
conduct, monitor and manage data for our current and future preclinical and clinical programs. We expect to continue to rely on these parties for execution
of our preclinical and clinical trials, and we control only certain aspects of their activities. Nevertheless, we are responsible for ensuring that each of our
studies is conducted in accordance with the applicable protocol and legal, regulatory and scientific standards, and our reliance on such third-party
contractors does not relieve us of our regulatory responsibilities. With respect to clinical trials, we and our CROs are required to comply with current Good
Clinical Practices (“GCP”), which are regulations and guidelines enforced by the FDA, the EMA and comparable foreign regulatory authorities for all of
our products in clinical development. Regulatory authorities enforce these GCP through periodic inspections of trial sponsors, principal investigators and
trial sites. If we or any of our CROs fail to comply with applicable GCP, the clinical data generated in our clinical trials may be deemed unreliable and the
FDA or comparable foreign regulatory authorities may require us to perform additional clinical trials before approving our marketing applications. We
cannot assure you that upon inspection by a given regulatory authority, such regulatory authority will determine that any of our clinical trials comply with
GCP requirements.
These third-party contractors are not our employees, we cannot effectively control whether or not they devote sufficient time and resources to our
ongoing clinical, nonclinical and preclinical programs, and except for remedies available to us under our agreements with such third-party contractors, we
may be unable to recover losses that result from any inadequate work on such programs. If such third-party contractors do not successfully carry out their
contractual duties or obligations or meet expected deadlines or if the quality or accuracy of the data they obtain is compromised due to the failure to adhere
to our clinical protocols, regulatory requirements or for other reasons, our development efforts and clinical trials may be extended, delayed or terminated
and we may not be able to obtain regulatory approval for or successfully commercialize our product candidates. As a result, our results of operations and
the commercial prospects for our product candidates would be harmed, our costs could increase and our ability to generate revenues could be delayed. To
the extent we are unable to successfully identify and manage the performance of such third-party contractors in the future, our business may be adversely
affected.
We have initiated the development of a recombinant AAT product candidate; however, any continued development of this product will be dependent on
our ability to attract a suitable development/commercialization partner for this project, and we may not be able to successfully complete its development
or commercialize such product candidate for numerous reasons.
During 2020, we initiated the development of a recombinant version of AAT, through external services of a contract development and
manufacturing organization (“CDMO”). See “Item 4. Information on the Company — Our Development Product Pipeline — Recombinant AAT.”. The
main advantage of recombinant AAT is its potentially wider availability, and ease of large-scale manufacturing. However, continued investment in the
development of this product will be subject to identifying a suitable development and commercialization partner, and we may not be able to identify such a
suitable partner or be successful in entering into an agreement with any particular partner on acceptable terms or at all. Further, even if we are successful in
entering into an arrangement with such a partner, we may not be able to successfully develop or commercialize a recombinant product for numerous
reasons.
We may encounter unforeseen events that delay or prevent us from receiving regulatory approval for our product candidates.
We have experienced unforeseen events that have delayed our ability to receive regulatory approval for certain of our product candidates, and may
in the future experience similar or other unforeseen events during, or as a result of, preclinical testing or the clinical trial process that could delay or prevent
our ability to receive regulatory approval or commercialize our product candidates, including the following:
● delays may occur in obtaining our clinical materials;
● our preclinical tests or clinical trials may produce negative or inconclusive results, and we may decide, or regulators may require us, to
conduct additional preclinical testing or clinical trials or to abandon strategic projects;
● the number of patients required for our clinical trials may be larger than we anticipate, enrollment in our clinical trials may be slower or more
difficult than we anticipate (due to various reasons including challenges that may be imposed as a result of events outside our control, such as
the COVID-19 pandemic which resulted in a significant slow-down in patient recruitment to our on-going Inhaled AAT Phase 3 study), or
participants may withdraw from our clinical trials at higher rates than we anticipate;
● delays may occur in reaching agreement on acceptable clinical trial agreement terms with prospective sites or obtaining institutional review
board approval;
● our strategic partners may not achieve their clinical development goals and/or comply with their relevant regulatory requirements, which
could affect our ability to conduct our clinical trials or obtain marketing authorization;
● we may be forced to suspend or terminate our clinical trials if the participants are being exposed to unacceptable health risks or if any
participant experiences an unexpected serious adverse event;
● regulators or institutional review boards may require that we hold, suspend or terminate clinical research for various reasons, including
noncompliance with regulatory requirements;
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● regulators may not authorize us to commence or conduct a clinical trial within a country or at a prospective trial site, or according to the
clinical trial outline we propose;
● undetected or concealed fraudulent activity by a clinical researcher, if discovered, could preclude the submission of clinical data prepared by
that researcher, lead to the suspension or substantive scientific review of one or more of our marketing applications by regulatory agencies,
and result in the recall of any approved product distributed pursuant to data determined to be fraudulent;
● the cost of our clinical and preclinical trials may be greater than we anticipate;
● an audit of preclinical tests or clinical studies by the FDA, the EMA, the regulatory authorities in Israel or other regulatory authorities may
reveal noncompliance with applicable regulations, which could lead to disqualification of the results of such studies and the need to perform
additional tests and studies; and
● our product candidates may not achieve the desired clinical benefits, or may cause undesirable side effects, or the product candidates may
have other unexpected characteristics.
If we are required to conduct additional clinical trials or other testing of our product candidates beyond those that we contemplate, if we are unable
to successfully complete our clinical trials or other testing, if the results of these trials or tests are not positive or are only modestly positive or if safety
concerns arise, we may:
● be delayed in obtaining regulatory or marketing approval for our product candidates;
● be unable to obtain regulatory and marketing approval;
● decide to halt the clinical trial or other testing;
● be required to conduct additional trials under a conditional approval;
● be unable to obtain reimbursement for our products in all or some countries;
● only obtain approval for indications that are not as broad as we initially intend;
● have the product removed from the market after obtaining marketing approval from the FDA, the EMA, the regulatory authorities in Israel or
other regulatory authorities; and
● be delayed in, or prevented from, the receipt of clinical milestone payments from our strategic partners.
Our ability to enroll patients in our clinical trials in sufficient numbers and on a timely basis is subject to several factors, including the size of the
patient population, the time of year during which the clinical trial is commenced, the hesitance of certain patients to leave their current standard of care for
a new treatment, and the number of other ongoing clinical trials competing for patients in the same indication and eligibility criteria for the clinical trial.
For example, during 2020 and 2021, we encountered challenges to recruit patients to our ongoing pivotal Phase 3 InnovAAT clinical study as a result of the
COVID-19 pandemic, resulting in significant delays in recruitment. In addition, patients may drop out of our clinical trials at any point, which could impair
the validity or statistical significance of the trials. Delays in patient enrollment or unexpected drop-out rates may result in longer development times.
Our product development costs will also increase if we experience delays in testing or approvals. There can be no assurance that any preclinical
test or clinical trial will begin as planned, not need to be restructured or be completed on schedule, if at all. Because we generally apply for patent
protection for our product candidates during the development stage, significant preclinical or clinical trial delays also could lead to a shorter patent
protection period during which we may have the exclusive right to commercialize our product candidates, if approved, or could allow our competitors to
bring products to market before we do, impairing our ability to commercialize our products or product candidates. For example, in the past, we have
experienced delays in the commencement of clinical trials, such as a delay in patient enrollment (including as a result of the COVID-19 pandemic) for our
clinical trials in Europe and the United States for Inhaled AAT for AATD.
Pre-clinical studies, including studies of our product candidates in animal models of disease, may not accurately predict the result of human
clinical trials of those product candidates. In addition, product candidates studied in Phase 1 and 2 clinical trials may be found not to be safe and/or
efficacious when studied further in Phase 3 trials. To satisfy FDA or other applicable regulatory approval standards for the commercial sale of our product
candidates, we must demonstrate in adequate and controlled clinical trials that our product candidates are safe and effective. Success in early clinical trials,
including Phase 1 and 2 trials, does not ensure that later clinical trials will be successful. Initial results from Phase 1 and 2 clinical trials also may not be
confirmed by later analysis or subsequent larger clinical trials. A number of companies in the pharmaceutical industry, including us, have suffered
significant setbacks in advanced clinical trials, even after obtaining promising results in earlier clinical trials.
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We may not be able to commercialize our product candidates in development for numerous reasons.
Even if preclinical and clinical trials are successful, we still may be unable to commercialize a product because of difficulties in obtaining
regulatory approval for its production process or problems in scaling that process to commercial production. In addition, the regulatory requirements for
product approval may not be explicit, may evolve over time and may diverge among jurisdictions and our third-party contractors, such as CROs, may fail
to comply with regulatory requirements or meet their contractual obligations to us.
Even if we are successful in our development and regulatory strategies, we cannot provide assurance that any product candidates we may seek to
develop or are currently developing, such as Inhaled AAT for AATD, will ever be successfully commercialized. We may not be able to successfully address
patient needs, persuade physicians and payors of the benefit of our product, and lead to usage and reimbursement. If such products are not eventually
commercialized, the significant expense and lack of associated revenue could materially adversely affect our business.
We may not be able to successfully build and implement a commercial organization or commercialization program, with or without collaborating
partners. The scale-up from research and development to commercialization requires significant time, resources, and expertise, which will rely, to a large
extent, on third parties for assistance to help us in our efforts. Such assistance includes, but is not limited to, persuading physicians and payors of the
benefit of our product to lead to utilization and reimbursement, developing a healthcare compliance program, and complying with post-marketing
regulatory requirements.
Research and development efforts invested in our pipeline of specialty and other products may not achieve expected results.
We must invest increasingly significant resources to develop specialty products through our own efforts and through collaborations with third
parties in the form of partnerships or otherwise. The development of specialty pharmaceutical products involves high-level processes and expertise and
carries a significant risk of failure. For example, the average time from the pre-clinical phase to the commercial launch of a specialty pharmaceutical
product can be 15 years or longer, and involves multiple stages: not only intensive preclinical, clinical and post clinical testing, but also highly complex,
lengthy, and expensive regulatory approval processes as well as reimbursement proceedings, which can vary from country to country. The longer it takes to
develop a pharmaceutical product, the longer it may take for us to recover our development costs and generate profits, and, depending on various factors,
we may not be able to ever recover such costs or generate profits.
During each stage of development, we may encounter obstacles that delay the development process and increase expenses, leading to significant
risks that we will not achieve our goals and may be forced to abandon a potential product in which we have invested substantial amounts of time and
money. These obstacles may include the following: preclinical-study failures; difficulty in enrolling patients in clinical trials; delays in completing
formulation and other work needed to support an application for approval; adverse reactions or other safety concerns arising during clinical testing;
insufficient clinical trial data to support the safety or efficacy of a product candidate; other failures to obtain, or delays in obtaining, the required regulatory
approvals for a product candidate or the facilities in which a product candidate is manufactured; regulatory restrictions which may delay or block market
penetration and the failure to obtain sufficient intellectual property rights for our products.
Accordingly, there can be no assurance that the continued development of our Inhaled AAT and any other product candidate will be successful and
will result in an FDA and/or EMA approvable indication.
Because of the amount of time and expense required to be invested in augmenting our pipeline of specialty and other products, including the
unique know-how which may be required for such purpose, we may seek partnerships or joint ventures with third parties from time to time, and
consequently face the risk that some or all of these third parties may fail to perform their obligations, or that the resulting arrangement may fail to produce
the levels of success that we are relying on to meet our revenue and profit goals.
We may not obtain orphan drug status for our products, or we may lose orphan drug designations, which would have a material adverse effect on our
business.
One of the incentives provided by an orphan drug designation is market exclusivity for seven years in the United States and ten years in the
European Union for the first product in a class approved for the treatment of a rare disease. Although several of our products and product candidates,
including Inhaled AAT for AATD, have been granted the designation of an orphan drug, we may not be the first product licensed for the treatment of
particular rare diseases in the future or our approved indication may vary from that subject to the orphan designation, or our products may not secure
orphan drug exclusivity for other reasons. In such cases we would not be able to take advantage of market exclusivity and instead another sponsor would
receive such exclusivity.
Additionally, although the marketing exclusivity of an orphan drug would prevent other sponsors from obtaining approval of the same drug
compound for the same indication, such exclusivity would not apply in the case that a subsequent sponsor could demonstrate clinical superiority or a
market shortage occurs and would not prevent other sponsors from obtaining approval of the same compound for other indications or the use of other types
of drugs for the same use as the orphan drug. In the event we are unable to fill demand for any orphan drug, it is possible that the FDA or the EMA may
view such unmet demand as a market shortage, which could impact our market exclusivity.
The FDA and the EMA may also, in the future, revisit any orphan drug designation that they have respectively conferred upon a drug and retain
the ability to withdraw the relevant designation at any time. Additionally, the U.S. Congress has considered, and may consider in the future, legislation that
would restrict the duration or scope of the market exclusivity of an orphan drug, and, thus, we cannot be sure that the benefits to us of the existing statute in
the United States will remain in effect. Furthermore, some court decisions have raised questions about FDA’s interpretation of the orphan drug exclusivity
provisions, which could potentially affect our ability to secure orphan drug exclusivity.
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If we lose our orphan drug designations or fail to obtain such designations for our new products and product candidates, our ability to successfully
market our products could be significantly affected, resulting in a material adverse effect on our business and results of operations.
The commercial success of the products that we may develop, if any, will depend upon the degree of market acceptance by physicians, patients,
healthcare payors, opinion leaders, patients’ organizations, and others in the medical community that any such product obtains.
Any products that we bring to the market may not gain market acceptance by physicians, patients, healthcare payors, opinion leaders, patients’
organizations and others in the medical community. If these products do not achieve an adequate level of acceptance, we may not generate material product
revenue and we may not sustain profitability. The degree of market acceptance of our product candidates, if approved for commercial sale, will depend on a
number of factors, some of which are beyond our control, including:
● the prevalence and severity of any side effects;
● the efficacy, potential advantages and timing of introduction to the market of alternative treatments;
● our ability to offer our product candidates for sale at competitive prices;
● relative convenience and ease of administration of our products;
● the willingness of physicians to prescribe our products;
● the willingness of patients to use our products;
● the strength of marketing and distribution support; and
● third-party coverage or reimbursement.
If we are not successful in achieving market acceptance for any new products that we have developed and that have been approved for commercial
sale, we may be unable to recover the large investment we will have made and have committed ourselves to making in research and development efforts
and our growth strategy will be adversely affected.
In addition, the proposal of or issuance of recommendations by government agencies, physician or patient organizations, or other industry
specialists that limit the use or acceptance of a particular product, whether adopted or not, could result in reduced sales of a product.
Risks Related to Our Operations and Industry
Regulatory approval for our products is limited by the FDA, EMA, the IMOH and similar authorities in other jurisdictions to those specific indications
and conditions for which clinical safety and efficacy have been demonstrated, and the prescription or promotion of off-label uses could adversely affect
our business.
Any regulatory approval of our Proprietary and Distribution products is limited to those specific diseases and indications for which our products
have been deemed safe and effective by the FDA, EMA, the IMOH or similar authorities in other jurisdictions. In addition to the regulatory approval
required for new formulations, any new indication for an approved product also requires regulatory approval. Once we produce a plasma-derived
therapeutic, we rely on physicians to prescribe and administer it as the product label directs and for the indications described on the labeling. To the extent
any off-label (i.e., unapproved) uses and departures from the approved administration directions become pervasive and produce results such as reduced
efficacy or other reported adverse effects, the reputation of our products in the marketplace may suffer. In addition, to the extent off-label uses are
associated with reduced efficacy or increases in reported adverse events, there could be a decline in our revenues or potential revenues. Furthermore, the
off-label use of our products may increase the risk of product liability claims, which are expensive to defend and could divert our management’s attention,
result in substantial damage awards against us, and harm our reputation.
Furthermore, while physicians may choose to prescribe drugs for uses that are not described in the product’s labeling and for uses that differ from
those approved by regulatory authorities, our ability to promote the products is limited to those indications that are specifically approved by the FDA,
EMA, the IMOH or other regulators. Although regulatory authorities generally do not regulate the behavior of physicians, they do restrict communications
by manufacturers on the subject of off-label use. If our promotional activities fail to comply with these regulations or guidelines, we may be subject to
warnings from, or enforcement action by, these authorities. In addition, failure to follow FDA, EMA, the IMOH or similar authorities in other jurisdictions
rules and guidelines relating to promotion and advertising can lead to other negative consequences that could hurt us, such as the suspension or withdrawal
of an approved product from the market, enforcement letters, restrictions on marketing or manufacturing, injunctions and corrective actions. Other
regulatory authorities may separately impose penalties including, but not limited to, fines, disgorgement of money, suspension of ongoing clinical trials,
refusal to approve pending applications or supplements to approved applications submitted by us; restrictions on our or our contract manufacturers’
operations; product seizure or detention, refusal to permit the import or export of products or criminal prosecution.
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Regulatory inspections or audits conducted by regulatory bodies and our partners may lead to monetary losses and inability to adequately manufacture
or sell our products.
The regulatory authorities, including the FDA, EMA, the IMOH, as well as our partners may, at any time and from time to time, audit or inspect
our facilities. Such audits or inspections may lead to disruption of work, and if we fail to pass such audits or inspections, the relevant regulatory authority
or partner may require remedial measures that may be costly or time consuming for us to implement and may result in the temporary or permanent
suspension of the manufacture, sale and distribution of our products.
Laws and regulations governing the conduct of international operations may negatively impact our development, manufacture, and sale of products
outside of the United States and require us to develop and implement costly compliance programs.
We must comply with numerous laws and regulations in Israel and in each of the other jurisdictions in which we operate or plan to operate. The
creation and implementation of any required compliance programs is costly, and the programs are often difficult to enforce, particularly where we must rely
on third parties.
For example, the U.S. Foreign Corrupt Practices Act (“FCPA”) prohibits any U.S. individual or business from paying, offering, authorizing
payment or offering 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 requires companies whose
securities are listed in the United States to comply with certain accounting provisions. For example, such companies must maintain books and records that
accurately and fairly reflect all transactions of the company, including international subsidiaries, and devise and maintain an adequate system of internal
accounting controls for international operations. The anti-bribery provisions of the FCPA are enforced primarily by the U.S. Department of Justice, and the
U.S. Securities and Exchange Commission (the “SEC”) is involved with enforcement of the books and records provisions of the FCPA.
Compliance with the FCPA and similar laws 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 as foreign officials. Additionally, pharmaceutical products are usually marketed by the local
distributors through government tenders, and the majority of pharmaceutical companies’ clients are HMOs which are foreign government officials under
the FCPA. Certain payments to hospitals in connection with clinical trials and other work, and certain payments to HMOs have been deemed to be
improper payments to government officials and have led to FCPA enforcement actions.
The failure to comply with laws governing international business practices may result in substantial penalties, including suspension or debarment
from government contracting. Violation of the FCPA can result in significant civil and criminal penalties. Indictment alone under the FCPA can lead to
suspension of the right to do business with the U.S. government until the pending claims are resolved. Conviction of a violation of the FCPA can result in
long-term disqualification as a government contractor. The termination of a government contract or relationship as a result of our failure to satisfy any of
our obligations under laws governing international business practices would have a negative impact on our operations and harm our reputation and ability
to procure government contracts. Additionally, the SEC also may suspend or bar issuers from trading securities on U.S. exchanges for violations of the
FCPA’s accounting provisions.
If our manufacturing facility in Beit Kama, Israel were to suffer a serious accident, contamination, force majeure event (including, but not limited to, a
war, terrorist attack, earthquake, major fire or explosion etc.) materially affecting our ability to operate and produce saleable plasma-derived protein
therapeutics, all of our manufacturing capacity could be shut down for an extended period.
We rely on a single manufacturing facility in Beit Kama, which is located in southern Israel, approximately 20 miles east of the Gaza Strip. A
significant part of our revenues in our Proprietary Products segment were derived, and are expected to continue to be derived from products manufactured
at this facility and some of the products that are imported by us under our Distribution segment, are packed and stored in this manufacturing facility. If this
facility were to suffer an accident or a force majeure event such as war, terrorist attack, earthquake, major fire or explosion, major equipment failure or
power failure lasting beyond the capabilities of our backup generators or similar event, or contamination, our revenues would be materially adversely
affected. In this situation, our manufacturing capacity could be shut down for an extended period, we could experience a loss of raw materials, work in
process or finished goods and imported products inventory and our ability to operate our business would be harmed. In addition, in any such event, the
reconstruction of our manufacturing facility and storage facilities, and the regulatory approval of the new facilities could be time-consuming. During this
period, we would be unable to manufacture our plasma-derived protein therapeutics.
Our insurance against property damage and business interruption insurance may be insufficient to mitigate the losses from any such accident or
force majeure event. We may also be unable to recover the value of the lost plasma or work-in-process inventories, as well as the sales opportunities from
the products we would be unable to produce or distribute, or the loss of customers during such period.
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If our shipping or distribution channels were to become inaccessible due to an accident, act of terrorism, strike, epidemic or pandemic (such as the
COVID-19 pandemic) or any other force majeure event, our supply, production and distribution processes could be disrupted.
Most of our Proprietary and Distribution products as well as most of the raw materials we utilize, including plasma and plasma derivatives, must
be transported under controlled temperature conditions, including temperature of -20 degrees Celsius (-4 degrees Fahrenheit), to ensure the preservation of
their proteins. Not all shipping or distribution channels are equipped to transport products or materials at these temperatures. If any of our shipping or
distribution channels become inaccessible because of a serious accident, act of terrorism, strike, epidemic or pandemic (such as the COVID-19 pandemic)
or any other force majeure event, we may experience disruptions in continued availability of plasma and other raw materials, delays in our production
process or a reduction in our ability to distribute our Proprietary and Distribution products to our customers in the markets in which we operate.
Failure to maintain the security of protected health information or compliance with security requirements could damage our reputation with
customers, cause us to incur substantial additional costs and become subject to litigation.
Pursuant to applicable privacy laws, we must comply with comprehensive privacy and security standards with respect to the use and disclosure of
protected health information and other personal information. If we do not comply with existing or new laws and regulations related to protecting privacy
and security of personal or health information, we could be subject to litigation costs and damages, monetary fines, civil penalties, or criminal sanctions.
We may be required to comply with the data privacy and security laws of other countries in which we operate or from which we receive data transfers.
For example, the General Data Protection Regulation (“GDPR”) which took effect May 25, 2018, has broad application and enhanced penalties for
noncompliance. The GDPR, which is wide-ranging in scope, governs the collection and use of personal data in the European Union and imposes
operational requirements for companies that receive or process personal data of residents of the European Union. The GDPR may apply to our clinical
development operations. In addition, the Israeli Privacy Protection Regulations (Information Security), 2017, which apply to our operations in Israel,
require us to take certain security measures to secure the processing of personal data. Furthermore, U.S. federal and state regulators continue to adopt new,
or modify existing laws and regulations addressing data privacy and the collection, processing, storage, transfer and use of data, including the U.S. Health
Insurance Portability and Accountability Act of 1996, as amended, and implementing regulations (“HIPAA”). These privacy, security and data protection
laws and regulations could impose increased business operational costs, require changes to our business, require notification to customers or workers of a
security breach, or restrict our use or storage of personal information. Our efforts to implement programs and controls that comply with applicable data
protection requirements are likely to impose additional costs on us, and we cannot predict whether the interpretations of the requirements, or changes in our
practices in response to new requirements or interpretations of the requirements, could have a material adverse effect on our business.
We rely upon our CROs, third party contractors and distributors to process personal information on our behalf, and we control only certain aspects
of their activities. Nevertheless, we are responsible for ensuring that their activities are conducted in accordance with privacy regulations and our reliance
on such CROs, third-party contractors and distributors does not relieve us of our regulatory responsibilities. While we take reasonable and prudent steps to
protect personal and health information and use such information in accordance with applicable privacy laws, a compromise in our security systems that
results in personal information being obtained by unauthorized persons or our failure to comply with security requirements for financial transactions could
adversely affect our reputation with our clients and result in litigation against us or the imposition of penalties, all of which may adversely impact our
results of operations, financial condition and liquidity. In addition, given that the privacy laws and regulations in the jurisdictions in which we operate are
new and subject to further judicial review and interpretation, it may be determined at a future time that although we take prudent measures to comply with
such laws and regulations, such measures will not be sufficient to meet future elaborations or interpretations of such laws and regulations.
If we are unable to successfully introduce new products and indications or fail to keep pace with advances in technology, our business, financial
condition, and results of operations may be adversely affected.
Our continued growth depends, to a certain extent, on our ability to develop and obtain regulatory approvals of new products, new enhancements
and/or new indications for our products and product candidates. Obtaining regulatory approval in any jurisdiction, including from the FDA, EMA or any
other relevant regulatory agencies involves significant uncertainty and may be time consuming and require significant expenditures. See “—Research and
development efforts invested in our pipeline of specialty and other products may not achieve expected results.”
The development of innovative products and technologies that improve efficacy, safety, patients’ and clinicians’ ease of use and cost-effectiveness,
involve significant technical and business risks. The success of new product offerings will depend on many factors, including our ability to properly
anticipate and satisfy customer needs, adapt to new technologies, obtain regulatory approvals on a timely basis, demonstrate satisfactory clinical results,
manufacture products in an economic and timely manner, engage qualified distributors for different territories and establish our sales force to sell our
products, and differentiate our products from those of our competitors. If we cannot successfully introduce new products, adapt to changing technologies or
anticipate changes in our current and potential customers’ requirements, our products may become obsolete and our business could suffer.
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Product liability claims or product recalls involving our products, or products we distribute, could have a material adverse effect on our business.
Our business exposes us to the risk of product liability claims that are inherent in the manufacturing, distribution and sale of our Proprietary and
Distribution products and other drug products. We face an inherent risk of product liability exposure related to the testing of our product candidates in
human clinical trials and an even greater risk when we commercially sell any products, including those manufactured by others that we distribute in Israel.
If we cannot successfully defend ourselves against claims that our product candidates or products caused injuries, or if the indemnities we have negotiated
do not adequately cover losses, we could incur substantial liabilities. Regardless of merit or eventual outcome, liability claims may result in:
● decreased demand for our Proprietary and Distribution products and any product candidates that we may develop;
● injury to our reputation;
● difficulties in recruitment of new participants to our future clinical trials and withdrawal of current clinical trial participants;
● costs to defend the related litigation;
● substantial monetary awards to trial participants or patients;
● difficulties in finding distributors for our products;
● difficulties in entering into strategic partnerships with third parties;
● diversion of management’s attention;
● loss of revenue;
● the inability to commercialize any products that we may develop; and
● higher insurance premiums.
Plasma is biological matter that is capable of transmitting viruses, infections and pathogens, whether known or unknown. Therefore, plasma
derivative products, if not properly tested, inactivated, processed, manufactured, stored and transported, could cause serious disease and possibly death to
the patient. Further, even when such steps are properly affected, viral and other infections may escape detection using current testing methods and may not
be susceptible to inactivation methods. Any transmission of disease through the use of one of our products or third-party products sold by us could result in
claims against us by or on behalf of persons allegedly infected by such products.
In addition, we sell and distribute third-party products in Israel, and the laws of Israel could also expose us to product liability claims for those
products. Furthermore, the presence of a defect (or a suspicion of a defect) in a product could require us to carry out a recall of such product. A product
liability claim or a product recall could result in substantial financial losses, negative reputational repercussions, loss of business and an inability to retain
customers. Although we maintain insurance for certain types of losses, claims made against our insurance policies could exceed our limits of coverage or
be outside our scope of coverage. Additionally, as product liability insurance is expensive and can be difficult to obtain, a product liability claim could
increase our required premiums or otherwise decrease our access to product liability insurance on acceptable terms. In turn, we may not be able to maintain
insurance coverage at a reasonable cost and may not be able to obtain insurance coverage that will be adequate to satisfy liabilities that may arise.
Uncertainty surrounding and future changes to healthcare law in the United States and other United States Government related mandates may
adversely affect our business.
In the U.S. and in some foreign jurisdictions there has been, and continues to be, significant legislative and regulatory changes and proposed
changes regarding the healthcare system that could prevent or delay marketing approval of product candidates, restrict or regulate post-approval activities,
and affect the profitable sale of product candidates. This legislation and regulatory activity have created uncertainty as to whether the industry will continue
to experience fundamental change as a result of regulatory reform or legislative reform. There is significant interest among legislators and regulators in
promoting changes in healthcare systems with the stated goals of containing healthcare costs, improving quality and/or expanding access. In the United
States, for example, the pharmaceutical industry has been a particular focus of these efforts and has been significantly affected and continues to face major
uncertainty due to the status of legislative initiatives surrounding healthcare reform. The Patient Protection and Affordable Care Act of 2010, as amended
by the Healthcare and Education Reconciliation Act of 2010, substantially changed the way healthcare is financed by both governmental and private
insurers, and significantly affected the pharmaceutical and healthcare industries. On August 16, 2022, the Inflation Reduction Act of 2022 (“IRA”) was
signed into law. The IRA includes several provisions to lower prescription drug costs for people with Medicare and reduce drug spending by the federal
government. Implementation of novel and seminal provisions in the IRA related to prescription drug pricing and spending will continue over the next
several years and could impact our operations and could have an adverse impact on our ability to generate revenues in the United States.
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In the coming years, additional changes could be made to U.S. governmental healthcare programs and U.S. healthcare laws that could significantly
impact the success of our products.
In addition, individual states have enacted drug price transparency laws that may impact our decision-making about price increases, including the
rate and frequency of such increases. The requirements under these laws vary state-by-state and include obligating manufacturers to provide advance notice
of planned price increases, increase amounts and factors considered for those amounts, wholesale acquisition costs, as well as additional information for
new drugs. Many states may impose penalties for noncompliance with these requirements, including for failure to report or submission of inaccurate or late
reports.
We cannot predict what other legislation relating to our business or to the health care industry may be enacted, or what effect such legislation or
other regulatory actions may have on our business, prospects, operating results and financial condition.
The COVID-19 pandemic shined a spotlight on the supply chain for essential medical products, medical countermeasures, and critical inputs to
those products and raised legislative and regulatory interest in creating more resiliency in the supply chain, including more domestic manufacturing of
essential medical products, medical countermeasures, and critical inputs. There has been significant congressional interest in oversight of pharmaceutical
supply chain resiliency as well as a number of legislative proposals to create incentives for domestic manufacturing. There has also been significant
executive branch activity to encourage American manufacturing, which may impact FDA-related products. We expect there will continue to be legislative
and regulatory efforts to increase domestic manufacturing, including potentially efforts to expedite drug approvals for products that could be competitors to
ours, and we cannot predict what effect such legislation or regulatory actions may have on our business, prospects, operating results and financial
condition.
Our products and any future approved products remain subject to extensive ongoing regulatory obligations and oversight, including post-approval
requirements, that could result in penalties and significant additional expenses and could negatively impact our and our collaborators' ability to
commercialize our current and any future approved products.
Any product that has received regulatory approval remains subject to extensive ongoing obligations and continued review from applicable
regulatory agencies. These obligations include, among other things, drug safety reporting and surveillance, submission of other post-marketing information
and reports, pre-clearance of certain promotional materials, manufacturing processes and practices, product labeling, confirmatory or post-approval clinical
research, import and export requirements and record keeping. These obligations may result in significant expense and limit our ability to commercialize our
current and any future approved products. Any violation of ongoing regulatory obligations could result in restrictions on the applicable product, including
the withdrawal of the applicable product from the market.
If FDA approval is granted via the accelerated approval pathway or a product receives conditional marketing authorization from another
comparable regulatory agency, we may be required to conduct a post-marketing confirmatory trial in support of full approval and to comply with other
additional requirements. An unsuccessful post-marketing study or failure to complete such a study with due diligence could result in the withdrawal of
marketing approval. Post-marketing studies may also suggest unfavorable safety information that could require us to update the product's prescribing
information or limit or prevent the product's widespread use. Recent legislation has given the FDA additional authority to require accountability and
enforce the post-marketing requirements and commitments associated with accelerated approval.
We and the manufacturers of our current and any future approved products are also required, or will be required, to comply with cGMP,
regulations, which include requirements relating to quality control and quality assurance as well as the corresponding maintenance of records and
documentation. Further, regulatory agencies must approve these manufacturing facilities before they can be used to manufacture our products and product
candidates, and these facilities are subject to ongoing regulatory inspections. In addition, any approved product, its manufacturer and the manufacturer's
facilities are subject to continual regulatory review and inspections, including periodic unannounced inspections. Failure to comply with applicable FDA
and other regulatory requirements may subject us to administrative or judicially imposed sanctions and other consequences, including:
● issuance of Form FDA 483 notices or Warning Letters by the FDA or other regulatory agencies;
● imposition of fines and other civil penalties;
● criminal prosecutions;
● injunctions, suspensions or revocations of regulatory approvals;
● suspension of any ongoing clinical trials;
● total or partial suspension of manufacturing;
● delays in regulatory approvals and commercialization;
● refusal by the FDA to approve pending applications or supplements to approved applications submitted by us;
● refusals to permit drugs to be imported into or exported from the United States;
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● restrictions on operations, including costly new manufacturing requirements;
● product recalls or seizures or withdrawal of the affected product from the market; and
● reputational harm.
The policies of the FDA and other regulatory agencies may change and additional laws and regulations may be enacted that could prevent or delay
regulatory approval of our product candidates or of our products in any additional indications or territories, or further restrict or regulate post-approval
activities. Any problems with a product or any violation of ongoing regulatory obligations could result in restrictions on the applicable product, including
the withdrawal of the applicable product from the market. If we are not able to maintain regulatory compliance, we might not be permitted to
commercialize our current or any future approved products and our business would suffer.
Laws pertaining to health care fraud and abuse could materially adversely affect our business, financial condition and results of operations.
The laws governing our conduct in the United States are enforceable by criminal, civil and administrative penalties. Violations of laws such as the
Federal False Claims Act (the “FCA”), the Physician Payments Sunshine Act or a provision of the U.S. Social Security Act known as the “federal Anti-
Kickback Statute,” or any regulations promulgated under their authority may result in jail sentences, fines or exclusion from federal and state health care
programs, as may be determined by the Department of Health and Human Services, the Department of Defense, other federal and state regulatory
authorities and the federal and state courts. There can be no assurance that our activities will not come under the scrutiny of regulators and other
government authorities or that our practices will not be found to violate applicable laws, rules and regulations or prompt lawsuits by private citizen
“relators” under federal or state false claims laws.
For example, under the federal Anti-Kickback Statute, and similar state laws and regulations, even common business arrangements, such as
discounted terms and volume incentives for customers in a position to recommend or choose drugs and devices for patients, such as physicians and
hospitals, can result in substantial legal penalties, including, among others, exclusion from Medicare and Medicaid programs, if those business
arrangements are not appropriately structured. Also, a person or company need not have actual knowledge of statute or specific intent to violate certain
such laws in order to have committed a violation. Therefore, our arrangements with potential referral sources must be structured with care to comply with
applicable requirements. Also, certain business practices, such as payment of consulting fees to healthcare providers, sponsorship of educational or research
grants, charitable donations, interactions with healthcare providers that prescribe products for uses not approved by the FDA and financial support for
continuing medical education programs, must be conducted within narrowly prescribed and controlled limits to avoid the possibility of wrongfully
influencing healthcare providers to prescribe or purchase particular products or as a reward for past prescribing. Manufacturers like us can be held liable
under the False Claims Act if they are determined to have caused the submission of false or fraudulent claims to the government for reimbursement. This
can result from prohibited activities such as off-label marketing, providing inaccurate billing or coding information to healthcare providers and other
customers, or violations of the federal Anti-Kickback Statute Significant enforcement activity has been the result of actions brought by relators, who file
complaints in the name of the United States (and if applicable, particular states) under federal and state False Claims Act statutes and can be entitled to
receive a significant portion (often as great as 30%) of total recoveries. Also, violations of the False Claims Act can result in treble damages, and each false
claim submitted can be subject to a penalty of up to $27,018 per claim. Transfers of value to certain healthcare practitioners and institutions must be tracked
and reported in accordance with the Physician Payments Sunshine Act and various state laws. Through the Physician Payments Sunshine Act, the
healthcare reform law imposes reporting and disclosure requirements for pharmaceutical and medical device manufacturers with regard to a broad range of
payments, ownership interests, and other transfers of value made to certain physicians, physician assistants, nurse practitioners, clinical nurse specialists,
certified registered nurse anesthetists, certified nurse-midwives and certain teaching hospitals. A number of states have similar laws in place and often
require reporting for other categories of healthcare professionals, such as nurses. Additional and stricter prohibitions could be implemented by federal and
state authorities. Where practices have been found to involve improper incentives to use products, government investigations and assessments of penalties
against manufacturers have resulted in substantial damages and fines. Many manufacturers have been required to enter into consent decrees, corporate
integrity agreements, or orders that prescribe allowable corporate conduct. Failure to satisfy requirements under the FDCA can also result in penalties, as
well as requirements to enter into consent decrees or orders that prescribe allowable corporate conduct. On November 16, 2020, the U.S. Health and
Human Services (HHS) Office of Inspector General (OIG) issued a Special Fraud Alert discussing the fraud and abuse risks associated with payments to
physicians related to speaker programs sponsored by pharmaceutical and medical device companies. OIG expressed skepticism regarding the educational
value of these industry-sponsored speaker programs and warned of the inherent fraud and abuse risks of these programs.
To market and sell our products outside the United States, we must obtain and maintain regulatory approvals and comply with regulatory
requirements in such jurisdictions. The approval procedures vary among countries in complexity and timing. We may not obtain approvals from regulatory
authorities outside the United States on a timely basis, if at all, and in such case, we would be precluded from commercializing products in those markets.
In addition, some countries, particularly the countries of the European Union, regulate the pricing of prescription pharmaceuticals. In these countries,
pricing discussions 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 may be required to conduct a clinical trial that compares the cost-effectiveness of our product candidate to other
available therapies. Such trials may be time-consuming and expensive and may not show an advantage in cost-efficacy for our products. If reimbursement
of our products is unavailable or limited in scope or amount, or if pricing is set at unsatisfactory levels, in either the United States or the European Union,
we could be adversely affected. Also, under the FCPA, the United States has regulated conduct by U.S. businesses occurring outside of the United States,
generally prohibiting remuneration to foreign officials for the purpose of obtaining or retaining business. Additionally, similar to the Physician Payments
Sunshine Act, there are legal and regulatory obligations outside the United States that include reporting requirements detailing interactions with and
payments to healthcare practitioners. See — General Risks – “We are subject to risks associated with doing business globally”.
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To enhance compliance with applicable health care laws, and mitigate potential liability in the event of noncompliance, regulatory authorities,
such as the HHS OIG, have recommended the adoption and implementation of a comprehensive health care compliance program that generally contains the
elements of an effective compliance and ethics program described in Section 8B2.1 of the U.S. Sentencing Commission Guidelines Manual. Increasing
numbers of U.S.-based pharmaceutical companies have such programs. We are in the process of adopting U.S. healthcare compliance and ethics programs
that generally incorporate the HHS OIG’s recommendations; however, there can be no assurance that following the adoption of such programs we will
avoid any compliance issues.
In addition to the federal fraud, waste, and abuse laws noted, there are analogous U.S. state laws and regulations, such as state anti-kickback and
false claims laws, and other state laws addressing the medical product and healthcare industries, which may apply to items or services reimbursed by any
third-party payor, including commercial insurers, and in some cases may apply regardless of payor (i.e., even if reimbursement is not available). Some state
laws are constructed in accordance with certain industry voluntary compliance guidelines (e.g., the PhRMA or AdvaMed Codes of Ethics), or the relevant
compliance program guidance promulgated by the federal government (HHS-OIG) in addition to other requirements, many of which differ from each other
in significant ways and may not have the same effect, thus complicating compliance efforts.
Compliance efforts related to such laws is costly, and failure to comply could subject us to enforcement action.
Finally, regulations in both the U.S. and other countries are subject to constant change. There can be no assurance that we can meet the
requirements of future regulations or that compliance with current regulations assures future capability to distribute and sell our products.
We could be adversely affected if other government or private third-party payors decrease or otherwise limit the amount, price, scope or other eligibility
requirements for reimbursement for the purchasers of our products.
Prices in many of our principal markets are subject to local regulation and certain pharmaceutical products, such as our Proprietary and
Distribution products, are subject to price controls. In the United States, where reimbursement levels for our products are substantially established by third-
party payors, a reduction in the payors’ amount of reimbursement for a product may cause groups or individuals dispensing the product to discontinue
administration of the product, to administer lower doses, to substitute lower cost products or to seek additional price-related concessions. These actions
could have a negative effect on our financial results, particularly in cases where our products command a premium price in the marketplace or where
changes in reimbursement rates induce a shift in the site of treatment. The existence of direct and indirect price controls and pressures over our products has
affected, and may continue to materially adversely affect, our ability to maintain or increase gross margins.
Also, the intended use of a drug product by a physician can affect pricing. Physicians frequently prescribe legally available therapies for uses that
are not described in the product’s labeling and that differ from those tested in clinical studies and approved by the FDA or similar regulatory authorities in
other countries. These off-label uses are common across medical specialties, and physicians may believe such off-label uses constitute the preferred
treatment or treatment of last resort for many patients in varied circumstances. Reimbursement for such off-label uses may not be allowed by government
payors. If reimbursement for off-label uses of products is not allowed by Medicare or other third-party payors, including those in the United States or the
European Union, we could be adversely affected. For example, Centers for Medicare and Medicaid (“CMS”) could initiate an administrative procedure
known as a National Coverage Determination (“NCD”), by which the agency determines which uses of a therapeutic product would be reimbursable under
Medicare and which uses would not. This determination process can be lengthy, thereby creating a long period during which the future reimbursement for a
particular product may be uncertain.
If we fail to comply with our obligations under U.S. governmental pricing programs, we could be required to reimburse government programs for
underpayments and could pay penalties, sanctions, and fines.
The issuance of regulations and coverage expansion by various governmental agencies relating to the Medicaid rebate program will increase our
costs and the complexity of compliance and will be time-consuming. Changes to the definition of “average manufacturer price” (AMP), and the Medicaid
rebate amount under the Affordable Care Act and CMS and the issuance of final regulations implementing those changes has affected and could further
affect our 340B “ceiling price” calculations. When we participate in the Medicaid rebate program, we are required to report “average sales price” (ASP),
information to CMS for certain categories of drugs that are paid for under Part B of the Medicare program. Future statutory or regulatory changes or CMS
binding guidance could affect the ASP calculations for our products and the resulting Medicare payment rate and could negatively impact our results of
operations.
Generally, the Medicaid rebate program, also known as the “340B Program,” has been subject to numerous recent challenges, leading to ongoing
uncertainty in various areas. There is pending litigation regarding on what can reasonably constitute a 340B eligible patient, which could significantly
expand the covered entity patient description. Recent litigation also clarified that manufacturers have no obligation under the 340B statute to provide 340B
drugs to an unlimited number of contract pharmacy locations, as the program struggles with increasing participation by contract pharmacies. Most notably,
on June 15, 2022, after many years of ongoing litigation, the U.S. Supreme Court unanimously overturned a substantial Medicare Part B payment reduction
to many 340B Program participating hospitals related to certain outpatient prescription drugs provided to Medicare patients in American Hospital
Association v. Becerra. It is unclear how such current and pending litigation could spur new regulations and also affect the scope and demands of the 340B
Program, which could affect our products and operations in ensuring compliance with Program requirements.
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Pricing and rebate calculations vary among products and programs, involve complex calculations and are often subject to interpretation by us,
governmental or regulatory agencies and the courts. The Medicaid rebate amount is computed each quarter based on our submission to CMS of our current
AMP and “best price” for the quarter. If we become aware that our reporting for a prior quarter was incorrect or has changed as a result of recalculation of
the pricing data, we are obligated to resubmit the corrected data for a period not to exceed twelve quarters from the quarter in which the data originally
were due. Any such revisions could have the impact of increasing or decreasing our rebate liability for prior quarters, depending on the direction of the
revision. Such restatements and recalculations would increase our costs for complying with the laws and regulations governing the Medicaid rebate
program. Price recalculations also may affect the “ceiling price” at which we are required to offer our products to certain covered entities, such as safety-
net providers, under the 340B/Public Health Service (PHS) drug pricing program.
In addition, if we are found to have made a misrepresentation in the reporting of ASP, we are subject to civil monetary penalties for each such
price misrepresentation and for each day in which such price misrepresentation was applied. If we are found to have knowingly submitted false AMP or
“best price” information to the government, we may be liable for civil monetary penalties per item of false information. Any refusal of a request for
information or knowing provision of false information in connection with an AMP survey verification would also subject us to civil monetary penalties. In
addition, our failure to submit monthly/quarterly AMP or “best price” information on a timely basis could result in a civil monetary penalty per day for
each day the information is late beyond the due date. Such failure also could be grounds for CMS to terminate our Medicaid drug rebate agreement, under
which we participate in the Medicaid program. In the event that CMS terminates our rebate agreement, no federal payments would be available under
Medicaid or Medicare Part B for our covered outpatient drugs. Governmental agencies may also make changes in program interpretations, requirements or
conditions of participation, some of which may have implications for amounts previously estimated or paid. We cannot assure that our submissions will not
be found by CMS to be incomplete or incorrect.
In order for our products to be reimbursed by the primary federal governmental programs, we must report certain pricing data to the USG.
Compliance with reporting and other requirements of these federal programs is a pre-condition to: (i) the availability of federal funds to pay for our
products under Medicaid and Medicare Part B; and (ii) procurement of our products by the Department of Veterans Affairs (DVA), and by covered entities
under the 340B/PHS program. The pricing data reported are used as the basis for establishing Federal Supply Schedule (FSS), and 340B/PHS program
contract pricing and payment and rebate rates under the Medicare Part B and Medicaid programs, respectively. Pharmaceutical companies have been
prosecuted under federal and state false claims laws for submitting inaccurate and/or incomplete pricing information to the government that resulted in
increased payments made by these programs. Although we maintain and follow strict procedures to ensure the maximum possible integrity for our federal
pricing calculations, the process for making the required calculations is complex, involves some subjective judgments and the risk of errors always exists,
which creates the potential for exposure under the false claims laws. If we become subject to investigations or other inquiries concerning our compliance
with price reporting laws and regulations, and our methodologies for calculating federal prices are found to include flaws or to have been incorrectly
applied, 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.
To be eligible to have our products paid for with federal funds under the Medicaid and Medicare Part B programs and purchased by certain federal
agencies and grantees, we also must participate in the DVA FSS pricing program. To participate, we are required to enter into an FSS contract with the
DVA, under which we must make our innovator “covered drugs” available to the “Big Four” federal agencies-the DVA, the DoD, the Public Health Service
(including the Indian Health Service), and the Coast Guard-at pricing that is capped under a statutory federal ceiling price (FCP) formula set forth in
Section 603 of the Veterans Health Care Act of 1992 (VHCA). The FCP is based on a weighted average wholesale price known as the Non-Federal
Average Manufacturer Price (Non-FAMP), which manufacturers are required to report on a quarterly and annual basis to the DVA. Under the VHCA,
knowingly providing false information in connection with a Non-FAMP filing can subject us to significant penalties for each item of false information. If
we overcharge the government in connection with our FSS contract or Section 703 Agreement, whether due to a misstated FCP or otherwise, we are
required to disclose the error and refund the difference to the government. The failure to make necessary disclosures and/or to identify contract overcharges
can result in allegations against us under the False Claims Act and other laws and regulations. Unexpected refunds to the government, and responding to a
government investigation or enforcement action, can be expensive and time-consuming, and could have a material adverse effect on our business, financial
condition, results of operations and growth prospects.
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We are subject to extensive environmental, health and safety, and other laws and regulations.
Our business involves the controlled use of hazardous materials, various biological compounds and chemicals. The risk of accidental
contamination or injury from these materials cannot be eliminated. If an accident, spill or release of any regulated chemicals or substances occurs, we could
be held liable for resulting damages, including for investigation, remediation and monitoring of the contamination, including natural resource damages, the
costs of which could be substantial. In addition, some of the license and permits granted to us may be suspended or revoked, resulting in our inability to
conduct our regular business activity, manufacture and/or distribute our products for an extended period of time or until we take remedial actions. We are
also subject to numerous environmental, health and workplace safety laws and regulations, including those governing laboratory procedures, exposure to
blood-borne pathogens and the handling of biohazardous materials and chemicals. Although we maintain workers’ compensation insurance to cover the
costs and expenses that may be incurred because of injuries to our employees resulting from the use of these materials, this insurance may not provide
adequate coverage against potential liabilities. Additional or more stringent federal, state, local or foreign laws and regulations affecting our operations may
be adopted in the future. We may incur substantial capital costs and operating expenses and may be required to obtain consents to comply with any of these
or certain other laws or regulations and the terms and conditions of any permits required pursuant to such laws and regulations, including costs to install
new or updated pollution control equipment, modify our operations or perform other corrective actions at our respective facilities. In addition, fines and
penalties may be imposed for noncompliance with environmental, health and safety and other laws and regulations or for the failure to have, or comply
with the terms and conditions of, required environmental or other permits or consents. We are subject to future audits by the Environmental Health
Department of the Regional Health Bureau of the IMOH and the Ministry of Environmental Protection of Israel and may be required to perform certain
actions from time to time in order to comply with these guidelines and their requirements. We do not expect the costs of complying with these guidelines to
be material to our business. See “Item 4. Information on the Company — Environmental.”
Under the Israeli Economic Competition Law, 5758-1988, as amended (the “Competition Law”), a company that supplies or acquires more than
50% of any product or service in Israel in a relevant market may be deemed to be a monopoly. In addition, any company that has “significant market
power” (within the meaning of the Competition Law), even if it does not hold market share that is greater than 50%, shall be deemed to be a monopolist
under the Competition Law. A monopolist is prohibited from participating in certain business practices, including unreasonably refusing to sell products or
provide services over which a monopoly exists, charging unfair prices for such products or services, and abusing its position in the market in a manner that
might reduce business competition or harm the public. In addition, the General Director of the Israeli Competition Authority may determine that a company
is a monopoly and has the right to order such company to change its conduct in matters that may adversely affect business competition or the public,
including by imposing restrictions on its conduct. Depending on the analysis and the definition of the different products we distribute in the markets in
which we operate, we may be deemed to be a “monopoly” under the Competition Law with respect to certain of our products. Furthermore, following an
amendment to the Competition Law that became effective in August 2015, which repealed the statutory exemption that existed under the Competition Law
for restrictive arrangements that were mutually exclusive arrangements, we may face difficulties in certain cases negotiating distribution agreements with
foreign pharmaceutical manufacturers.
We have entered into a collective bargaining agreement with the employees’ committee and the Histadrut (General Federation of Labor in Israel), and
we have incurred and could in the future incur labor costs or experience work stoppages or labor strikes as a result of any disputes in connection with
such agreement.
In December 2013, we signed a collective bargaining agreement with the employees’ committee established by our employees at our Beit Kama
production facility in Israel and the Histadrut (General Federation of Labor in Israel) (“Histadrut”), which expired in December 2017. In November 2018,
we signed a further collective bargaining agreement with the employees’ committee and the Histadrut, which expired in December 2021. In July 2022, we
signed a new collective agreement with the Histadrut; while the agreement will be effective through the end of 2029, certain economic terms may be
renegotiated by the parties following the lapse of the four year anniversary of the agreement. We have experienced labor disputes and work stoppages in the
past. For example, on March 3, 2022, during the course of our negotiations with the Histadrut and the employees’ committee on the renewal of the
collective bargaining agreement, the employee’s committee declared a labor dispute, and on April 26, 2022, a strike was initiated by the employee’s
committee, which continued until the new agreement was signed in July 2022. As a result of the labor strike, in the year ended December 31, 2022, our
gross profit was impacted by a $4.3 million loss associated with the effect of the work-stoppage at the Israeli plant. In addition, in December 2020, during
the course of our negotiations with the Histadrut and the employees’ committee on severance remuneration for employees who may be laid-off as part of
the workforce down-sizing as a result of the transfer of GLASSIA manufacturing to Takeda that we implemented during 2021, the employee’s committee
declared a labor dispute, which was subsequently concluded during February 2021 following the execution of a special collective bargaining agreement
governing such severance terms. In March 2023, we entered into an additional special collective bargaining agreement with the employees’ committee and
the Histadtrut governing severance remuneration terms for employees who may be laid-off in connection with the potential staff reductions, when needed,
in order to adjust to lower plant utilization. Any future disputes with the employees’ committee and the Histadrut over the implementation or the
interpretation or the renewal of the collective bargaining agreement may lead to additional labor costs and/or work stoppages, which could adversely affect
our business operations, including through a loss of revenue and strained relationships with customers.
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Following the establishment of our U.S. commercial operations through our subsidiaries Kamada Inc. and Kamada Plasma LLC, we have entered into
intercompany agreements for the transfer of products, which require us to meet transfer pricing requirements under both Israeli and U.S. tax
legislation.
Following the establishment of our U.S. commercial operations through our subsidiaries Kamada Inc. and Kamada Plasma LLC, we have entered
into intercompany agreements for the transfer of products. Our intercompany agreements for the sale of products or provision of services are required to be
made on an arms-length basis and must comply with transfer pricing provisions of tax laws in Israel and the U.S. In order to determine the adequate
transfer pricing arrangement, we are required to perform a transfer pricing study to compare the contemplated intercompany transaction with similar
transactions entered into amongst non-related parties. There can be no assurance that the Israeli and/or tax authorities would accept such transfer pricing
study when determining our, or any of our subsidiary’s income, profitability and tax assessment. Failure to comply with transfer pricing rules may result in
increased tax expenses, penalties and legal actions against us, our subsidiaries or our executive officer.
We may be exposed to tax reporting requirements and tax expense in multiple jurisdictions in which our products are being distributed.
We are incorporated under the laws of the State of Israel and some of our subsidiaries are organized under the laws of Delaware and Ireland and as
a result, we are subject to local tax requirements and potential tax expenses in these territories. We store, distribute and sell our Proprietary products in
multiple other countries in which we do not have any subsidiaries or physical presence; nevertheless, in some of these countries, pursuant to local
legislation, we may be considered as “conducting business activities” which may expose us to certain reporting requirements and potential direct or indirect
tax payments. Failure to comply with such local legislation may result in increased tax expenses, penalties and legal actions against us, our subsidiaries or
our executive officers.
Risks Related to Intellectual Property
Our success depends in part on our ability to obtain and maintain protection in the United States and other countries for the intellectual property
relating to or incorporated into our technology and products, including the patents protecting our manufacturing process.
Our success depends in large part on our ability to obtain and maintain protection in the United States and other countries for the intellectual
property covering or incorporated into our technology and products, especially intellectual property related to our manufacturing processes. At present, we
consider our patents relating to our manufacturing process to be material to the operation of our business as a whole.
However, the patent landscape in the biotechnology and pharmaceutical fields is highly complicated and uncertain and involves complex legal,
factual and scientific questions. Changes in either patent laws or in the interpretation of patent laws in the United States and other countries may diminish
the value and strength of our intellectual property or narrow the scope of our patent protection. In addition, we may fail to apply for or be unable to obtain
patents necessary to protect our technology or products or enforce our patents due to lack of information about the exact use of our processes by third
parties. Even if patents are issued to us or to our licensors, they may be challenged, narrowed, invalidated, held to be unenforceable or circumvented, which
could limit our ability to prevent competitors from using similar technology or marketing similar products, or limit the length of time our technologies and
products have patent protection. Additionally, many of our patents relate to the processes we use to produce our products, not to the products themselves. In
many cases, the plasma-derived products we produce or intend to develop in the future will not, in and of themselves, be patentable. Since many of our
patents relate to processes or uses of the products obtained therefrom, if a competitor is able to utilize a process that does not rely on our protected
intellectual property, that competitor could sell a plasma-derived product similar to one we have developed or sell it without infringing these patents.
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Patent rights are territorial; thus, any patent protections we have will only be enforceable in those countries in which we have issued patents. In
addition, the laws of certain countries do not protect our intellectual property rights to the same extent as do the laws of the U.S. and the European Union.
Competitors may successfully challenge our patents, produce similar drugs or products that do not infringe our patents, or produce drugs in countries where
we have not applied for patent protection or that do not recognize or provide enforcement mechanisms for our patents. Furthermore, it is not possible to
know the scope of claims that will be allowed in pending applications or which claims of granted patents, if any, will be deemed enforceable in a court of
law.
Due to the extensive time needed to develop, test and obtain regulatory approval for our therapeutic candidates or any product we may sell or
market, any patents that protect our therapeutic candidates or any product we may sell or market may expire early during commercialization. This may
reduce or eliminate any market advantages that such patents may give us. Following patent expiration, we may face increased competition through the
entry of recombinant or generic products into the market and a subsequent decline in market share and profits.
In some cases we may rely on our licensors or partners to conduct patent prosecution, patent maintenance or patent defense on our behalf.
Therefore, our ability to ensure that these patents are properly prosecuted, maintained, or defended may be limited, which may adversely affect our rights in
our therapeutic candidates and potential approved for marketing products. Any failure by our licensors or development or commercialization partners to
properly conduct patent prosecution, maintenance, enforcement, or defense could materially harm our ability to obtain suitable patent protection covering
our therapeutic candidates or products or ensure freedom to commercialize the products in view of third-party patent rights, thereby materially reducing our
potential profits.
Our patents also may not afford us protection against competitors or other third parties with similar technology. Because patent applications
worldwide are typically not published until 18 months after their filing, and because publications of discoveries in scientific literature often lag behind
actual discoveries, neither we nor our licensors can be certain that we or they were the first to file for protection of the inventions set forth in such patent
applications. As a result, the patents we own and license may be invalidated in the future, and the patent applications we own and license may not be
granted. Moreover, in the US, during 2012, the Leahy-Smith America Invents Act (“AIA”) created a new legal proceeding, the inter partes review petition,
that allows third parties to challenge the validity of patents before the Patent Trials and Appeals Board.
The costs of these proceedings could be substantial and our efforts in them could be unsuccessful, resulting in a loss of our anticipated patent
position. In addition, if a third party prevails in such a proceeding and obtains an issued patent, we may be prevented from practicing technology or
marketing products covered by that patent. Additionally, patents and patent applications owned by third parties may prevent us from pursuing certain
opportunities such as entering into specific markets or developing or commercializing certain products or reducing the cost effectiveness of the relevant
business as a result of needing to make royalty payments or other business conciliations. Finally, we may choose to enter into markets where certain
competitors have patents or patent protection over technology that may impede our ability to compete effectively.
Our patents are due to expire at various dates between 2024 and 2041. However, because of the extensive time required for development, testing
and regulatory review of a potential product, it is possible that, before any of our products can be commercialized, any related patent may expire or remain
in force for only a short period following commercialization, thereby limiting advantages of the patent. Our pending and future patent applications may not
lead to the issuance of patents or, if issued, the patents may not be issued in a form that will provide us with any competitive advantage. We also cannot
guarantee that: any of our present or future patents or patent claims or other intellectual property rights will not lapse or be invalidated, circumvented,
challenged or abandoned; our intellectual property rights will provide competitive advantages or prevent competitors from making or selling competing
products; our ability to assert our intellectual property rights against potential competitors or to settle current or future disputes will not be limited by our
agreements with third parties; any of our pending or future patent applications will be issued or have the coverage originally sought; our intellectual
property rights will be enforced in jurisdictions where competition may be intense or where legal protection may be weak; or we will not lose the ability to
assert our intellectual property rights against, or to license our technology to, others and collect royalties or other payments. In addition, our competitors or
others may design around our patents or protected technologies. Effective protection of our intellectual property rights may also be unavailable, limited or
not applied in some countries, and even if available, we may fail to pursue or obtain necessary intellectual property protection in such countries. In
addition, the legal systems of certain countries do not favor the aggressive enforcement of patents and other intellectual property rights, and the laws of
foreign countries may not protect our rights to the same extent as the laws of the United States. As a result, our intellectual property may not provide us
with sufficient rights to exclude others from commercializing products similar or identical to ours. In order to preserve and enforce our patent and other
intellectual property rights, we may need to make claims, apply certain patent or other regulatory procedures or file lawsuits against third parties. Such
proceedings could entail significant costs to us and divert our management’s attention from developing and commercializing our products. Lawsuits may
ultimately be unsuccessful, and may also subject us to counterclaims and cause our intellectual property rights to be challenged, narrowed, invalidated or
held to be unenforceable.
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Additionally, unauthorized use of our intellectual property may have occurred or may occur in the future, including, for example, in the production
of counterfeit versions of our products. Counterfeit products may use different and possibly contaminated sources of plasma and other raw materials, and
the purification process involved in the manufacture of counterfeit products may raise additional safety concerns, over which we have no control. Although
we have taken steps to minimize the risk of unauthorized uses of our intellectual property, including for the production of counterfeit products, any failure
to identify unauthorized use of, and otherwise adequately protect, our intellectual property could adversely affect our business, including reducing the
demand for our products. Additionally, any reported adverse events involving counterfeit products that purported to be our products could harm our
reputation and the sale of our products in particular and consumer willingness to use plasma-derived therapeutics in general. Moreover, if we are required
to commence litigation related to unauthorized use, whether as a plaintiff or defendant, such litigation would be time-consuming, force us to incur
significant costs and divert our attention and the efforts of our management and other employees, which could, in turn, result in lower revenue and higher
expenses.
In addition to patented technology, we rely on our unpatented proprietary technology, trade secrets, processes and know-how.
We rely on proprietary information (such as trade secrets, know-how and confidential information) to protect intellectual property that may not be
patentable, or that we believe is best protected by means that do not require public disclosure. We generally seek to protect this proprietary information by
entering into confidentiality agreements, or consulting, services, material transfer agreements or employment agreements that contain non-disclosure and
non-use provisions, as well as ownership provisions, with our employees, consultants, service providers, contractors, scientific advisors and third parties.
However, we may fail to enter into the necessary agreements, and even if entered into, these agreements may be breached or otherwise fail to prevent
disclosure, third-party infringement or misappropriation of our proprietary information, may be limited as to their term and may not provide an adequate
remedy in the event of unauthorized disclosure or use of proprietary information. We have limited control over the protection of trade secrets used by our
third-party manufacturers, suppliers, other third parties which are granted with license to use our know-how and former employees and could lose future
trade secret protection if any unauthorized disclosure of such information occurs. In addition, our proprietary information may otherwise become known or
be independently developed by our competitors or other third parties. To the extent that our employees, consultants, service providers, contractors,
scientific advisors and other third parties use intellectual property owned by others in their work for us, disputes may arise as to the rights in related or
resulting know-how and inventions. Costly and time-consuming litigation could be necessary to enforce and determine the scope of our proprietary rights,
and failure to obtain or maintain protection for our proprietary information could adversely affect our competitive business position. Furthermore, laws
regarding trade secret rights in certain markets where we operate may afford little or no protection to our trade secrets.
We also rely on physical and electronic security measures to protect our proprietary information, but we cannot provide assurance that these
security measures will not be breached or provide adequate protection for our property. There is a risk that third parties may obtain and improperly utilize
our proprietary information to our competitive disadvantage. We may not be able to detect or prevent the unauthorized use of such information or take
appropriate and timely steps to enforce our intellectual property rights. See “—Our business and operations would suffer in the event of computer system
failures, cyber-attacks on our systems or deficiency in our cyber security measures.”
Changes in either U.S. or foreign patent law or in the interpretation of such laws could diminish the value of patents in general, thereby impairing our
ability to protect our products.
Our success, like the success of many other biotechnology companies, is heavily dependent on intellectual property and on patents in particular.
The procurement and enforcement of patents in the biotechnology industry is complex from a technological and legal standpoint, and the process is
therefore costly, time-consuming and inherently uncertain. In addition, on September 16, 2011, the AIA was signed into law. The AIA included a number
of significant changes to U.S. patent law, including provisions that affect the way patent applications are prosecuted. An important change introduced by
the AIA is that, as of March 16, 2013, the United States transitioned to a “first-to-file” system for deciding which party should be granted a patent when
two or more patent applications are filed by different parties claiming the same invention. A third party that files a patent application with the United States
Patent and Trademark Office (“USPTO”) after that date but before us could therefore be awarded a patent covering an invention of ours even if we had
made the invention before it was made by the third party. As a result of this change of law, if we do not promptly file a patent application at the time of a
new product’s invention, and if a third party subsequently invented and patented such product, we would lose our right to patent such invention.
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The AIA also introduced new limitations on where a patentee may file a patent infringement suit and new opportunities for third parties to
challenge any issued patent in the USPTO. Such changes apply to all of our U.S. patents, even those issued before March 16, 2013. Because of a lower
evidentiary standard necessary to invalidate a patent claim in USPTO proceedings compared to the evidentiary standard in U.S. federal court, a third party
could potentially provide evidence in a USPTO proceeding sufficient for the USPTO to hold a claim invalid even though the same evidence would be
insufficient to invalidate the claim if first presented in a district court action. Accordingly, a third party may attempt to use the USPTO procedures to
invalidate our patent claims that would not have been invalidated if first challenged by the third party as a defendant in a district court action.
Depending on decisions by the U.S. Congress, federal courts, the USPTO, or similar authorities in foreign jurisdictions, the laws and regulations
governing patents could change in unpredictable ways that would weaken our ability to obtain new patents and enforce our existing and future patents.
We may be subject to claims that we infringe, misappropriate or otherwise violate the intellectual property rights of third parties.
The conduct of our business, our Proprietary and/or Distribution products or product candidates may infringe or be accused of infringing one or
more claims of an issued patent or may fall within the scope of one or more claims in a published patent application that may be subsequently issued and to
which we do not hold a license or other rights. For example, certain of our competitors and other third parties own patents and patent applications in the
realm of our biosimilars distribution products, or in areas relating to critical aspects of our business and technology, including the separation and
purification of plasma proteins, the composition of AAT, the use of AAT for different indications, and the distribution or use of recombinant or biosimilar
pharmaceutical products, and these competitors may in the future allege that we are infringing on their patent rights. We may also be subject to claims that
we are infringing, misappropriating or otherwise violating other intellectual property rights, such as trademarks, copyrights or trade secrets. Third parties
could therefore bring claims against us or our strategic partners that would cause us to incur substantial expenses and, if successful against us, could cause
us to pay substantial damages. Further, if such a claim were brought against us, our strategic partners or our manufacturer suppliers for Distribution
products, we or they could be forced to permanently or temporarily stop or delay manufacturing, exportation or sales of such product or product candidate
that is the subject of the dispute or suit. See also “We recently entered into agreements for future distribution in Israel of several biosimilar product
candidates, and the successful future distribution of these products is dependent upon several factors some of which are beyond our control.”
In addition, we are a party to certain license agreements that may impose various obligations upon us as a licensee, including the obligation to bear
the cost of maintaining the patents subject to the license and to make milestone and royalty payments. If we fail to comply with these obligations, the
licensor may terminate the license, in which event we might not be able to market any product that is covered by the licensed intellectual property.
If we are found to be infringing, misappropriating or otherwise violating the patent or other intellectual property rights of a third party, or in order
to avoid or settle claims, we or our strategic partners may choose or be required to seek a license, execute cross-licenses or enter into a covenant not to sue
agreement from a third party and be required to pay license fees or royalties or both, which could be substantial. These licenses may not be available on
acceptable terms, or at all. Even if we or our strategic partners were able to obtain a license, the rights may be nonexclusive, 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 claims, we or our strategic partners are unable to enter into licenses on acceptable
terms.
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There have been substantial litigation and other proceedings regarding patent and other intellectual property rights in the pharmaceutical and
biotechnology industries. In addition, to the extent that we gain greater visibility and market exposure as a public company in the United States, we face a
greater risk of being involved in such litigation. In addition to infringement claims against us, we may become a party to other patent litigation and other
proceedings, including interference, opposition, cancellation, re-examination and similar proceedings before the USPTO and its foreign counterparts and
other regulatory authorities, regarding intellectual property rights with respect to our products. The cost to us of any patent litigation or other proceeding,
even if resolved in our favor, could be substantial. Some of our competitors may be able to sustain the costs of such litigation or proceedings more
effectively than we can because of their substantially greater financial resources. Uncertainties resulting from the initiation and continuation of patent
litigation or other proceedings could have a material adverse effect on our ability to compete in the marketplace or to conduct our business in accordance
with our plans and budget, and patent litigation and other proceedings may also absorb significant management time.
Some of our employees, consultants and service providers, were previously employed or hired at universities, medical institutes, or other
biotechnology or pharmaceutical companies, including our competitors or potential competitors. While we take steps to prevent them from using the
proprietary information or know-how of others in their work for us, we may be subject to claims that we or they have inadvertently or otherwise used or
disclosed intellectual property, trade secrets or other proprietary information of any such employee’s former employer or former ordering service or that
they have breached certain non-compete obligations to their former employers. Litigation may be necessary to defend against these claims and, even if we
are successful in defending ourselves, could result in substantial costs to us or be distracting to our management. If we fail to defend any such claims
successfully, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel.
If we are unable to protect our trademarks from infringement, our business prospects may be harmed.
We own trademarks that identify certain of our products, our business name and our logo, and have registered these trademarks in certain key
markets. Although we take steps to monitor the possible infringement or misuse of our trademarks, it is possible that third parties may infringe, dilute or
otherwise violate our trademark rights. Any unauthorized use of our trademarks could harm our reputation or commercial interests. In addition, our
enforcement against third-party infringers or violators may be unduly expensive and time-consuming, and the outcome may be an inadequate remedy. Even
if trademarks are issued to us or to our licensors, they may be challenged, narrowed, cancelled, or held to be unenforceable or circumvented.
Risks Related to Our Financial Position and Capital Resources
We have incurred significant losses since our inception and while we were profitable in the three years ended December 31, 2020, we incurred
operating losses in the last two fiscal years and may not be able to achieve or sustain profitability.
As of December 31, 2022, our cash and cash equivalents and short-term investments were $34.3 million. Since inception, we have incurred
significant operating losses, and while we were profitable in the three years ended December 31, 2020, we incurred net losses of $2.3 million and $2.2
million for the years ended December 31, 2022 and 2021, respectively. As of December 31, 2022, we had an accumulated deficit of $48.5 million.
The acquisition of the portfolio of four FDA-approved products in November 2021 resulted in the recognition of significant balances of intangible
assets as well as contingent consideration and other long-term liabilities. The recognized value of the intangible assets is amortized over their expected
useful life, resulting in significant amortization expenses captured as costs of goods sold and sales and marketing expenses. For the year ended December
31, 2022, such amortization expenses totaled $7.1 million. The contingent consideration and other long-term liabilities are reevaluated at the end of each
reporting period resulting in significant reevaluation cost recognized as financial expenses. For the year ended December 31, 2022, such financial expenses
totaled $6.3 million. We estimate to incur these significant depreciation and financial expenses for the foreseeable future. For additional information, see
Note 5b in our consolidated financial statements included in this Annual Report.
While the recent acquisition of a portfolio of four FDA-approved plasma-derived hyperimmune commercial products represented an important
growth driver and revenue source, there can be no assurance that we will be able to continue to reap the benefits of such acquisition and we may not be able
to generate or sustain profitability in future years.
Our financial position and operations may be affected as a result of the indebtedness we incurred and the liabilities we assumed in connection with the
recent acquisition of the portfolio of four FDA-approved products.
On November 15, 2021, to partially fund the acquisition of the portfolio of four FDA-approved products, we obtained a $40 million debt facility
from Bank Hapoalim B.M., comprised of a $20 million short-term revolving credit facility and a $20 million five-year loan. Effective as of January 1,
2023, the financing facility was amended such that the $20 million short-term revolving credit facility was replaced with a NIS 35 million (approximately
$10 million) credit facility. The indebtedness incurred may have significant adverse consequences on our business, including:
● limit our ability to borrow additional funds for working capital, capital expenditures, acquisitions, or other general business purposes;
● require the use of a substantial portion of our cash to service our indebtedness rather than investing our cash to fund our strategic growth
opportunities and plans, working capital and capital expenditures;
● expose us to the risk of increased interest rates as these borrowings are subject to the Secured Overnight Financing Rate (“SOFR”), (i) in the
case of the long-term loan, SOFR + 2.18%; and (ii) in the case of the credit facility, PRIME + 0.55;
● limit our flexibility to plan for, or react to, changes in our business and industry;
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● increase our vulnerability to the impact of adverse economic, competitive and industry conditions;
● prevent us from pledging our assets as collateral, which could limit our ability to obtain additional debt financing;
● place us at a competitive disadvantage compared to our competitors that have less debt, better debt servicing options or stronger debt
servicing capacity; and
● increase our cost of borrowing.
In addition, the terms of the loan and credit facility contain restrictive covenants that may limit our ability to engage in activities that may be in
our long-term best interest. These restrictive covenants include, among others, limitations on restructuring, the sale of purchase of assets, material licenses,
certain changes of control and the creation of floating charges over our property and assets. Under the terms of these facilities, we are also required to
maintain certain financial covenants, including minimum equity capital, maximum working capital to debt ratio and minimum debt coverage ratio. Our
failure to comply with those covenants could result in an event of default which, if not cured or waived, could result in the acceleration of substantially all
of our debt.
In addition, as part of the acquisition of the portfolio of four FDA-approved products, we agreed to pay and assumed the following liabilities:
● Up to $50 million of contingent consideration subject to achievement of sales thresholds through December 31, 2034.
● A total amount of $14.2 million on account of acquired inventory which will be paid in ten equal quarterly instalments of $1.5M each (or the
remaining balance at the final instalment).
● Future payment of royalties (some of which are perpetual) and milestone payments to third parties subject to the achievement of
corresponding CYTOGAM related net sales thresholds and milestones.
The future payments of such obligations may have a significant effect on our cash availability in future periods and may potentially require us to
assume more debt. For additional information, see Note 5b in our consolidated financial statements included in this Annual Report.
Our business requires substantial capital, including potential investments in large capital projects, to operate and grow and to achieve our strategy of
realizing increased operating leverage. Despite our indebtedness, we may still incur significantly more debt.
In order to obtain and maintain FDA, EMA and other regulatory approvals for product candidates and new indications for existing products, we
may be required to enhance the facilities and processes by which we manufacture existing products, to develop new product delivery mechanisms for
existing products, to develop innovative product additions and to conduct clinical trials. We face a number of obstacles that we will need to overcome in
order to achieve our operating goals, including but not limited to the successful development of experimental products for use in clinical trials, the design
of clinical study protocols acceptable to the FDA, the EMA and other regulatory authorities, the successful outcome of clinical trials, scaling our
manufacturing processes to produce commercial quantities or successfully transition technology, obtaining FDA, EMA and other regulatory approvals of
the resulting products or processes and successfully marketing an approved or new product with applicable new processes. To finance these various
activities, we may need to incur future debt or issue additional equity. We may not be able to structure our debt obligations on favorable economic terms
and any offering of additional equity would result in a dilution of the equity interests of our current shareholders. To the extent that we raise additional
funds to fund our activities through debt financing, if available, would result in increased fixed payment obligations and may involve agreements that
include covenants limiting or restricting our ability to take specific actions such as incurring debt, making capital expenditures or declaring dividends. If we
raise additional funds through collaboration, strategic alliance and licensing arrangements with third parties, we may have to relinquish valuable rights to
our technologies, future revenue streams or product candidates, or grant licenses on terms that are not favorable to us. A failure to fund these activities may
harm our growth strategy, competitive position, quality compliance and financial condition.
In addition, our manufacturing facility requires continued investment and upgrades. Moreover, any enhancements to our manufacturing facilities
necessary to obtain FDA or EMA approval for product candidates or new indications for existing products could require large capital projects. We may also
undertake such capital projects in order to maintain compliance with cGMP or expand capacity. Capital projects of this magnitude involve technology and
project management risks. Technologies that have worked well in a laboratory or in a pilot plant may cost more or not perform as well, or at all, in full scale
operations. Projects may run over budget or be delayed. We cannot be certain that any such project will be completed in a timely manner or that we will
maintain our compliance with cGMP, and we may need to spend additional amounts to achieve compliance. Additionally, by the time multi-year projects
are completed, market conditions may differ significantly from our initial assumptions regarding competitors, customer demand, alternative therapies,
reimbursement and public policy, and as a result capital returns may not be realized. In addition, to fund large capital projects, we may similarly need to
incur future debt or issue additional dilutive equity. A failure to fund these activities may harm our growth strategy, competitive position, quality
compliance and financial condition.
Our current working capital may not be sufficient to complete our research and development with respect to any or all of our pipeline products or to
commercialize our products.
As of December 31, 2022, we had cash and short-term investments of $34.3 million. We plan to fund our future operations through continued sale
and distribution of our proprietary and distribution products, commercialization and or out-licensing of our pipeline product candidates, and as requires
raising additional capital through the sale of equity or debt. These amounts may not be sufficient to complete the research and development of all of our
candidates, and there can be no assurances of the financial success of our commercialization activities or our ability to access the equity and debt capital
markets on terms acceptable to us, if at all. To the extent we are unable to fund our research and development, our future product development activities
could be materially adversely affected.
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We are subject to foreign currency exchange risk.
We receive payment for our sales and make payments for resources in a number of different currencies. While our sales and expenses are primarily
denominated in U.S. dollars, our financial results may be adversely affected by fluctuations in currency exchange rates as a portion of our sales and
expenses are denominated in other currencies, including the NIS and the Euro. Market volatility and currency fluctuations may limit our ability to cost-
effectively hedge against our foreign currency exposure and, in addition, our ability to hedge our exposure to currency fluctuations in certain emerging
markets may be limited. Hedging strategies may not eliminate our exposure to foreign exchange rate fluctuations and may involve costs and risks of their
own, such as devotion of management time, external costs to implement the strategies and potential accounting implications. Foreign currency fluctuations,
independent of the performance of our underlying business, could lead to materially adverse results or could lead to positive results that are not repeated in
future periods.
Events in global credit markets may impact our ability to obtain financing or increase the cost of future financing, including interest rate fluctuations
based on macroeconomic conditions that are beyond our control.
During periods of volatility and disruption in the U.S., European, Israeli or global credit markets, obtaining additional or replacement financing
may be more difficult and the cost of issuing new debt could be higher than the costs we incur under our current debt. The higher cost of new debt may
limit our ability to have cash on hand for working capital, capital expenditures and acquisitions on terms that are acceptable to us.
To service our indebtedness and other obligations, we will require a significant amount of cash and our ability to generate cash depends on many
factors beyond our control.
The capability to pay and refinance our indebtedness and to fund working capital requirements and planned capital expenditures will depend on
our ability to generate cash in the future. A significant reduction in our operating cash flows resulting from changes in economic conditions, increased
competition or other events beyond our control could increase the need for additional or alternative sources of liquidity and could have a material adverse
effect on our business, financial condition, results of operations, prospects and our ability to service our debt and other obligations. If we are unable to
service our indebtedness through sufficient cash flows from operations, we will be forced to shift to alternative strategies, which may include the reducing
of capital expenditures, the sale of assets, the restructuring or refinancing of our debt or the seeking of additional equity. We cannot assure that these
alternative strategies, if any, could be implemented on satisfactory and commercially reasonable terms, that they would provide sufficient funds to make the
required payments on our debt or to fund our other liquidity needs.
The failure of Silicon Valley Bank and recent turmoil in the banking industry may negatively impact our business, results of operations and financial
condition.
On March 10, 2023, the California Department of Financial Protection and Innovation closed Silicon Valley Bank (“SVB”) and appointed Federal
Deposit Insurance Corporation (the “FDIC”) receiver. On March 12, 2023, the Department of the Treasury, the Federal Reserve, and the FDIC jointly
released a statement that depositors at SVB would have access to their funds, even those in excess of the standard FDIC insurance limits, under a systemic
risk exception.
As of March 10, 2023, our wholly owned subsidiary KI Biopharma LLC had approximately $0.6 million held at SVB, which represents
approximately 3% of our consolidated cash and cash equivalents balance as of March 10, 2023. Our subsidiary could experience payment disruptions
during the interim. Notwithstanding the situation with SVB, we believe our current cash and cash equivalents and expected future cash to be generated by
our operational activities will be sufficient to satisfy our liquidity requirements for at least the next 12 months.
Despite the measures taken by the United States federal government, there is great uncertainty in the markets regarding the stability of regional
banks and the safety of deposits in excess of the FDIC insured deposit limits. The ultimate outcome of these events, and whether further regulatory actions
will be taken, cannot be predicted. Further, these events may make equity or debt financing more difficult to obtain, and additional equity or debt financing
might not be available on reasonable terms, if at all; difficulties obtaining equity or debt financing could have a material adverse effect on our financial
condition, as well as our ability to continue to grow our operations.
Risks Related to Our Ordinary Shares
The requirements of being a public company in the United States, as well as in Israel, may strain our resources and distract our management, which
could make it difficult to manage our business and could have a negative effect on our results of operations and financial condition.
As a public company whose shares are traded on Nasdaq and the Tel Aviv Stock Exchange (the “TASE”), we are required to comply with various
regulatory and reporting requirements, including those required by the SEC. Complying with these reporting and regulatory requirements is time
consuming, and may result in increased costs to us and could have a negative effect on our business, results of operations and financial condition. As a
public company in the United States, we are subject to the reporting requirements of the Securities Exchange Act of 1934, as amended (the “Exchange
Act”) and the requirements of the Sarbanes-Oxley Act of 2002 (“SOX”). These requirements may place a strain on our systems and resources. The
Exchange Act requires that we file annual and current reports, and file or make public certain additional information, with respect to our business and
financial condition. SOX requires that we maintain effective disclosure controls and procedures and internal controls over financial reporting. To maintain
and improve the effectiveness of our disclosure controls and procedures, we may need to commit significant resources, hire additional staff and provide
additional management oversight. These activities may divert management’s attention from other business concerns, which could have a material adverse
effect on our business, financial condition and results of operations. Furthermore, as our business changes and if we expand either through acquisitions or
by means of organic growth, our internal controls may become more complex and we will require significantly more resources to ensure our internal
controls remain effective. Failure to implement required new or improved controls, or difficulties encountered in their implementation, could impact our
financial information and adversely affect our operating results or cause us to fail to meet our reporting obligations. If we identify material weaknesses, the
disclosure of that fact, even if quickly remediated, could require significant resources to remediate, expose us to legal or regulatory proceedings, and reduce
the market’s confidence in our financial statements and negatively affect our share price.
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Our share price may be volatile.
The market price of our ordinary shares is highly volatile and could be subject to wide fluctuations in price as a result of various factors, some of
which are beyond our control. These factors include:
● actual or anticipated fluctuations in our financial condition and operating results;
● overall conditions in the specialty pharmaceuticals market;
● loss of significant customers or changes to agreements with our strategic partners;
● changes in laws or regulations applicable to our products;
● actual or anticipated changes in our growth rate relative to our competitors’;
● announcements of clinical trial results, technological innovations, significant acquisitions, strategic alliances, joint ventures or capital
commitments by us or our competitors;
● changes in key personnel;
● fluctuations in the valuation of companies perceived by investors to be comparable to us;
● the issuance of new or updated research reports by securities analysts;
● disputes or other developments related to proprietary rights, including patents, litigation matters and our ability to obtain intellectual property
protection for our technologies;
● announcement of, or expectation of, additional financing efforts;
● sales of our ordinary shares by us or our shareholders;
● share price and volume fluctuations attributable to inconsistent trading volume levels of our shares;
● recalls and/or adverse events associated with our products;
● the expiration of contractual lock-up agreements with our executive officers and directors; and
● general political, economic and market conditions.
Furthermore, the stock markets have experienced extreme price and volume fluctuations that have affected and continue to affect the market price
of equity securities of many companies. Broad market and industry fluctuations, as well as general economic, political and market conditions, may
negatively impact the market price of our ordinary shares. For example, during the year ended December 31, 2022, the stock market experienced extreme
price and volume fluctuations, and our share price declined.
In the past, companies that have experienced volatility in the market price of their shares have been subject to securities class action litigation or
derivative actions. We, as well as our directors and officers, may also be the target of these types of litigation and actions in the future. Securities litigation
against us could result in substantial costs and divert our management’s attention from other business concerns, which could seriously harm our business.
If securities or industry analysts do not publish or cease publishing research or reports about us, our business, or our market, or if they adversely
change their recommendations or publish negative reports regarding our business or our shares, our share price and trading volume could be
negatively impacted.
The trading market for our ordinary shares may be influenced by the research and reports that industry or securities analysts may publish about us,
our business, our market, or our competitors. We do not have any control over these analysts, and we cannot provide any assurance that analysts will cover
us or, if they do, provide favorable coverage. If any of the analysts who may cover us adversely change their recommendation regarding our shares, or
provide more favorable relative recommendations about our competitors, our share price would likely decline. If any analyst who may cover us were to
cease coverage of our company or fail to regularly publish reports on us, we could lose visibility in the financial markets, which in turn could negatively
impact our share price or trading volume.
38
Our shareholders may experience significant dilution as a result of any additional financing using our equity securities or may experience a decrease
in the share price due to sales of our equity securities.
To the extent that we raise additional funds to fund our activities through the sale of equity or securities that are convertible into or exchangeable
for, or that represent the right to receive, ordinary shares or substantially similar securities, your ownership interest will be diluted. Any additional capital
raised through the sale of equity securities will likely dilute the ownership percentage of our shareholders.
Future sales of ordinary shares by affiliates could cause our share price to fall.
The FIMI Opportunity Funds own 9,452,708 of our outstanding ordinary shares (representing an ownership percentage of 21.1% of the
outstanding shares and 20.2% on a fully diluted basis as of March 15, 2023). Pursuant to a registration rights agreement entered into with FIMI Opportunity
Funds on January 20, 2020, they have “demand” and “piggyback” registration rights covering the ordinary shares of our company held by them. All shares
of FIMI Opportunity Funds sold pursuant to an offering covered by a registration statement would be freely transferable. Sales of a substantial number of
shares of our ordinary shares, or the perception that the FIMI Opportunity Funds may exercise their registration rights, could put downward pressure on the
market price of our ordinary shares and could impair our future ability to raise capital through an offering of our equity securities.
The significant share ownership positions and board representation of the FIMI Opportunity Funds, Leon Recanati and Jonathan Hahn may
limit our shareholders’ ability to influence corporate matters.
The FIMI Opportunity Funds (three of whose partners are members of our board of directors, one of which serves as our Chairman), Leon
Recanati and Jonathan Hahn, members of our board of directors, beneficially owned, directly and indirectly, approximately 21.1%, 8.1% and 4.3% of our
outstanding ordinary shares, respectively, as of March 15, 2023. For additional information, see “Item 6. Directors, Senior Management and Employees —
Share Ownership” and “Item 7. Major Shareholders and Related Party Transactions — Major Shareholders.” Accordingly, the FIMI Opportunity Funds,
Leon Recanati, and the Hahn family through their equity ownership and board representation, individually and collectively, have significant influence over
the outcome of matters required to be submitted to our shareholders for approval, including decisions relating to the election of our board of directors and
the outcome of any proposed acquisition, merger or consolidation of our company. Their interests may not be consistent with those of our other
shareholders. In addition, these parties’ significant interest in us may discourage third parties from seeking to acquire control of us, which may adversely
affect the market price of our shares. On March 6, 2013, a shareholders agreement was entered into, effective March 4, 2013, pursuant to which Mr.
Recanati and any company controlled by him (collectively, the “Recanati Group”), on the one hand, and Damar Chemicals Inc. (“Damar”), TUTEUR
S.A.C.I.F.I.A (“Tuteur”) (companies controlled by the Hahn family) and their affiliates (collectively, the “Damar Group”), on the other hand, have each
agreed to vote the ordinary shares beneficially owned by them in favor of the election of director nominees designated by the other group as follows: (i)
three director nominees, so long as the other group beneficially owns at least 7.5% of our outstanding share capital, (ii) two director nominees, so long as
the other group beneficially owns at least 5.0% (but less than 7.5%) of our outstanding share capital, and (iii) one director nominee, so long as the other
group beneficially owns at least 2.5% (but less than 5.0%) of our outstanding share capital. In addition, to the extent that after the designation of the
foregoing director nominees there are additional director vacancies, each of the Recanati Group and Damar Group have agreed to vote the ordinary shares
beneficially owned by them in favor of such additional director nominees designated by the party who beneficially owns the larger voting rights in our
company. We are not party to such agreement or bound by its terms. As a result of such voting agreement, the Recanati Group and the Damar Group and
their affiliates together have significant influence over the election of directors of the company.
Our ordinary shares are traded on more than one market and this may result in price variations.
Our ordinary shares have been traded on the TASE since August 2005, and on Nasdaq since May 2013. Trading in our ordinary shares on these
markets takes place in different currencies (U.S. dollars on Nasdaq and NIS on the TASE), and at different times (as a result of different time zones, trading
days and public holidays in the United States and Israel). The trading prices of our ordinary shares on these two markets may differ due to these and other
factors. Any decrease in the price of our ordinary shares on the TASE could cause a decrease in the trading price of our ordinary shares on Nasdaq, and a
decrease in the price of our ordinary shares on Nasdaq could likewise cause a decrease in the trading price of our ordinary shares on the TASE.
Our U.S. shareholders may suffer adverse tax consequences if we are characterized as a passive foreign investment company.
Generally, if, for any taxable year, at least 75% of our gross income is passive income, or at least 50% of the value of our assets is attributable to
assets that produce passive income or are held for the production of passive income, we would be characterized as a passive foreign investment company
(“PFIC”) for U.S. federal income tax purposes. If we are characterized as a PFIC, our U.S. shareholders may suffer adverse tax consequences, including
having gains realized on the sale of our ordinary shares treated as ordinary income, rather than capital gain, the loss of the preferential rate applicable to
dividends received on our ordinary shares, and having interest charges apply to distributions by us and the proceeds of share sales. See “Item 10.
Additional Information — E. Taxation — United States Federal Income Taxation.”
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We are a “foreign private issuer” and have disclosure obligations that are different from those of U.S. domestic reporting companies. As a result, we
may not provide you the same information as U.S. domestic reporting companies or we may provide information at different times, which may make it
more difficult for you to evaluate our performance and prospects.
We are a foreign private issuer and, as a result, are not subject to the same requirements as U.S. domestic issuers. Under the Exchange Act, we are
subject to reporting obligations that, in certain respects, are less detailed and/or less frequent than those of U.S. domestic reporting companies. For
example, we are not required to issue quarterly reports, proxy statements that comply with the requirements applicable to U.S. domestic reporting
companies, or individual executive compensation information that is as detailed as that required of U.S. domestic reporting companies. We also have four
months after the end of each fiscal year to file our annual reports with the SEC and are not required to file current reports as frequently or promptly as U.S.
domestic reporting companies. Furthermore, our directors and executive officers are not required to report equity holdings under Section 16 of the
Exchange Act and are not subject to the insider short-swing profit disclosure and recovery regime.
As a foreign private issuer, we are also exempt from the requirements of Regulation FD (Fair Disclosure) which, generally, are meant to ensure
that select groups of investors are not privy to specific information about an issuer before other investors. However, we are still subject to the anti-fraud and
anti-manipulation rules of the SEC, such as Rule 10b-5 under the Exchange Act. Since many of the disclosure obligations imposed on us as a foreign
private issuer differ from those imposed on U.S. domestic reporting companies, you should not expect to receive the same information about us and at the
same time as the information provided by U.S. domestic reporting companies.
As we are a “foreign private issuer” and follow certain home country corporate governance practices instead of otherwise applicable Nasdaq corporate
governance requirements, our shareholders may not have the same protections afforded to shareholders of domestic U.S. issuers that are subject to all
Nasdaq corporate governance requirements.
As a foreign private issuer, we have the option to, and we do, follow Israeli corporate governance practices rather than certain corporate
governance requirements of Nasdaq, except to the extent that such laws would be contrary to U.S. securities laws, and provided that we disclose the
requirements we are not following and describe the home country practices we follow instead. We have relied on this “foreign private issuer exemption”
with respect to all the items listed under the heading “Item 16G. Corporate Governance,” including with respect to shareholder approval requirements in
respect of equity issuances and equity-based compensation plans, the requirement to have independent oversight on our director nominations process and to
adopt a formal written charter or board resolution addressing the nominations process, the quorum requirement for meetings of our shareholders and the
Nasdaq requirement to have a formal charter for the compensation committee. We may in the future elect to follow home country practices in Israel with
regard to other matters. As a result, our shareholders may not have the same protections afforded to shareholders of companies that are subject to all
Nasdaq corporate governance requirements. See “Item 16G. Corporate Governance.”
We have never paid cash dividends on our ordinary shares and we do not anticipate paying any dividends in the foreseeable future. Consequently, any
gains from an investment in our ordinary shares will likely depend on whether the price of our ordinary shares increases, which may not occur.
We have never declared or paid any cash dividends on our ordinary shares and do not intend to pay any cash dividends. Any agreements that we
may enter into in the future may contain terms prohibiting or limiting the amount of dividends that may be declared or paid on our ordinary shares. In
addition, Israeli law limits our ability to declare and pay dividends and may subject our dividends to Israeli withholding taxes. We anticipate that we will
retain all of our future earnings for use in the development of our business and for general corporate purposes. Any determination to pay dividends in the
future will be at the discretion of our board of directors. Accordingly, investors must rely on sales of their ordinary shares after price appreciation, which
may never occur, as the only way to realize any future gains on their investments.
Risks Relating to Our Incorporation and Location in Israel
Conditions in Israel could adversely affect our business.
We are incorporated under Israeli law and our principal offices and manufacturing facilities are located in Israel. Accordingly, political, economic
and military conditions in Israel and the surrounding region may directly affect our business. Since the State of Israel was established in 1948, a number of
armed conflicts have occurred between Israel and its Arab neighbors. Although Israel has entered into various agreements with Egypt, Jordan and the
Palestinian Authority, there has been terrorist activity with varying levels of severity over the years. In the event that our facilities are damaged as a result
of hostile action or hostilities otherwise disrupt the ongoing operation of our facilities or the airports and seaports on which we depend to import and export
our supplies and products, our ability to manufacture and deliver products to customers could be materially adversely affected. Additionally, the operations
of our Israeli suppliers and contractors may be disrupted as a result of hostile action or hostilities, in which event our ability to deliver products to
customers may be materially adversely affected.
Our commercial insurance does not cover losses that may occur as a result of events associated with war. Losses resulting from acts of terrorism
may be partially covered under certain circumstance. Although the Israeli government currently covers certain value of direct damages that are caused by
terrorist attacks or acts of war, we cannot assure you that this government coverage will be maintained or that it will sufficiently cover our potential
damages. Any losses or damages incurred by us could have a material adverse effect on our business.
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Further, in the past, the State of Israel and Israeli companies have been subjected to economic boycotts. Several countries, principally in the
Middle East, restrict doing business with Israel and Israeli companies, and additional countries may impose restrictions on doing business with Israel and
Israeli companies if hostilities in Israel or political instability in the region continues or increases. These restrictions may limit materially our ability to
obtain raw materials from these countries or sell our products to companies in these countries. Any hostilities involving Israel or the interruption or
curtailment of trade between Israel and its present trading partners, or significant downturn in the economic or financial condition of Israel, could adversely
affect our operations and product development, cause our sales to decrease and adversely affect the share price of publicly traded companies having
operations in Israel, such as us.
In addition, the Israeli Government recently proposed a broad judicial reform in Israel. In response to the foregoing developments, individuals,
organizations and institutions, both within and outside of Israel, have voiced concerns that the proposed judicial reform, if adopted, may negatively impact
the business environment in Israel including due to reluctance of foreign investors to invest or conduct business in Israel, as well as to increased currency
fluctuations, downgrades in credit rating, increased interest rates, increased volatility in securities markets, and other changes in macroeconomic
conditions. Such proposed judicial reform may also adversely affect the labor market in Israel or lead to political instability or civil unrest. Actual or
perceived political or judicial instability in Israel or any negative changes in the political environment may adversely affect the Israeli economy and
financial condition and, in turn, our business, financial condition, results of operations, growth prospects and market price of our shares, as well as on our
ability to raise additional capital.
Our operations may be disrupted by the obligations of personnel to perform military service.
As of December 31, 2022, we had 360 employees based in Israel. Certain of our Israeli employees may be called upon to perform up to 36 days
(and in some cases more) of annual military reserve duty until they reach the age of 40 (and in some cases, up to 45 or older) and, in emergency
circumstances, could be called to active duty. In response to increased tension and hostilities, there have been occasional call-ups of military reservists, and
it is possible that there will be additional call-ups in the future. Our operations could be disrupted by the absence of a significant number of our employees
related to their, or their spouse’s, military service or the absence for extended periods of one or more of our key employees for military service. Such
disruption could materially adversely affect our business and results of operations. Additionally, the absence of a significant number of the employees of
our Israeli suppliers and contractors related to military service or the absence for extended periods of one or more of their key employees for military
service may disrupt their operations, in which event our ability to deliver products to customers may be materially adversely affected.
The tax benefits under Israel tax legislation that are available to us require us to continue to meet various conditions and may be terminated or reduced
in the future, which could increase our costs and taxes.
We have obtained a tax ruling from the Israel Tax Authority according to which, among other things, our activity has been qualified as an
“industrial activity,” as defined in the Israeli Law for the Encouragement of Capital Investments, 1959 (the “Investment Law”), and is also eligible for tax
benefits as a “Privileged Enterprise,” which apply to the turnover attributed to such enterprise, for a period of up to ten years from the first year in which
we generated taxable income. The tax benefits under the Privileged Enterprise status are scheduled to expire at the end of 2023.
In order to remain eligible for the tax benefits of a Privileged Enterprise, we must continue to meet certain conditions stipulated in the Investment
Law and its regulations, as amended, and must also comply with the conditions set forth in the tax ruling. These conditions include, among other things,
that the production, directly or through subcontractors, of all our products should be performed within certain regions of Israel. If we do not meet these
requirements, the tax benefits would be reduced or canceled and we could be required to refund any tax benefits that we received in the past, in whole or in
part, linked to the Israeli consumer price index, together with interest. Further, these tax benefits may be reduced or discontinued in the future. If these tax
benefits are canceled, our Israeli taxable income would be subject to regular Israeli corporate tax rates. The standard corporate tax rate for Israeli
companies is 23% since 2018. For more information about applicable Israeli tax regulations, see “Item 10. Additional Information — E. Taxation — Israeli
Tax Considerations and Government Programs.”
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In the future, we may not be eligible to receive additional tax benefits under the Investment Law if we increase certain of our activities outside of
Israel. Additionally, in the event of a distribution of a dividend from the abovementioned tax exempt income, in addition to withholding tax at a rate of 20%
(or a reduced rate under an applicable double tax treaty), we will be subject to tax on the otherwise exempt income (grossed-up to reflect the pre-tax
income that we would have had to earn in order to distribute the dividend) at the corporate tax rate applicable to our Privileged Enterprise’s income, which
would have been applied had we not enjoyed the exemption. Similarly, in the event of our liquidation or a share buyback, we will be subject to tax on the
grossed-up amount distributed or paid at the corporate tax rate which would have been applied to our Privileged Enterprise’s income had we not enjoyed
the exemption. For more information about applicable Israeli tax regulations, see “Item 10. Additional Information — E. Taxation — Israeli Tax
Considerations and Government Programs.”
Tax matters, including changes in tax laws, adverse determinations by taxing authorities and imposition of new taxes could adversely affect our results
of operations and financial condition. Furthermore, we may not be able to fully utilize our net operating loss carryforwards.
We are subject to the tax laws and regulations of the State of Israel and numerous other jurisdictions in which we do business. Many judgments are
required in determining our provision for income taxes and other tax liabilities, and the applicable tax authorities may not agree with our tax positions. In
addition, our tax liabilities are subject to other significant risks and uncertainties, including those arising from potential changes in laws and/or regulations
in the State of Israel and the other countries in which we do business, the possibility of adverse determinations with respect to the application of existing
laws, changes in our business or structure and changes in the valuation of our deferred tax assets and liabilities. As of December 31, 2022, we had net
operating loss carryforwards (“NOLs”) for tax purposes of approximately $26.5 million. If we are unable to fully utilize our NOLs to offset taxable income
generated in the future, our future cash taxes could be materially and negatively impacted. For further detail regarding our NOLs, see Note 22 in our
consolidated financial statements included in this Annual Report.
It may be difficult to enforce a U.S. judgment against us and our officers and directors in Israel or the United States, or to assert U.S. securities laws
claims in Israel or serve process on our officers and directors.
We are incorporated in Israel. All of our directors and executive officers and the Israeli experts named in this Annual Report reside outside the
United States. The majority of our assets and the assets of these persons are located outside the United States. Therefore, it may be difficult for an investor,
or any other person or entity, to enforce a U.S. court judgment based upon the civil liability provisions of the U.S. federal securities laws against us or any
of these persons in a U.S. or Israeli court, or to effect service of process upon these persons in the United States. Additionally, it may be difficult for an
investor, or any other person or entity, to assert U.S. securities law claims in original actions instituted in Israel. Israeli courts may refuse to hear a claim
based on an alleged violation of U.S. securities laws on the grounds that Israel is not the most appropriate forum in which to bring such a claim. Even if an
Israeli court agrees to hear a claim, it may determine that Israeli law and not U.S. law is applicable to the claim. If U.S. law is found to be applicable, the
content of applicable U.S. law must be proved as a fact by expert witnesses, which can be a time-consuming and costly process. Certain matters of
procedure will also be governed by Israeli law. There is little binding case law in Israel addressing the matters described above.
Moreover, an Israeli court will not enforce a non-Israeli judgment if it was given in a state whose laws do not provide for the enforcement of
judgments of Israeli courts (subject to exceptional cases), if its enforcement is likely to prejudice the sovereignty or security of the State of Israel, if it was
obtained by fraud or in the absence of due process, if it is at variance with another valid judgment that was given in the same matter between the same
parties, or if a suit in the same matter between the same parties was pending before a court or tribunal in Israel at the time the foreign action was brought.
Your rights and responsibilities as our shareholder are governed by Israeli law, which may differ in some respects from the rights and responsibilities of
shareholders of U.S. corporations.
Since we are incorporated under Israeli law, the rights and responsibilities of our shareholders are governed by our articles of association and
Israeli law. These rights and responsibilities differ in some respects from the rights and responsibilities of shareholders of U.S.-based corporations. In
particular, a shareholder of an Israeli company has a duty to act in good faith and in a customary manner in exercising its rights and performing its
obligations towards the company and other shareholders and to refrain from abusing its power in the company, including, among other things, in voting at
the general meeting of shareholders on certain matters, such as an amendment to the company’s articles of association, an increase of the company’s
authorized share capital, a merger of the company and approval of related party transactions that require shareholder approval. A shareholder also has a
general duty to refrain from discriminating against other shareholders. In addition, a controlling shareholder or a shareholder who knows that it possesses
the power to determine the outcome of a shareholders vote, or who has the power to appoint or prevent the appointment of an office holder in the company
or has other powers towards the company, has a duty to act in fairness towards the company. However, Israeli law does not define the substance of this duty
of fairness. See “Item 6. Directors, Senior Management and Employees — Fiduciary Duties and Approval of Specified Related Party Transactions under
Israeli Law — Duties of Shareholders.” There is limited case law available to assist us in understanding the nature of this duty or the implications of these
provisions. These provisions may be interpreted to impose additional obligations and liabilities on our shareholders that are not typically imposed on
shareholders of U.S. corporations.
42
Provisions of Israeli law and our articles of association may delay, prevent or make undesirable an acquisition of all or a significant portion of our
shares or assets.
Certain provisions of Israeli law and our articles of association could have the effect of delaying or preventing a change in control and may make it
more difficult for a third party to acquire us or for our shareholders to elect different individuals to our board of directors, even if doing so would be
beneficial to our shareholders, and may limit the price that investors may be willing to pay in the future for our ordinary shares. For example, Israeli
corporate law regulates mergers and requires that a tender offer be effected when more than a specified percentage of shares in a public company are
purchased. Under our articles of association, a merger shall require the approval of two-thirds of the voting rights represented at a meeting of our
shareholders and voting on the matter, in person or by proxy, and any amendment to such provision shall require the approval of 60% of the voting rights
represented at a meeting of our shareholders and voting on the matter, in person or by proxy. Further, Israeli tax considerations may make potential
transactions undesirable to us or to some of our shareholders whose country of residence does not have a tax treaty with Israel granting tax relief to such
shareholders from Israeli tax. With respect to certain mergers, while Israeli tax law permits tax deferral, the deferral is contingent on certain restrictions on
future transactions, including with respect to dispositions of shares received as consideration, for a period of two years from the date of the merger. See
Exhibit 2.1, “Description of Securities —Acquisitions Under Israeli Law,” incorporated herein by reference.
General Risks
The loss of one or more of our key employees could harm our business.
We depend on the continued service and performance of our key employees, including Amir London, our Chief Executive Officer, and our other
senior management staff. We have entered into employment agreements with all of our senior management, including Mr. London, and other key
employees. Either party, however, can terminate these agreements for any reason. The loss of key members of our executive management team could
disrupt our operations, commercial and business development activities, or product development and have an adverse effect on our ability to meet our
targets and grow our business.
Our ability to attract, recruit, retain and develop qualified employees is critical to our success and growth.
We compete in a market that involves rapidly changing technological and regulatory developments that require a wide-ranging set of expertise and
intellectual capital. In order for us to successfully compete and grow, we must attract, recruit, retain and develop the necessary personnel who can provide
the needed expertise across the entire spectrum of our intellectual capital needs. While we have a number of our key personnel who have substantial
experience with our operations, we must also develop and exercise our personnel to provide succession plans capable of maintaining continuity in the midst
of the inevitable unpredictability of human capital. However, the market for qualified personnel is competitive, and we may not succeed in recruiting
additional experienced or professional personnel, retaining current personnel or effectively replacing current personnel who depart with qualified or
effective successors. Many of the companies with which we compete for experienced personnel have greater resources than us.
Our effort to retain and develop personnel may also result in significant additional expenses, which could adversely affect our profitability. There
can be no assurance that qualified employees will continue to be employed or that we will be able to attract and retain qualified personnel in the future.
Failure to retain or attract qualified personnel could have a material adverse effect on our business, financial condition and results of operations.
We are subject to risks associated with doing business globally.
Our operations are subject to risks inherent to conducting business globally and under the laws, regulations and customs of various jurisdictions
and geographies. These risks include fluctuations in currency exchange rates, changes in exchange controls, loss of business in government and public
tenders that are held annually in many cases, nationalization, expropriation and other governmental actions, availability of raw materials, changes in
taxation, importation limitations, export control restrictions, changes in or violations of applicable laws, including applicable anti-bribery and anti-
corruption laws, such as the FCPA and the U.K. Bribery Act of 2010, pricing restrictions, economic and political instability, disputes between countries,
personnel culture differences, diminished or insufficient protection of intellectual property, and disruption or destruction of operations in a significant
geographic region regardless of cause, including war, terrorism, riot, civil insurrection or social unrest. Failure to comply with, or material changes to, the
laws and regulations that affect our global operations could have an adverse effect on our business, financial condition or results of operations.
As a result of our increased global presence, we face increasing challenges that could adversely impact our results of operations, reputation and
business.
In light of our global presence, especially following our entry into new international markets and particularly in the MENA region, we face a
number of challenges in certain jurisdictions that provide reduced legal protection, including poor protection of intellectual property, inadequate protection
against crime (including bribery, corruption and fraud) and breaches of local laws or regulations, unstable governments and economies, governmental
actions that may inhibit the flow of goods and currency, challenges relating to competition from companies that already have a local presence in such
markets and difficulties in recruiting sufficient personnel with appropriate skills and experience.
43
Local business practices in jurisdictions in which we operate, and particularly in the MENA region, may be inconsistent with international
regulatory requirements, such as anti-corruption and anti-bribery laws and regulations (including the FCPA and the U.K. Bribery Act of 2010) to which we
are subject. Although we implement policies and procedures designed to ensure compliance with these laws, we cannot guarantee that none of our
employees, contractors, service providers, partners, distributors and agents, will not violate our policies or applicable law. Any such violation could have an
adverse effect on our business and reputation and may expose us to criminal or civil enforcement actions, including penalties and fines.
Developments in the economy may adversely impact our business.
Our operating and financial performance may be adversely affected by a variety of factors that influence the general economy in the United States,
Europe, Israel, Russia, Latin America, Asia and other territories worldwide, including global and local economic slowdowns, challenges faced banks and
the health of markets for the sovereign debt. Many of our largest markets, including the United States, Latin America and states that are members of the
Commonwealth of Independent States previously experienced dramatic declines in the housing market, high levels of unemployment and
underemployment, and reduced earnings, or, in some cases, losses, for businesses across many industries, with reduced investments in growth.
A recessionary economic environment may adversely affect demand for our plasma-derived protein therapeutics. As a result of job losses, patients
in the U.S. and other markets may lose medical insurance and be unable to purchase needed medical products or may be unable to pay their share of
deductibles or co-payments. Hospitals may steer patients adversely affected by the economy to less costly therapies, resulting in a reduction in demand, or
demand may shift to public health hospitals, which purchase our products at a lower government price. A recessionary economic environment may also
lead to price pressure for reimbursement of new drugs, which may adversely affect the demand for our future plasma-derived protein therapeutics.
A breakdown in our information technology (IT) systems could result in a significant disruption to our business.
Our operations are highly dependent on our information technology (IT) systems. If we were to suffer a breakdown in our systems, storage,
distribution or tracing, we could experience significant disruptions affecting all our areas of activity, including our manufacturing, research, accounting and
billing processes and potentially cause disruptions to our manufacturing process for products currently in production. We may also suffer from partial loss
of information and data due to such disruption.
Our business and operations would suffer in the event of computer system failures, cyber-attacks on our systems or deficiency in our cyber security
measures.
Despite the implementation of security measures, our internal computer systems, and those of third parties on which we rely, are vulnerable to
damage from computer viruses, unauthorized access, malware, natural disasters, fire, terrorism, war and telecommunication, electrical failures, cyber-
attacks or cyber-intrusions over the Internet, attachments to emails, persons inside our organization, or persons with access to systems inside our
organization. The risk of a security breach or disruption, particularly through cyber-attacks or cyber intrusion, including by computer hackers, foreign
governments, and cyber terrorists, has generally increased as the number, intensity and sophistication of attempted attacks and intrusions from around the
world have increased. To the extent that any disruption or security breach results in a loss of or damage to our data or applications, or inappropriate
disclosure of confidential or proprietary information and personal information, we could incur liability due to lost revenues resulting from the unauthorized
use or theft of sensitive business information, remediation costs, and litigation risks including potential regulatory action by governmental authorities. In
addition, any such disruption, security breach or other incident could delay the further development of our future product candidates due to theft or
corruption of our proprietary data or other loss of information. Our business and operations could also be harmed by any reputational damage with
customers, investors or third parties with whom we work, and our competitive position could be adversely impacted.
Tax legislation in the United States may impact our business.
Changes to the Internal Revenue Code, the issuance of administrative rulings or court decisions could impact our business. Tax legislation enacted
in recent years made significant and wide-ranging changes to the U.S. Internal Revenue Code. Many aspects of such legislation that could affect our
business remain subject to considerable uncertainty. Further, it is impossible to predict the occurrence or timing of any additional tax legislation or other
changes in tax law that materially affect our business or investors.
Current and future accounting pronouncements and other financial reporting standards, especially but not only concerning revenue recognition, might
negatively impact our financial results.
We regularly monitor our compliance with applicable financial reporting standards and review new pronouncements and drafts thereof that are relevant to
us. As a result of new standards, changes to existing standards, including but not limited to IFRS 15 on revenue from contracts with customers that we
adopted in 2018 and IFRS 16 on leases that we adopted in 2019 and changes in their interpretation, we might be required to change our accounting policies,
particularly concerning revenue recognition, to alter our operational policies so that they reflect new or amended financial reporting standards, or to restate
our published financial statements. Such changes might have an adverse effect on our reputation, business, financial position, and profit, or cause an
adverse deviation from our revenue and operating profit target.
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The Russian invasion of Ukraine may have a material adverse impact on us.
Commencing in 2021, Russian President Vladimir Putin ordered the Russian military to begin massing thousands of military personnel and
equipment near its border with Ukraine and in Crimea, representing the largest mobilization since the illegal annexation of Crimea in 2014. President Putin
has initiated troop movements into the eastern portion of Ukraine and continues to threaten an all-out invasion of Ukraine. On February 22, 2022, the
United States and several European nations announced sanctions against Russia in response to Russia’s actions. On February 24, 2022, President Putin
commenced a full-scale invasion of Russia’s pre-positioned forces into Ukraine, which has had a negative impact on supply chains and the economy and
business activity globally. Furthermore, Russia’s ongoing military actions in Ukraine, and the varying involvement of the United States and other NATO
countries precludes prediction as to the ultimate adverse impact on global economic and market conditions, and, as a result, presents material uncertainty
and risk with respect to our operations and the price of our shares.
To date, our operations have not been materially impacted by Russia’s invasion of Ukraine, however, we may not be able to continue and supply
our products to our Russian distributor, and even if we are able to continue the supply of product, there can be no assurance that our distributor may be able
to pay us for such products given the actions by the Russian government to seize all international foreign currency payments. Our revenues, profitability
and financial condition may be affected if we are unable to continue to sell our products to the Russian market and/or are not able to collect due proceeds
from previous and/or future product sales. Additionally, the impact of higher energy prices and higher prices for certain raw materials and goods and
services resulting in higher inflation and disruptions to financial markets and disruptions to manufacturing and supply and distribution chains for certain
raw materials and goods and services across the globe may impact our business in the future. We continue to assess and respond where appropriate to any
direct or indirect impact that the Russian invasion of Ukraine has on the availability or pricing of the raw materials for our products, manufacturing and
supply and distribution chains for our products and on the pricing and demand for our products.
Increasing scrutiny of, and evolving expectations for, sustainability and environmental, social, and governance (“ESG”) initiatives could increase our
costs or otherwise adversely impact our business.
Public companies are facing increasing scrutiny related to ESG practices and disclosures from certain investors, capital providers, shareholder
advocacy groups, other market participants and other stakeholder groups. Such increased scrutiny may result in increased costs, enhanced compliance or
disclosure obligations, or other adverse impacts on our business, financial condition or results of operations. While we may at times engage in voluntary
ESG initiatives, such initiatives may be costly and may not have the desired effect. If our ESG practices and reporting do not meet investor or other
stakeholder expectations, which continue to evolve, we may be subject to investor or regulator engagement regarding such matters. In addition, new
sustainability rules and regulations have been adopted and may continue to be introduced in various states and other jurisdictions. For example, the SEC
has published proposed rules that would require companies to provide significantly expanded climate-related disclosures in their periodic reporting, which
may require us to incur significant additional costs to comply and impose increased oversight obligations on our management and board of directors. Our
failure to comply with any applicable rules or regulations could lead to penalties and adversely impact our reputation, access to capital and employee
retention. Such ESG matters may also impact our third-party contract manufacturers and other third parties on which we rely, which may augment or cause
additional impacts on our business, financial condition, or results of operations.
Item 4. Information on the Company
Corporate Information
We were incorporated under the laws of the State of Israel on December 13, 1990, under the name Kamada Ltd. In August 2005, we successfully
completed an initial public offering on the TASE. In June 2013, we successfully completed an initial public offering in the United States on Nasdaq. The
address of our principal executive office is 2 Holzman St., Science Park, P.O. Box 4081, Rehovot 7670402, Israel, and our telephone number is +972 8
9406472. Our website address is www.kamada.com. The reference to our website is intended to be an inactive textual reference and the information on, or
accessible through, our website is not intended to be part of this Annual Report. The SEC maintains a website at www.sec.gov that contains reports, proxy
and information statements and other information regarding registrants like us that file electronically with the SEC. You can also inspect the Annual Report
on that website.
We have irrevocably appointed Puglisi & Associates as our agent to receive service of process in any action against us in any United States federal
or state court. The address of Puglisi & Associates is 850 Library Avenue, Suite 204, P.O. Box 885, Newark, Delaware 19715.
Capital Expenditures
For a discussion of our capital expenditures, see “Item 5. Operating and Financial Review and Prospects—Liquidity and Capital Resources.”
Business Overview
We are a commercial stage global biopharmaceutical company with a portfolio of marketed products indicated for rare and serious conditions and
a leader in the specialty plasma-derived field focused on diseases of limited treatment alternatives. We are also advancing an innovative development
pipeline targeting areas of significant unmet medical need. Our strategy is focused on driving profitable growth from our significant commercial catalysts
as well as our manufacturing and development expertise in the plasma-derived and biopharmaceutical markets.
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We operate in two segments: (i) the Proprietary Products segment, which includes our six FDA approved plasma-derived biopharmaceutical
products - CYTOGAM, KEDRAB, WINRHO SDF, VARIZIG, HEPGAM B and GLASSIA, as well as KAMRAB, KAMRHO (D) and two types of
equine-based anti-snake venom (ASV) products; all of which we market internationally in more than 30 countries. We manufacture our proprietary
products at our cGMP compliant FDA-approved production facility located in Beit Kama, Israel, using our proprietary platform technology and know-how
for the extraction and purification of proteins and IgGs from human plasma, as well as at third party contract manufacturing facilities; and (ii) the
Distribution segment, in which we leverage our expertise and presence in the Israeli market by distributing, for use in Israel, more than 25 pharmaceutical
products supplied by international manufacturers and have recently added eleven biosimilar products to our portfolio, which, subject to EMA and IMOH
approvals, are expected to be launched in Israel through 2028.
As part of our Proprietary Products segment, we sell CYTOGAM, a Cytomegalovirus Immune Globulin Intravenous (Human) (CMV-IGIV),
indicated for prophylaxis of CMV disease associated with solid organ transplantation in the United States and Canada. Total revenues from sales of
CYTOGAM for the year ended December 31, 2022, the first full year during which we sold the product, was $22.6 million.
We market KEDRAB, a human rabies immune globulin (HRIG), in the United States through a strategic distribution and supply agreement with
Kedrion. Our 2022 revenues from sales of KEDRAB to Kedrion totaled $16.2 million as compared to $11.9 million and $18.3 million during 2021 and
2020, respectively. Sales of KEDRAB by Kedrion in the United States during the years 2022, 2021 and 2020 totaled $36.2 million, $24.7 million, and
$23.7 million, respectively. Based on the information provided by Kedrion, these sales represent approximately 32%, 27% and 23% share of the relevant
U.S. market in each of these years, respectively. KEDRAB in-market sales by Kedrion during 2022 grew in comparison to the pre-COVID-19 pandemic
sales and we anticipate this trend to continue during 2023 and beyond.
We believe that sales of CYTGOM and KEDRAB in the U.S. market, which generated more than 50% of gross profitability in the year ended
December 31, 2022, will continue to increase in the coming years and will be a major growth catalyst for the foreseeable future.
We sell WINRHO SDF, VARIZIG and HEPGAM B, in the United States, Canada and several other international markets, mainly in the Middle
East and North Africa (“MENA”) regions. Total revenues from sales of these products for the year ended December 31, 2022, the first full year during
which we sold these products, was $29.5 million.
For the year ended December 31, 2022, we generated combined revenues of $52.1 million through sales of CYTOGAM, WINRHO SDF,
VARIZIG and HEPGAM B, the portfolio of four FDA-approved products that we acquired in November 2021. The 2022 revenues from this portfolio
represent a 24% year over year increase compared to the $41.9 million of total revenues generated by this portfolio during the year ended December 31,
2021.
We market GLASSIA in the United States through a strategic partnership with Takeda. During 2021, Takeda completed the technology transfer of
GLASSIA manufacturing to its facility in Belgium and received the required FDA approval and initiated its own production of GLASSIA for the U.S.
market. In addition, during 2021, Takeda obtained a marketing authorization approval for GLASSIA from Health Canada. During the first quarter of 2022,
Takeda began to pay us royalties on sales of GLASSIA manufactured by Takeda, at a rate of 12% on net sales through August 2025 and at a rate of 6%
thereafter until 2040, with a minimum of $5 million annually for each of the years from 2022 to 2040. In 2022, we received a total of $14.2 million from
Takeda, of which $12.2 of sales-based royalty income (for the period between March and December of 2022) and a $2.0 million one-time payment on
account of the transfer, to Takeda, of the GLASSIA U.S. BLA. Based on current GLASSIA sales in the U.S. and forecasted future growth, we expect to
receive royalties from Takeda in the range of $10 million to $20 million per year for 2023 to 2040 on GLASSIA sales. Historically, we generated revenues
on sales of GLASSIA, manufactured by us, to Takeda for further distribution in the United States. Our revenues from sales of GLASSIA to Takeda totaled
$26.2 million and $64.9 million during 2021 and 2020, respectively. During 2021, we also recognized revenues of $5.0 million on account of a sales
milestone associated with GLASSIA sales by Takeda.
We also market GLASSIA in other counties through local distributors. Total revenues derived from sales of GLASSIA in all other countries
during 2022 was $5.9 million, as compared to $7.6 million and $5.5 million during 2021 and 2020, respectively. These ex-U.S. market sales of GLASSIA
generated approximately 40% gross margin in the year ended December 31, 2022.
Our 2022 revenues from the sales of the remaining Proprietary products, including KAMRAB (a human rabies immune globulin (HRIG) sold by
us outside the U.S. market) and KAMRHO (D) IM (for prophylaxis of hemolytic disease of newborns), as well as our anti-snake venoms, totaled $13.9
million, as compared to $18.4 million and $11.2 million during 2021 and 2020, respectively.
We own an FDA licensed plasma collection center that we acquired in March 2021 from the privately held B&PR based in Beaumont, Texas,
which currently specializes in the collection of hyper-immune plasma used in the manufacture of KAMRHO (D). For the year ended December 31, 2022,
we generated $0.4 million in revenues from this plasma collection center, which were included in our Proprietary Products revenues. See below “— Recent
Acquisitions.” We are in the process of significantly expanding our hyper-immune plasma collection capacity in this center. We obtained FDA approval for
the collection of hyper-immune plasma to be used in the manufacture of KEDRAB, which is plasma that contains high levels of antibodies from donors
who have been previously vaccinated by an active rabies vaccine and plan to start collections of such plasma during 2023. We also intend to leverage our
FDA license to establish additional plasma collection centers in the United States, with the intention of collecting normal source plasma to be sold for
manufacturing by third parties, as well as hyper-immune specialty plasma required for manufacturing of our proprietary products. We believe that the
expansion of our plasma collection capabilities will allow us to better support our plasma needs as well as generate additional revenues through sales of
collected normal source plasma. To that end, during March 2023, we entered into a lease for a new plasma collection center in Uvalde, Houston, Texas and
expect to commence operations at the new center following the completion of its construction and obtaining the required regulatory approvals.
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Our Distribution segment is comprised of sales in Israel of pharmaceutical products manufactured by third parties. Sales generated by our
Distribution segment during 2022 totaled $ 26.7 million, as compared to $28.1 million and $32.3 million during 2021 and 2020, respectively. The majority
of the revenues generated in our Distribution segment are from plasma-derived products manufactured by European companies, and its sales represented
approximately 75%, 84% and 89% of our Distribution segment revenues for the years ended December 31, 2022, 2021 and 2020, respectively. Over the
past several years we continued to extend our Distribution segment products portfolio to non-plasma derived products, including recently entering into an
agreement with Alvotech and two additional companies for the distribution in Israel of eleven different biosimilar products which, subject to EMA and
subsequently IMOH approvals, are expected to be launched in Israel through 2028. We believe that sales generated by the launch of the biosimilar products
portfolio will become a major growth catalyst. We currently estimate the potential aggregate peak revenues, achievable within several years of launch,
generated by the distribution of all eleven biosimilar products to be approximately $40 million annually.
In addition to our commercial operation, we invest in research and development of new product candidates. Our leading investigational product is
Inhaled AAT for AATD, for which we are continuing to progress the InnovAATe clinical trial, a randomized, double-blind, placebo-controlled, pivotal
Phase 3 trial. We have additional product candidates in early development stage. For additional information regarding our research and development
activities, see “— Our Development Product Pipeline”.
We continue to focus on driving profitable growth through expanding our growth catalysts which include: investment in the commercialization
and life cycle management of our commercial Proprietary products, led by CYTOGAM and KEDRAB sales in the U.S. market; continued growth of our
Proprietary hyper-immune portfolio’s revenues in existing and new geographic markets through registration and launch of the products in new territories;
expanding sales of GLASSIA in ex-U.S. markets; generating royalties from GLASSIA sales by Takeda; expanding our plasma collection capabilities in
support of our growing demand for hyper-immune plasma as well as sales of normal source plasma to other plasma-derived manufacturers; continued
increase of our Distribution segment revenues specifically through launching the eleven biosimilar products in Israel; and leveraging our FDA-approved
IgG platform technology, manufacturing, research and development expertise to advance development and commercialization of additional product
candidates, including our investigational Inhaled AAT product, and identify potential commercial partners for this product.
We currently expect to generate total revenues for the fiscal year 2023 in the range of $138 million to $146 million and EBITDA in the range of
$22 million to $26 million. The mid- range points of the projected 2023 revenue and EBITDA forecast represent a 10% and 35% growth over fiscal year
2022, respectively.
Recent Acquisitions
Acquisition of IgG portfolio
In November 2021, we acquired a portfolio of four FDA approved plasma-derived hyper-immune commercial products from Saol. For a
description of the four products acquired from Saol, CYTOGAM, HEPAGAM B, VARIZIG and WINRHO SDF, see below “— Our Commercial Product
Portfolio — Proprietary Products Segment.” The acquisition of this portfolio furthered our core objective to become a fully integrated specialty plasma
company with strong commercial capabilities in the U.S. market, as well as to expand to new markets, mainly in the MENA region, and to broaden our
portfolio offering in existing markets. Our wholly owned U.S. subsidiary, Kamada Inc., is responsible for the commercialization of the four products in the
U.S. market, including direct sales to wholesalers and local distributers.
Under the terms of the agreement, we paid Saol a $95 million upfront payment, and agreed to pay up to an additional $50 million of contingent
consideration subject to the achievement of sales thresholds for the period commencing on the acquisition date and ending on December 31, 2034. The first
sales threshold was achieved by the end of 2022, and a $3 million contingent consideration payment was paid to Saol during the first quarter of 2023.
Subject to certain conditions defined in the agreement between the parties, we may be entitled for up to $3.0 million credit deductible from the contingent
consideration payments due for the years 2023 through 2027. In addition, we acquired inventory valued at $14.4 million and agreed to pay the
consideration to Saol in ten quarterly installments of $1.5 million each or the remaining balance at the final installment, of which we paid four installments
of $1.5 million each to Saol during 2022.
To partially fund the acquisition costs, we obtained a $40 million financing facility from the Israeli Bank Hapoalim B.M., comprised of a $20
million five-year loan and a $20 million short-term revolving credit facility. Effective as of January 1, 2023, the financing facility was amended such that
the $20 million short-term revolving credit facility was replaced with a NIS 35 million (approximately $10 million) credit facility. For information
regarding the financing, see “Item 5. Operating and Financial Review and Prospects—Liquidity and Capital Resources—Credit Facility and Loan
Agreement with Bank Hapoalim B.M.”
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In connection with the acquisition, we entered into a transition services agreement (TSA) with Saol, under which Saol provided to us during 2022
certain services and support (including, managing sales and distribution, payment collection, logistics management, price reporting, regulatory affairs,
medical inquiries, quality control complaints and pharmacovigilance), in order to secure the smooth transfer of the acquired assets and related
commitments. During the transition period to date, we have recruited staff as needed, and have gradually assumed all operational responsibilities related to
the acquired products, including distribution and sales, quality oversight, supply chain activities and finance related issues. In addition, we assumed
regulatory responsibility for all products in the United States as of September 2022 following FDA acknowledgment of the BLAs transfer, and we assumed
regulatory responsibility in Canada for CYTOGAM, WINRHO SDF and VARIZIG as of June 2022 and for HEPAGAM B as of October 2022, following
acknowledgment of the Drug Identification Number (“DIN”) transfer by Health Canada. We continue to market inventory acquired from Saol under its
label and product serial number.
Pursuant to an earlier engagement with Saol, during 2019, we initiated technology transfer activities for transitioning CYTOGAM manufacturing
to our manufacturing facility in Beit Kama, Israel. As a result of the consummation of the IgG portfolio acquisition, which included the acquisition of all
rights relating to CYTOGAM, the previous engagement with Saol with respect to this product expired. During December 2022, we submitted a PAS to the
FDA for approval to manufacture CYTOGAM at the Beit Kama facility and FDA approval is currently expected by mid-2023. The anticipated FDA
approval will mark the successful conclusion of the technology transfer process of CYTOGAM from its previous manufacturer, CSL Behring. A similar
application to the Canadian health authorities was submitted in January 2023, with approval expected by the third quarter of 2023.
In connection with the acquisition, we assumed a contract manufacturing agreement with Emergent for the manufacturing of HEPAGAM B,
VARIZIG and WINRHO SDF. We expect to continue manufacturing these products with Emergent in the foreseeable future and are considering the
initiation of a technology transfer for transitioning the manufacturing of these products to our manufacturing facility in Beit Kama, Israel. The initiation of
such a technology transfer would be subject to executing a new, amended manufacturing services agreement with Emergent, as currently contemplated,
covering operational aspects and the technology transfer related services and scope. We anticipate that once initiated, such a technology transfer may be
completed within four to five years.
Plasma Collection Center Acquisition
In March 2021, we completed the acquisition of the FDA licensed plasma collection center and certain related assets from the privately held
B&PR based in Beaumont, Texas, which specializes in the collection of hyper-immune plasma used in the manufacturing of KAMRHO (D), used for
prophylaxis of hemolytic disease of newborns. This plasma collection center is one of the few FDA licensed centers in the U.S. collecting the specialty
plasma required for this product. The acquisition, for a total consideration of approximately $1.61 million, was consummated through Kamada Plasma
LLC, our wholly owned subsidiary, which operates our plasma collection activity in the United States.
Our Commercial Product Portfolio
Our commercial products portfolio includes our proprietary plasma-derived biopharmaceutical products in our Proprietary Products segment,
which are marked and sold directly or through strategic partners and local distributers in the U.S., Canada, and additional markets worldwide, as well as
licensed products, some of which are plasma-derived, which are marketed and sold by us in our Distribution segment in Israel.
Proprietary Products Segment
Our products in the Proprietary Products segment consist of plasma-derived protein and IgGs therapeutics derived from human plasma that are
administered by injection or infusion. We also manufacture anti-snake venom products from equine based serum.
Our Proprietary Products segment sales totaled $102.6 million, $75.5 million and $100.9 million for the years ended December 31, 2022, 2021
and 2020, respectively. For the years ended December 31, 2022, and 2021 (effective from November 22, 2021), revenues from sales of CYTOGAM,
HEPAGAM B, VARIZIG and WINRHO SDF totaled $52.1 million and $5.4 million, respectively. Revenues from sales of KEDRAB to Kedrion for further
distribution in the U.S. market totaled $16.2 million, $11.9 million and $18.3 million for the years ended December 31, 2022, 2021 and 2020, respectively.
In 2022, we recognized a total of $14.2 million as revenues from Takeda, of which $12.2 million of sales-based royalty income on account of GLASSIA
sales by Takeda (for the period between March and December 2022) and a $2.0 million one-time payment on account of the transfer, to Takeda, of the
GLASSIA U.S. BLA. Sales of GLASSIA to Takeda for further distribution in the U.S. were terminated during 2021; for the years ended December 31,
2021 and 2020 revenues from the sales of GLASSIA to Takeda totaled $26.2 million and $65.1 million, respectively. In addition, during 2021 we
recognized revenues of $5.0 million on account of a sales milestone due from Takeda. Sales of GLASSIA, other than to Takeda, for the years ended
December 31, 2022, 2021 and 2020, totaled $5.9 million, $7.6 million and $5.5 million, respectively. Sales of our other Proprietary products (including
sales of our development stage Anti-SARS-CoV-2 IgG product during 2020) accounted for the substantial balance of total revenues in the Proprietary
Products segment for the years ended December 31, 2022, 2021 and 2020.
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The following tables lists our Proprietary Products:
Product
CYTOGAM
KAMRAB/
KEDRAB
Indication
Prophylaxis of Cytomegalovirus
(CMV) disease in kidney, lung,
liver, pancreas, heart and
heart/lung transplants
Active Ingredient
Cytomegalovirus Immune Globulin
Intravenous (Human)
Geography
USA, Canada, and Qatar***
Prophylaxis of rabies disease
Anti-rabies immunoglobulin (Human)
USA, Israel, India, Thailand, El
Salvador, Bosnia***, Russia*,
Mexico*, Georgia*, Ukraine*,
Poland***, South Korea***,
Canada, Australia, Argentina***,
and Brazil***.
WINRHO SDF
Immune thrombocytopenic
Rho(D) immunoglobulin (Human)
USA, Canada, Egypt, Hong Kong,
purpura (ITP) and suppression of
rhesus isoimmunization (RH)
Kuwait, Saudi Arabia, South
Korea, Turkey, UAE, Uruguay, and
Iraq**
HEPAGAM B
Prevention of Hepatitis B
Hepatitis B immunoglobulin (Human)
USA, Canada, Turkey, Israel, Saudi
recurrence liver transplants and
post-exposure prophylaxis
VARIZIG
Post exposure prophylaxis of
Varicella Zoster Immunoglobulin (Human)
Varicella in high risk individuals
GLASSIA (or Ventia/Respikam in
certain countries)
Intravenous AATD
Alpha-1 Antitrypsin (Human)
Arabia***, UAE, Bahrain***,
Moldova*** and Kuwait*
USA, Canada, Belgium***,
Kuwait***, Netherlands***,
Sweden***, UAE***, Norway***,
Denmark***, Brazil and
Estonia***
USA, Canada**, Israel, Russia,
Brazil*, Argentina, Uruguay**,
South Africa***, Colombia**,
Albania**, Kazakhstan**, and
Costa Rica**
KamRho (D) IM
Prophylaxis of hemolytic disease
Rho(D) immunoglobulin (Human)
Israel, Brazil, India*, Argentina,
of newborns
Paraguay, Chile, Russia, Nigeria*,
Thailand*, Costa Rica** and the
Palestinian Authority
KamRho (D) IV
Treatment
of
immune
Rho(D) immunoglobulin (Human)
India* and Argentina*
Snake bite antiserum
thermobocytopunic purpura
Treatment of snake bites by the
Vipera palaestinae and the Echis
coloratus
Anti-snake venom
Israel
* We have regulatory approval but did not market the product in this country in 2022.
** Product was registered, but we have not yet started sales.
*** Product was marketed without registration.
Propriety Products
CYTOGAM
CYTOGAM (Cytomegalovirus Immune Globulin Intravenous (Human)) (CMV-IGIV) is indicated for CMV disease associated with the
transplantation of the kidney, lung, liver, pancreas and heart. CYTOGAM, approved by the FDA in 1998, is the sole FDA-approved immunoglobulin (IgG)
product for this indication, and was acquired by us from Saol in November 2021.
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CYTOGAM is administered within 72 hours after transplantation and then at weeks 2, 4, 6, 8, 12 and 16 after transplantation. The precise dosage
is adjusted according to patient’s weight. CMV seroprevalence in the US is estimated at 50-80% among adults. CMV is typically passed through direct
personal contact. A seropositive status indicates exposure to the virus and development of antibodies against CMV. After initial infection, CMV establishes
lifelong latency in the host. Immunocompetent individuals possess few defenses, which protect mostly from infection and clinical symptoms (cell-mediated
immunity). Immunocompromised patients, such as transplant patients, are vulnerable to both de novo and reactivation of CMV. In SOTs, seronegative
recipients (R-) receiving seropositive organs (D+) have the highest risk of CMV infection and disease. The occurrence of disease caused by CMV in
transplanted patients without prophylaxis in patients undergoing lung or heart-lung transplantation is 50%-75%, 9%-23% after heart transplantation,
22%-29% after liver transplantation, and 8%-32% after kidney transplantation. Investigational studies have shown that administration of CMV-IGIV is
associated with neutralization of free CMV particles, which may lead to specific activation of the immune system, by raising relevant antibodies to levels
capable of attenuating or reducing the incidence of serious CMV disease post-transplantation.
Based on the Organ Procurement and Transplantation Network (OPTN), in the U.S., there were more than 42,000 SOT procedures performed
during 2022. The OPTN also suggests that the number of transplants each year continues to accelerate and in each of the past 11 years, new annual records
have been set in the number of deceased donors nationwide. Transplantation has also increased as a result of greater and more successful usage of organs
from less traditional donors, including older individuals and people who have died of cardiorespiratory failure. Several available antivirals (ganciclovir and
valganciclovir) are being used and are considered standards of care for the prevention of CMV infection in high-risk patients. As CMV infection in
immunocompromised solid organ transplant patients can be severe and life-threatening, we believe that administration of CYTOGAM together with the
available antivirals may provide additional protection in preventing CMV disease for certain high-risk transplant populations, such as lung and heart
transplant. We believe there is an under-utilization of CYTOGAM as prophylaxis to CMV in high risk populations within SOT due to lack of new data and
awareness regarding the benefits of combination CYTOGAM and antiviral therapy, and by addressing these deficits, higher usage rates can be supported.
CYTOGAM is registered and sold in the United States and Canada. In addition, CYTOGAM is supplied on a named patient basis without
registration in Qatar. We plan to leverage our existing international distribution network to explore the opportunities to register and commercialize the
product in other territories. In addition, we are currently working with key opinion leaders (“KOLs”) in the U.S. to generate new clinical data in support of
CYTOGAM and may explore future label expansion opportunities for the use of CYTOGAM in other indications.
We obtained the approval from Health Canada for the transfer of the DIN in June 2022. We received FDA acknowledgment for the transfer of the
ownership of the U.S. BLA for CYTOGAM in September 2022. During December 2022, we submitted an application to the FDA to manufacture
CYTOGAM at the Beit Kama facility. The application was submitted as a PAS and FDA approval is currently expected by mid-2023. The anticipated FDA
approval will mark the successful conclusion of the technology transfer process of CYTOGAM from the previous manufacturer, CSL Behring. A similar
application to the Canadian health authorities was submitted in January 2023, with approval expected by the third quarter of 2023. Our currently available
inventory of CYTOGAM is sufficient to meet market demand until the currently anticipated approval schedule.
Total revenues from sales of CYTOGAM for the year ended December 31, 2022, the first full year during which we sold the product, was $22.6
million.
KAMRAB/KEDRAB
KAMRAB is a hyper-immune plasma-derived therapeutic for prophylactic treatment against rabies infection that is administered to patients after
exposure to an animal suspected of being infected with rabies. KAMRAB is manufactured at our manufacturing facility in Beit Kama, Israel from plasma
that contains high levels of antibodies from donors that have been previously vaccinated by an active rabies vaccine. KAMRAB is administered by a one-
time injection, and the precise dosage is a function of the patient’s weight (20 IU/kg).
According to the WHO, rabies is estimated to cause 59,000 human deaths annually in over 150 countries and each year more than 29 million
people worldwide receive a post-bite rabies vaccination. This is estimated to prevent hundreds of thousands of rabies deaths annually. The CDC
recommends that PEP treatment for people who have never been vaccinated against rabies previously should always include administration of both Human
Rabies Immuno Globulin (HRIG) and rabies vaccine. According to the CDC, the combination of HRIG and vaccine is recommended for both bite and non-
bite exposures, regardless of the interval between exposure and initiation of treatment.
KAMRAB has been sold by us in various markets outside the United States through local distributors since 2003 and is currently sold in 15
countries, including Canada where it received marketing approval in November 2018, in various South American markets through the PAHO, the
specialized international health agency for the Americas, and in Australia in which it received marketing approval in August 2021.
In July 2011, we signed a strategic distribution and supply agreement with Kedrion for the clinical development and marketing in the United
States of KAMRAB, pursuant to which Kedrion agreed to bear all the costs required for the Phase 2/3 clinical trials. See “— Strategic Partnerships —
Kedrion (KAMRAB/KEDRAB).” The results of a phase 2/3 study demonstrated that KAMRAB was non-inferior to the comparator HRIG product in
achieving Rabies Virus Neutralizing Antibody (RVNA) levels of ≥0.5 IU/mL on day 14, when each was co-administered with a rabies vaccine. In addition,
KAMRAB was found to be well-tolerated with a safety profile similar to that of the comparator HRIG product. Based on these results, in August 2017, we
received FDA approval for the marketing of KAMRAB in the United States for PEP against rabies infection, and in April 2018 we, together with Kedrion,
launched the product in the United States under the trademark KEDRAB.
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In June 2021, the FDA approved a label update for KEDRAB, establishing the product’s safety and effectiveness in children aged 0 to 17 years.
The updates to the KEDRAB label were based on data from the KEDRAB U.S. post marketing pediatric study, the first and only clinical trial to establish
pediatric safety and effectiveness of any HRIG in the United States. The KEDRAB U.S. pediatric trial was conducted at two sites, one in Arkansas and
another in Rhode Island. The study included 30 pediatric patients (ages 0-17 years old), each of whom received KEDRAB as part of PEP treatment
following exposure or suspected exposure to an animal suspected or confirmed to be rabid, and safety follow-up was conducted for up to 84 days. The
primary objective of the study was to confirm the safety of KEDRAB in the pediatric population. Secondary objectives included the evaluation of antibody
levels and the effectiveness of KEDRAB in the prevention of rabies disease when administered with a rabies vaccine according to the PEP recommended
guidelines. No serious adverse events were observed during the study. No incidence of rabies disease or deaths were recorded throughout the 84-day study
period. According to the CDC data, no children in the United States treated with post-exposure prophylaxis have been reported to have had rabies between
2018 and April 2021, which supports the use of KEDRAB in children.
Our revenues from sales of KEDRAB to Kedrion during 2022 totaled $16.2 million as compared to $11.9 million and $18.3 million during 2021
and 2020, respectively. Sales of KEDRAB by Kedrion in the United States during the years 2022, 2021 and 2020 totaled $36.2 million, $24.7 million, and
$23.7 million, respectively. Based on the information provided by Kedrion, these sales represent approximately 32%, 27% and 23% share of the relevant
U.S. market in each of these years, respectively. KEDRAB in-market sales by Kedrion during 2022 grew in comparison to the pre-COVID-19 pandemic
sales and we anticipate this trend to continue 2023 and beyond.
WINRHO SDF
WINRHO SDF is a Rho(D) Immune Globulin Intravenous (Human) product indicated for use in clinical situations requiring an increase in platelet
count to prevent excessive hemorrhage in the treatment of non-splenectomies, for Rho(D)-positive children with chronic or acute immune
thrombocytopenia (ITP), adults with chronic ITP, and children and adults with ITP secondary to HIV infection. WINRHO SDF is also used for suppression
of Rhesus (Rh) Isoimmunization during pregnancy and other obstetric conditions in non-sensitized, Rho(D)-negative women. WINRHO SDF, approved by
the FDA in 1995, was acquired by us from Saol in November 2021.
Immune thrombocytopenic purpura (ITP) is a blood disorder characterized by a decrease in the number of platelets – the cells that help blood clot.
Recent findings suggest that nearly 20,000 children and adults are newly diagnosed with ITP each year in the United States. Rho(D) immunoglobulin is an
effective option for rapidly increasing platelet counts in patients with symptomatic ITP.
HDN is a blood disorder in a fetus or newborn infant. In some infants, it can be fatal. During pregnancy, Red Blood Cells (RBCs) from the unborn
baby can cross into the mother’s blood through the placenta. HDN occurs when the immune system of the mother sees a baby’s RBCs as foreign.
Antibodies then develop against the baby’s RBCs. These antibodies attack the RBCs in the baby’s blood and cause them to break down too early. Rho(D)
immunoglobulin is administered to Rh-negative pregnant women as prophylactic therapy, to prevent the disease. The proportion of Rh-negative blood type
differs from country to country and in the United States approximately 15% of people are Rh-negative.
In the U.S. market WINRHO SDF is used almost solely as treatment of ITP, however due to an FDA black-box warning for Intravascular
Hemolysis (IVH) issued in 2011, as well as the introduction of new ITP therapies, its sales in the U.S. market dropped significantly between 2011 to 2017
and have remained relatively flat since. The current use of WINRHO SDF in the U.S. market is for treatment of acute ITP in which it competes with
corticosteroids and high-dose IVIG. We believe that as the only Rho (D) product positioned in the U.S. for ITP, maintaining awareness of the product will
continue to support ongoing usage rates.
WINRHO SDF is currently registered and sold in 10 territories including the United States and Canada, as well as Egypt, Hong Kong, Kuwait,
Saudi Arabia, South Korea, Turkey, the United Arab Emirates, and Uruguay. In ex-U.S. territories, the product is mainly used to treat HDN, and we are
continually evaluating with our existing international distribution network the registration and commercialization of the product in other territories.
We obtained FDA acknowledgment for the transfer of the ownership of the BLA for WINRHO SDF in September 2022. The ownership transfer of
the DIN was approved by Health Canada in June 2022, and we are in the process of submitting requests to transfer the registration of the product in other
international countries as applicable.
WINRHO SDF is currently manufactured by Emergent under a contract manufacturing agreement, which was assigned to us by Saol following the
consummation of the acquisition. We expect to continue manufacturing the product with Emergent in the foreseeable future, and are considering the
initiation of a technology transfer for transitioning the manufacturing of WINRHO SDF to our manufacturing facility in Beit Kama, Israel. The initiation of
such a technology transfer would be subject to executing a new revised manufacturing services agreement with Emergent, as currently contemplated
covering operational aspects and the technology transfer related services and scope. We anticipate that once initiated, such a technology transfer may be
completed within four to five years.
Our KAMRHO (D) is a comparable product to WINRHO SDF and approved for HDN. The two products are registered and distributed in different
markets.
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HEPAGAM B
HEPAGAM B is a hepatitis B Immune Globulin (Human) (HBIg) product indicated to both prevent hepatitis B virus (HBV) recurrence following
liver transplantation in hepatitis B surface antigen positive (HBsAg- positive) patients and to provide post-exposure prophylaxis treatment. HEPAGAM B,
which was approved by the FDA in 2006 for post-exposure prophylaxis and in 2007 as a prevention therapy, was acquired by us from Saol in November
2021.
Liver transplantation is the treatment of choice for patients with liver failure secondary to chronic hepatitis B. However, liver transplantation is
complicated by the risk of recurrent hepatitis B virus infection, which significantly impairs graft and patient survival. Prevention of hepatitis B virus (HBV)
reinfection includes use of antiviral therapy, with the addition of hepatitis B immune globulin. HBIG treatment is based upon the rationale that administered
antibody will bind to and neutralize circulating virions, thereby preventing graft infection.
In the U.S. market HEPAGAM B is mostly used for post-transplant prophylaxis in which it competes with Nabi-HB, a product of ADMA. Given
the expected continued increase in liver transplants in the ex-U.S. countries, and with our planned direct marketing efforts we believe product usage may
grow.
HEPAGAM B is registered and sold in six territories including the United States, Canada, Turkey, Israel, the United Arab Emirates and Kuwait (in
which territory sales have not yet initiated). In addition, HEPAGAM B is supplied on a named patient basis without registration in Moldova, Bahrain and
Saudi Arabia (in which the registration process is currently on going).
FDA acknowledgment of ownership transfer of the BLA of HEPAGAM B was received in September 2022. Health Canada approval for the DIN
transfer was obtained in October 2022. We are in the process of submitting requests to transfer the registration of the product in other international
countries as applicable.
HEPAGAM B is currently manufactured by Emergent under a contract manufacturing agreement which was assigned from Saol following the
consummation of the acquisition. We expect to continue manufacturing the product with Emergent in the foreseeable future, and are considering the
initiation of a technology transfer for transitioning the manufacturing of HEPAGAM B to our manufacturing facility in Beit Kama, Israel. The initiation of
such a technology transfer would be subject to executing a new, amended manufacturing services agreement with Emergent, as currently contemplated,
covering operational aspects and the technology transfer related services and scope. We anticipate that once initiated, such a technology transfer may be
completed within four to five years.
VARIZIG
VARIZIG (Varicella Zoster Immune Globulin (Human)) is a product that contains antibodies specific for VZV, and it is indicated for post-
exposure prophylaxis of varicella (chickenpox) in high-risk patient groups, including immunocompromised children, newborns, and pregnant women.
VARIZIG is intended to reduce the severity of chickenpox infections in these patients. The CDC recommends VARIZIG for post-exposure prophylaxis of
varicella for persons at high-risk for severe disease who lack evidence of immunity to varicella. VARIZIG, approved by the FDA in 2012, is the sole FDA-
approved IgG product for this indication, and was acquired by us from Saol in November 2021.
Varicella-zoster virus (VZV) causes varicella (chicken pox) and herpes zoster (shingles). Varicella is a common childhood illness. Herpes zoster is
caused by VZV reactivation. The incidence of herpes zoster increases with age or immunosuppression. Individuals at highest risk of developing severe or
complicated varicella include immunocompromised people, preterm infants, and pregnant women. Varicella zoster immune globulin (human) (VARIZIG)
is recommended by the CDC for post-exposure prophylaxis to prevent or attenuate varicella-zoster virus infection in high-risk individuals. VARIZIG may
help these vulnerable patients to be defended against serious disease from varicella exposure. It has been demonstrated that post-exposure administration of
VARIZIG was associated with low rates of varicella in high-risk patients.
VARIZIG is registered and sold in the United States and Canada. In addition, VARIZIG is supplied on a named patient basis or through a tender in
Belgium, Kuwait, Netherlands, Sweden, the United Arab Emirates, Norway, Denmark, and Estonia.
In July 2022, we secured an $11.4 million agreement to supply VARIZIG to the PAHO, which also serves as Regional Office for the WHO, for
further distribution in Latin America. The supply of the product commenced in the fourth quarter of 2022 and is expected to continue through the first half
of 2023.
FDA acknowledgment of ownership transfer of the BLA of VARIZIG was received in September 2022. Health Canada approval for the DIN
transfer was obtained in June 2022.
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VARIZIG is currently manufactured by Emergent under a contract manufacturing agreement which was assigned from Saol following the
consummation of the acquisition. We expect to continue manufacturing the product with Emergent in the foreseeable future, and are considering the
initiation of a technology transfer for transitioning the manufacturing of VARIZIG to our manufacturing facility in Beit Kama, Israel. The initiation of such
a technology transfer would be subject to executing a new, amended manufacturing services agreement with Emergent, as currently contemplated, covering
operation aspects and the technology transfer related services and scope. We anticipate that once initiated, such a technology transfer may be completed
within four to five years.
In October 2022, we were awarded an extension of an existing tender from the Canadian Blood Services (CBS) for the supply of the four IgG
products, CYTOGAM, HEPAGAM, VARIZIG and WINRHO SDF, for an additional three years, commencing on April 1, 2023, for an approximate total
value of $22 million, securing the ongoing sales of those products in the Canadian market. CBS manages the Canadian supply of blood products for all
Canadian provinces and territories, excluding Quebec. We have an option to extend the agreement for up to two additional years. In addition, in Quebec,
we also supply CYTOGAM, HEPAGAM, VARIZIG and WINRHO SDF under the agreement with H’ema Quebec that was assigned to us from Saol.
GLASSIA
GLASSIA is an intravenous AAT product produced from fraction IV plasma that is indicated by the FDA for chronic augmentation and
maintenance therapy in adults with emphysema due to congenital AATD. AAT is a naturally occurring protein found in a derivative of plasma known as
fraction IV. AAT regulates the activity of certain white blood cells known as neutrophils and reduces cell inflammation. Patients with genetic AATD suffer
from a chronic inflammatory state, lung tissue damage and a decrease in lung function. While GLASSIA does not cure AATD, it supplements the patient’s
insufficient physiological levels of AAT and is administered as a chronic treatment. As such, the patient must take GLASSIA indefinitely over the course of
his or her life in order to maintain the benefits provided by it. GLASSIA is administered through a single weekly intravenous infusion.
In the United States and Europe, we believe that AATD is currently significantly under-diagnosed and under-treated. Based on information
published by the Alpha-1 Foundation, there are approximately 100,000 people with AATD in the United States and about the same number in Europe, and
we estimate, based on medical literature, that only approximately 10% of all potential cases of AATD are treated. We believe that the primary reasons for
this significant gap are the non-availability of AAT products in many countries, under diagnosis of patients suffering from AATD, expensive and protracted
registration processes required to commence sales of AAT products in new markets and the absence of insurance reimbursement in various countries. We
expect diagnosis of AATD to continue to increase going forward as awareness of AATD increases. Based on a market analysis report from 2020, the
estimated annual growth rate of currently approved AATD therapies in the U.S. and the five largest European countries is approximately 6-8%.
According to the Centers for Medicare and Medicaid Services, published payment allowance limits for Medicare part B, the average sale price, as
of January 2023, of 10 mg of GLASSIA is $5.099, resulting in an annual cost of between $80,000 and $120,000 per each AATD patient. In the United
States, in some of the European countries and in Israel, we believe that the majority of the cost of treatment is covered by medical insurance programs.
GLASSIA was the first FDA-approved liquid AAT, which is ready for infusion and does not require reconstitution and mixing before infusion, as
is required from most other competing products. Additionally, in June 2016, the FDA approved an expanded label of GLASSIA for self-infusion at home
after appropriate training. GLASSIA has a number of advantages over other intravenous AAT products, including the reduction of the risk of contamination
during the preparation and infection during the infusion, reduced potential for allergic reactions due to the absence of stabilizing agents, simple and easy
use by the patient or nurse, and the possible reduction of the nurse’s time during home visits, in the clinic or in the hospital and the ability to self- infuse at
home.
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Currently, GLASSIA is registered in 12 countries, of which it is currently being sold in the United States, Argentina, Israel and Russia. GLASSIA
is also sold in South-Africa on a non-registered named-patient basis. During 2023-2024, we expect to launch and sell GLASSIA in some of the additional
countries where it is currently registered. The majority of sales of GLASSIA are in the United States, where it obtained FDA approval in July 2010 and
sales commenced in September 2010. As part of the approval, the FDA requested that we conduct post-approval Phase 4 clinical trials, as is common in the
pharmaceutical industry, aimed at collecting additional safety and efficacy data for GLASSIA. According to our agreement with Takeda (See “— Strategic
Partnerships — Takeda (Glassia).”), the Phase 4 clinical trials are financed and managed by Takeda, provided that if the cost of such Phase 4 clinical trials
exceeds a pre-defined amount, we will participate in financing such trial up to a certain amount by offsetting such amounts from future milestones, sales of
GLASSIA or royalties from Takeda. The first Phase 4 safety study completed enrollment of a total of 30 subject in the U.S. and Canada during 2020 and its
clinical study report was completed and was submitted to the FDA during 2022. The second Phase 4 efficacy study was initiated during 2016 and was
terminated two years after initiation based on the DSMB’s recommendation due to very low recruitment rates. During 2019, Takeda submitted a revised
Phase 4 protocol to the FDA. Following several interactions with the FDA with respect to the Phase 4 efficacy study requirements, Takeda decided not to
continue to pursue the study.
We market GLASSIA in the United States through a strategic partnership with Takeda. During 2021, Takeda completed the technology transfer of
GLASSIA manufacturing to its facility in Belgium and received the required FDA approval and initiated its own production of GLASSIA for the U.S.
market. In addition, during 2021, Takeda obtained a marketing authorization approval for GLASSIA from Health Canada. During the first quarter of 2022,
Takeda began to pay us royalties on sales of GLASSIA manufactured by Takeda, at a rate of 12% on net sales through August 2025 and at a rate of 6%
thereafter until 2040, with a minimum of $5 million annually for each of the years from 2022 to 2040. In 2022, we received a total of $14.2 million from
Takeda, of which $12.2 of sales-based royalty income (for the period between March and December of 2022) and a $2.0 million a one-time payment on
account of the transfer, to Takeda, of the GLASSIA U.S. BLA. Based on current GLASSIA sales in the U.S. and forecasted future growth, we expect to
receive royalties on GLASSIA sales from Takeda in the range of $10 million to $20 million per year for 2023 to 2040. Historically, we generated revenues
on sales of GLASSIA, manufactured by us, to Takeda for further distribution in the United States. Our revenues from the sale of GLASSIA to Takeda
totaled $26.2 million and $64.9 million during 2021 and 2020, respectively. During 2021 we also recognized revenues of $5.0 million on account of a sales
milestone associated with GLASSIA sales by Takeda.
KAMRHO (D)
KAMRHO (D), similar to WINRHO SDF, is indicated for the prevention of HDN, which is a blood disease that occurs where the blood type of the
mother is incompatible with the blood type of the fetus. KAMRHO (D) is produced from hyper-immune plasma and is administered through intra-muscular
injection (KAMRHO (D) IM).
We have completed the registration process for KAMRHO (D) in several countries and we currently sell it in seven countries, including Israel, as
well as countries in Latin America, Asia, Africa and Eastern Europe.
SNAKE BITE ANTISERUM
Our snake bite antiserum products are used for the treatment of people who have been bitten by the most common Israeli viper (Vipera
palaestinae) and by the Israeli Echis (Echis coloratus). The venom of these snakes is poisonous and causes, among other symptoms, severe immediate pain
with rapid swelling. These snake bites can lead to death if left untreated. Our snake bite antiserum products are produced from hyper-immune serum that
has been derived from horses that were immunized against Israeli viper and Israeli Echis venom. These products are the only treatment in the Israeli market
for Vipera palaestinae and Echis coloratus snake bites.
We manufacture the snake bite antiserums pursuant to an agreement with the IMOH entered into in March 2009 and as extended and amended in
November 2022. The agreement with the IMOH was initially entered into following a tender that we won, and the extension of the agreement was under an
exemption from a tender. We completed construction of the production facilities and laboratories for the product in accordance with the agreement, and
successfully passed the IMOH inspections. We began production of our snake bite antiserums in August 2011 and commenced sales to the IMOH in 2012.
Under the agreement and subject to its terms, the IMOH has undertaken to purchase from us, and we have undertaken to supply the IMOH, a minimum
quantity of snake bite antiserums each year during the term of the agreement. The agreement with the IMOH is currently in effect until September 2024.
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Plasma Collection
As part of our strategy of evolving into a fully integrated specialty plasma company, we established Kamada Plasma LLC, a newly formed wholly
owned subsidiary, which operates our plasma collection activity in the United States. In March 2021, we completed the acquisition of the FDA licensed
plasma collection center and certain related assets from the privately held B&PR based in Beaumont, Texas, which specializes in the collection of hyper-
immune plasma used in the manufacture of KAMRHO (D).
The acquisition of B&PR’s plasma collection center represented our entry into the U.S. plasma collection market. We intend to leverage this
acquisition to reduce our dependency on third-party suppliers in terms of plasma supply needs as well as generate sales from commercialization of
collected normal source plasma. We are in the process of significantly expanding our hyperimmune plasma collection capacity by investing in the acquired
plasma collection center in Beaumont, Texas. We obtained FDA approval for the collection of hyper-immune plasma to be used in the manufacture of
KEDRAB, which is plasma that contains high levels of antibodies from donors who have been previously vaccinated by an active rabies vaccine and plan
to start collections of such plasma during 2023. In addition, we initiated a project to leverage our FDA plasma collection license to establish a network of
new plasma collection centers in the United States, commencing in 2023, with the intention to collect normal source plasma for sale to other plasma-
derived manufacturers, as well as hyperimmune specialty plasma required for manufacturing of our Proprietary products. In connection with such project,
during March 2023, we entered into a lease for a new plasma collection center in Uvalde, Houston, Texas and expect to commence operations at the new
center following the completion of its construction and obtaining the required regulatory approvals.
Distribution Segment
Our Distribution segment is comprised of marketing and sales in Israel of pharmaceutical products manufactured by third parties. We engage third
party manufacturers, register their products with the IMOH, import the products to Israel, market, sell and distribute them to local HMOs, hospitals and
pharmacists. Sales generated by our Distribution segment during 2022 totaled $26.7 million, as compared to $28.1 million and $32.3 million during 2021
and 2020, respectively, and accounted for approximately 21%, 27% and 24% of our total revenues for the years ended December 31, 2022, 2021 and 2020,
respectively. Our primary products in the Distribution segment include pharmaceuticals for critical care delivered by injection, infusion or inhalation.
Currently, most of the revenues generated in our Distribution segment are from products produced from plasma or plasma-derivatives and are manufactured
by European companies. IVIG is our primary product in the Distribution segment, comprising approximately 59%, 73% and 76% of total revenues in the
Distribution segment for the years ended December 31, 2022, 2021 and 2020, respectively. The decrease in sales of IVIG during 2022 as compared to
previous years was as a result of supply shortages of our European manufacturers.
Over the past several years we continued to extend our Distribution segment products portfolio to non-plasma derived products and in December
2019, we entered into an agreement with Alvotech, a global biopharmaceutical company, to commercialize Alvotech’s portfolio of six biosimilar product
candidates in Israel, upon receipt of regulatory approval from the IMOH. During 2021 we added two additional products to the agreement, bringing the
total number of products in the portfolio to eight. Alvotech’s pipeline includes biosimilar product candidates aimed at treating autoimmunity, oncology and
inflammatory conditions. Subject to approval by the IMOH, we expect to launch the first of these products, in Israel during 2023 and two others during
2024. Following receipt of the EMA marketing approval by Alvotech, and subject to subsequent approval by the IMOH, the remaining seven products
included under the agreement with Alvotech are expected to be launched in Israel through 2028. In addition, in January 2021, we announced our entering
into agreements with two undisclosed international pharmaceutical companies to commercialize three additional biosimilar product candidates in Israel.
Subject to approval by the EMA and subsequently by the IMOH, the three products are expected to be launched in Israel through 2026. The two
pharmaceutical companies will maintain development, manufacturing and supply responsibilities for these three products.
Based on the projected list price reduction due to the continued increase in competition as a result of the launch of additional biosimilar products
and new competitors entering the biosimilar market, and anticipated market penetration potential, we currently estimate the potential aggregate peak
revenues from the sale of all eleven products, achievable within several years of launch, to be approximately $40 million annually.
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The following table sets forth our primary products in the Distribution segment.
Product
Respiratory
Indication
Active Ingredient
BRAMITOB
Management of chronic pulmonary infection due to pseudomonas aeruginosa in patients six
Tobramycin
years and older with cystic fibrosis
FOSTER
Regular treatment of asthma where use of a combination product (inhaled corticosteroid
Beclomethasone dipropionate,
and long-acting beta2-agonist) is appropriate
Formoterol fumarate
TRIMBOW
Maintenance treatment in adult patients with moderate to severe chronic obstructive
Beclomethasone dipropionate,
pulmonary disease (COPD)with Asthma Maintenance treatment of asthma
Formoterol fumarate,
GLYCOPYRRONIUM AS
BROMIDE
PROVOCHOLINE
Diagnosis of bronchial airway hyperactivity in subjects who do not have clinically apparent
Methacholine Chloride
asthma
AEROBIKA
OPEP device
RUPAFIN
Symptomatic treatment of Allergic rhinitis and Urticaria
None
Rupatadine
RUPAFIN ORAL
SOLUTION
Immunoglobulins
Symptomatic treatment of allergic rhinitis in children aged 2 to 11 years and urticaria in
Rupatadine
children aged 2 to 11 years
IVIG
Treatment of various immunodeficiency-related conditions
Gamma globulins (IgG) (human)
VARITECT
Preventive treatment after exposure to the virus that causes chicken pox and zoster herpes
Varicella zoster immunoglobulin
ZUTECTRA
Prevention of hepatitis B virus (HBV) re-infection in HBV-DNA negative patients 6
months after liver transplantation for hepatitis B induced liver failure
(human)
Human hepatitis B
immunoglobulin
HEPATECT CP
Prevent contraction of Hepatitis B by adults and children older than two years
Hepatitis B immunoglobulin
(human)
MEGALOTECT CP
Contains antibodies that neutralize CMV viruses and prevent their spread in
CMV immunoglobulin (human)
immunologically impaired patients
RUCONEST
Treatment of acute angioedema attacks in adults with hereditary angioedema (HAE) due to
Conestat Alfa
C1 esterase inhibitor deficiency
Critical Care
HEPARIN SODIUM
INJECTION
ALBUMIN and
ALBUMIN
Coagulation Factors
Treatment of thrombo-embolic disorders such as deep vein thrombosis, acute arterial
Heparin sodium
embolism or thrombosis, thrombophlebitis, pulmonary embolism, fat embolism.
Prophylaxis of deep vein thrombosis and thromboembolic events
Maintains a proper level in the patient’s blood plasma
Human serum Albumin
Factor VIII
Treatment of Hemophilia Type A diseases
Coagulation Factor VIII (human)
Factor IX
Treatment of Hemophilia Type B disease
Coagulation Factor IX (human)
COAGADEX
Treatment specifically for hereditary factor X deficiency
Coagulation factor X
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Vaccinations
IXIARO
Active immunization against Japanese encephalitis in adults, adolescents, children and
Japanese encephalitis purified
infants aged 2 months and older
inactivated vaccine
VIVOTIF
Immunization against disease caused by Salmonella Typhi
Typhoid vaccine live oral
Metabolic Disease
PROCYSBI
Nephropathic cystinosis in adults and children 1 year of age and older
Cysteamine Biartrate
LAMZEDE
Treatment of alpha-mannosidosis
Velmanase alfa
Oncology
ELIGARD
Management of advanced prostate cancer
Leuprolide acetate
Our Development Product Pipeline
Our research and development activities include conducting pre-clinical and clinical trials and other development activities for our Propriety
pipeline products, improving existing products and processes, conducting development work at the request of regulatory authorities and strategic partners,
as well as communicating with regulatory authorities regarding our commercial products and clinical and development programs. We incurred
approximately $13.2 million, $11.4 million and $13.6 million in research and development expenses in the years ended December 31, 2022, 2021 and
2020, respectively.
We are in various stages of pre-clinical and clinical development of new product candidates for our Proprietary Products segment.
Inhaled Formulations of AAT for AATD
We are in the process of clinical development of an inhaled formulation of AAT administered through the use of a nebulizer. The nebulizer was
developed by PARI. Inhaled AAT for AATD has been designated as an orphan drug for the treatment of AATD in the United States and Europe.
We have been able to leverage our expertise gained from the production of GLASSIA to develop a stable, high-purity Inhaled AAT product
candidate for the treatment of AATD. Existing treatment for AATD require weekly intravenous infusions of AAT therapeutics. We believe that Inhaled
AAT for AATD, if approved, will increase patient convenience and reduce or replace the need for patients to use intravenous infusions of AAT products,
decreasing the need for clinic visits or nurse home visits, improving the patient’s quality of life and reducing medical costs. If approved, Inhaled AAT for
AATD is estimated to be the first AAT product that is not required to be delivered intravenously and instead is administered non-invasively by inhalation
once daily.
The current standard care for AATD in the United States and in certain European countries, as well as in some additional international markets, is
a weekly intravenous infusion of an AAT therapeutic. We estimate that only 2% of the AAT dose reaches the lung when administered intravenously. We
have conducted a U.S. Phase 2 clinical study demonstrating that administration of an inhaled formulation of AAT through inhalation results in greater
dispersion of AAT to the target lung tissue, including the lower lobes and lung periphery. Accordingly, the inhaled formulation of AAT requires a
significantly lower therapeutic dose, and we believe it would be more effective in reducing inflammation of the lung tissue and inhibiting the uncontrolled
neutrophil elastase that causes the breakdown of the lung tissue and the emphysema.
Because of the smaller amount of AAT dose used in Inhaled AAT for AATD (since it is applied directly to the site of action rather than
administered systematically), we believe that this product, if approved, will enable us to treat significantly more patients from the same amount of plasma
and production capacity and may be more cost effective for patients and payors and may increase our profitability.
We conducted a double-blind randomized placebo-controlled Phase 2/3 pivotal trial, under EMA guidance, which was completed at the end of
2013. A total of 168 patients participated in the trial in seven countries in Europe and Canada. Subjects in this trial were administered with a twice daily
treatment of Inhaled AAT or equivalent dose of placebo for 50 consecutive weeks. The primary endpoint of the trial was the time from randomization to the
first event-based exacerbation with a severity of moderate or severe. Other endpoints, which were secondary and tertiary, included additional exacerbation
measures, lung function, lung density measured by CT scan and quality of life. The trial was 80% powered based on the number of exacerbation events
collected in the study, in order to detect a difference between the two groups after 50 weeks. A 20% difference between the two groups was required to
prove efficacy and was considered clinically meaningful, allowing the decision to prescribe the treatment. An open label extension of an additional 50
weeks on active drug was offered to study participants in most sites once they completed the initial 50-week period. Treatment in the open label extension
of the trial was completed in November 2014.
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This study did not meet its primary and secondary endpoints. However, lung function parameters, including Forced Expiratory Volume in One
Second (“FEV1”) % of Slow Vital Capacity (“SVC”) and FEV1 % predicted, FEV1 (liters) which was collected to support safety endpoints, showed
concordance of a potential treatment effect in the reduction of the inflammatory injury to the lung that is known to be associated with a reduced loss of
respiratory function.
In accordance with guidance received following the meetings conducted with the European rapporteur and co-rapporteur, we performed several
post hoc analyses. Results of the post hoc analyses indicated that after one year of daily inhalation of our Inhaled AAT, clinically and statistically
significant improvements were seen in spirometric measures of lung function, particularly in bronchial airflow measurements FEV1 (L), FEV1% predicted
and FEV1/SVC. These favorable results were even more evident when analyzing the overall treatment effect throughout the full year.
For lung function, overall effect for one year:
● FEV1 (L) rose significantly in AAT treated patients and decreased in placebo treated patients (+15ml for AAT vs. -27ml for placebo, a 42 ml
difference, p=0.0268)
● There was a trend towards better FEV1% predicted (0.54% for AAT vs. -0.62% for placebo, a 1.16% difference, p=0.065)
● FEV1/SVC% rose significantly in AAT treated patients and decreased in placebo treated patients (0.62% for AAT vs. -0.87% for placebo, a
1.49% difference, p=0.0074)
For lung function change at week 50 vs. baseline:
● There was a trend towards reduced FEV1 (L)decline (-12ml for AAT vs. -62ml for placebo, a 50 ml difference, p=0.0956)
● There was a trend towards a reduced decline in FEV1% predicted (-0.1323% for AAT vs. -1.6205% for placebo, a 1.4882% difference,
p=0.1032)
● FEV1/SVC% rose significantly in AAT treated patients and decreased in placebo treated patients (0.61% for AAT vs. -1.07% for placebo, a
1.68% difference, p=0.013)
During March 2014, we initiated a Phase 2 trial in the United States. The trial was completed in May 2016. This trial was intended to serve as a
supplementary trial to the European Phase 2/3 trial and was designed to incorporate parameters required by the FDA. This Phase 2, double-blind, placebo-
controlled study explored the Endothelial Lining Fluid (“ELF”) and plasma concentration as well as safety of Inhaled AAT in AATD subjects. The subjects
received one of two doses of Inhaled AAT or placebo. The study involved the daily inhalation of 80 mg or 160 mg of human AAT or placebo via the eFlow
device for 12 weeks. Following the 12-week double blind period, the subjects were offered to participate in an additional 12 weeks open label period during
which they receive only Inhaled AAT therapy. In December 2015, we completed the enrollment of patients in the study and in August 2016 we reported
positive top-line results, according to which we met the primary endpoint.
AATD patients treated with our Inhaled AAT product in such U.S. Phase 2 clinical trial, demonstrated a significant increase in ELF AAT antigenic
level compared to the placebo group (median increase 4551 nM, p-value<0.0005 (80 mg/day, n=12), and 13454 nM, p-value<0.002 (160mg/day, n=12)).
These results are more than twice the increase of ELF antigenic AAT level (+2600 nM) observed in our previously completed intravenous AAT pivotal
study (60mg/kg/week). Antigenic AAT represents the total amount of AAT in the lung, both active and inactive. The study results also showed that our
Inhaled AAT is more efficient than IV to restore ELF AAT level within the lung. In addition, ELF Anti-Neutrophil Elastase inhibitory (“ANEC”) level also
increased significantly [median increase 2766 nM, p-value<0.0005 (80mg/day) and 3557 nM, p-value<0.004 (160 mg/day)]. The increase in ELF ANEC
level was also more than twice that demonstrated in our previously completed IV AAT pivotal study. The ANEC level represents the active AAT that can
counterbalance further damage by neutrophil elastase.
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The updated data included in our poster presentation of May 2017 demonstrated that ELF-AAT, neutrophil elastase (NE)-AAT and ANEC
complexes concentration significantly increased in subjects receiving the 80 mg and 160 mg doses, (median increase of 38.7 neutrophil migration (nM), p-
value<0.0005 (80 mg/day, n=12), and median increase of 46.2 nM, p-value<0.002 (160 mg/day, n=10)). This is a specific measure of the anti-proteolytic
effect in the ELF and represents the amount of NE that was broken down by AAT. The increase in levels of functional AAT was six times higher (160 mg
per day) than is achievable with intravenous (IV) AAT. In addition, ELF NE decreased significantly. Also, the 80 mg data demonstrated a significant
reduction in the percentage of neutrophils. Finally, aerosolized M-specific AAT was detected in the plasma of all subjects receiving Inhaled AAT, consistent
with what was seen in the Phase 2/3 clinical trial of our Inhaled AAT conducted in the EU.
We filed the MAA for our Inhaled AAT for AATD during the first quarter of 2016 and in June 2017 we withdrew the MAA, as following
extensive discussions with the EMA we concluded that the EMA did not view the data submitted as sufficient, in terms of safety and efficacy, for approval
of the MAA, and that the supplementary data needed for approval required an additional clinical trial. While the post-hoc data indicated a statistically
significant and clinically meaningful improvement in lung function, the EMA was of the opinion that an overall positive conclusion on the effect of Inhaled
AAT for AATD could not be reached based on that post-hoc analysis, and that the treatment of AATD patients with our Inhaled AAT product should be
further evaluated in the clinic in order to obtain comprehensive long-term efficacy and safety data. The EMA was of the opinion that the study failed to
show sufficient beneficial effects in the population studied. In addition, there were concerns about the tolerability and safety profile of the AAT, mainly in
patients with severe lung disease. Lastly, the EMA raised concerns about the high rate of patients with antibodies (ADA) responding to AAT, which might
reduce its effects or make patients more prone to allergic reactions, despite evidence that none of the patients with such ADA response had allergic reaction
nor a lower level of AAT in the serum.
When presented with the European Phase 2/3 study data, the FDA expressed concerns and questions in connection with the safety and efficacy of
Inhaled AAT for the treatment of AATD and the risk/benefit balance to patients based on that data and product characteristics. Following several
discussions with the FDA and EMA, through which additional data and information were provided and we addressed both agencies’ guidance with respect
to our proposed subsequent Phase 3 pivotal study protocol, we received positive scientific advice from the Committee of Medicinal Products for Human
Use (“CHMP”) of the EMA related to the development plan for our proposed pivotal Phase 3 pivotal study for Inhaled AAT for AATD, and in April 2019,
we received a letter from the FDA stating that we had satisfactorily addressed the concerns and questions with respect to the proposed Phase 3 clinical trial.
During December 2019, we initiated our Phase 3 InnovAATe trial and announced the first-patient-in. InnovAATe is a randomized, double-blind,
placebo-controlled, pivotal Phase 3 trial designed to assess the efficacy and safety of Inhaled AAT in patients with AATD and moderate lung disease. Up to
220 patients will be randomized 1:1 to receive either Inhaled AAT at a dose of 80mg once daily, or placebo, over two years of treatment. The primary
endpoint of the InnovAATe trial is lung function measured by FEV1. Secondary endpoints include lung density changes as measured by CT densitometry,
as well as other parameters of disease severity, such as additional pulmonary functions, exacerbation rate and six-minute walk test. The safety profile will
be monitored continuously by a Data Monitoring Committee with predefined rules to be applied after the first 60 subjects have completed six months of
treatment. The study is led by Jan Stolk, M.D., Department of Pulmonology, Member of European Reference Network LUNG, Leiden University Medical
Center, the Netherlands.
During 2021 and 2022, enrolment in the pivotal Phase 3 InnovAATe clinical trial was negatively affected by the impact of COVID-19 pandemic
on healthcare systems. In 2022, following the moderation of the pandemic, the study was expanded to additional sites across Europe and enrollment
accelerated. By the end of February 2023, 50 patients were enrolled in the study, of whom 17 have completed the two-year study treatment period at the
initial trial site in Leiden, the Netherlands. Only one patient discontinued treatment prematurely due to airway irritation that started during the run-in period
(before introducing the drug/placebo), and no drug-related serious adverse events were reported. Additionally, as part of routine and planned monitoring
processes, and for the fourth time since study initiation, the independent DSMB recently recommended that the trial continue without modification.
Moreover, based on the encouraging safety observed to date, the DSMB supported an expansion to the inclusion criteria to also include subjects with severe
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