UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 10-K
(Mark One)
☒
ANNUAL REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
For the fiscal year ended December 31, 2019
OR
☐
TRANSITION REPORT PURSUANT TO SECTION 13 OR 15(d) OF THE SECURITIES EXCHANGE ACT OF 1934
FOR THE TRANSITION PERIOD FROM TO
Commission File Number 001-38244
Genprex, Inc.
(Exact Name of Registrant as Specified in Its Charter)
Delaware
(State or other jurisdiction of incorporation or organization)
90-0772347
(I.R.S. Employer Identification Number)
1601 Trinity Street, Bldg B, Suite 3.322
Austin, Texas
(Address of principal executive offices)
78712
(Zip Code)
Registrant’s telephone number, including area code: (512) 370-4081
Securities registered pursuant to Section 12(b) of the Act:
Title of each class
Common Stock, par value $0.001 per share
Trading
Symbol(s)
GNPX
Name of each exchange on which registered
The Nasdaq Capital Market
Securities registered pursuant to 12(g) of the Act: None
Indicate by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. YES ☐ NO ☒
Indicate by check mark if the registrant is not required to file reports pursuant to Section 13 or 15(d) of the Act. YES ☐ NO ☒
Indicate by check mark whether the registrant (1) has filed all reports required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the
preceding 12 months (or for such shorter period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past
90 days. YES ☒ NO ☐
Indicate by check mark whether the registrant has submitted electronically, every Interactive Data File required to be submitted pursuant to Rule 405 of
Regulation S-T (§232.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant was required to submit such files). YES ☒ NO ☐
Indicate by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, a smaller reporting company or an emerging
growth company. See the definitions of “large accelerated filer,” “accelerated filer,” “smaller reporting company” and “emerging growth company” in Rule 12b-2 of the
Exchange Act.
Large accelerated filer:
Non-accelerated filer:
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☒
Accelerated filer
Smaller reporting company
Emerging growth company
☐
☒
☒
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with
any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☒
Indicate by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). YES ☐ NO ☒
The aggregate market value of the voting and non-voting common equity held by non-affiliates of the registrant as of June 28, 2019 was
approximately $30.4 million, computed by reference to the closing price of the registrant’s common stock on June 28, 2019 (the last business day of the
registrant's most recently completed second fiscal quarter) of $1.24 per share, as reported by The Nasdaq Capital Market.
As of March 27, 2020, there were 32,849,841 shares of the registrant’s common stock outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
Portions of the registrant’s definitive proxy statement to be filed with the Securities and Exchange Commission, or SEC, subsequent to the date hereof
pursuant to Regulation 14A in connection with the registrant’s 2020 annual meeting of stockholders, are incorporated by reference into Part III of this
Annual Report on Form 10-K. Such proxy statement will be filed with the SEC not later than 120 days after the conclusion of the registrant’s fiscal year
ended December 31, 2019.
TABLE OF CONTENTS
PART I
Item 1.
Item 1A.
Item 1B.
Item 2.
Item 3.
Item 4.
Business
Risk Factors
Unresolved Staff Comments
Properties
Legal Proceedings
Mine Safety Disclosures
Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities
Selected Financial Data
Management’s Discussion and Analysis of Financial Condition and Results of Operations
PART II
Item 5.
Item 6.
Item 7.
Item 7A. Quantitative and Qualitative Disclosures About Market Risk
Financial Statements and Supplementary Data
Item 8.
Changes in and Disagreements With Accountants on Accounting and Financial Disclosure
Item 9.
Controls and Procedures
Item 9A.
Other Information
Item 9B.
PART III
Item 10.
Item 11.
Item 12.
Item 13.
Item 14.
Directors, Executive Officers and Corporate Governance
Executive Compensation
Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters
Certain Relationships and Related Transactions, and Director Independence
Principal Accounting Fees and Services
PART IV
Item 15.
Item 16.
Exhibits, Financial Statement Schedules
Form 10-K Summary
SIGNATURES
CONSOLIDATED FINANCIAL STATEMENTS
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F-1
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K (this “Annual Report”) contains forward-looking statements that involve substantial risks and uncertainties.
Any statements in this Annual Report about our expectations, beliefs, plans, objectives, assumptions or future events or performance are not historical facts
and are forward-looking statements. These statements are often, but not always, made through the use of words or phrases such as “believe,” “will,”
“expect,” “anticipate,” “estimate,” “intend,” “plan” and “would.” For example, statements concerning financial condition, possible or assumed future
results of operations, growth opportunities, industry ranking, plans and objectives of management, markets for our common stock and future management
and organizational structure are all forward-looking statements. Forward-looking statements are not guarantees of performance. They involve known and
unknown risks, uncertainties and assumptions that may cause actual results, levels of activity, performance or achievements to differ materially from any
results, levels of activity, performance or achievements expressed or implied by any forward-looking statement. We do not assume any obligation to update
forward-looking statements as circumstances change and thus you should not unduly rely on these statements.
Any forward-looking statements are qualified in their entirety by reference to the risk factors discussed throughout this Annual Report. Some of
the risks, uncertainties and assumptions that could cause actual results to differ materially from estimates or projections contained in the forward-looking
statements include but are not limited to:
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Market conditions;
Our capital position;
Our ability to compete with larger better financed pharmaceutical companies;
Our uncertainty of developing marketable products;
Our ability to develop and commercialize our products;
Our ability to obtain regulatory approvals;
Our ability and third parties’ ability to maintain and protect intellectual property rights;
The inability to raise additional future financing and lack of financial and other resources;
The success of our clinical trials through all phases of clinical development;
Any delays in regulatory review and approval of product candidates in clinical development;
Our dependence on third-party manufacturers to supply or manufacture our products;
Our ability to control product development costs;
We may not be able to attract and retain key employees;
We may not be able to compete effectively;
We may not be able enter into new strategic collaborations, licensing or other arrangements;
Changes in government regulation affecting product candidates could increase our development costs;
Our involvement in patent and other intellectual property litigation could be expensive and could divert management’s attention;
The possibility that there will be no market acceptance for our products; and
Changes in third-party reimbursement policies could adversely affect potential future sales of any of our products that are approved for
marketing.
The foregoing list sets forth some, but not all, of the factors that could affect our ability to achieve results described in any forward-looking
statements, which speak only as of the date of this Annual Report. We assume no obligation and expressly disclaim any duty to update any forward-looking
statement to reflect events or circumstances after the date of this Annual Report or to reflect the occurrence of unanticipated events. In addition, we cannot
assess the impact of each factor on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially
from those contained in any forward-looking statements contained in this Annual Report. All written and oral forward-looking statements attributable to us
or any person acting on our behalf are expressly qualified in their entirety by the cautionary statements contained or referred to in this section.
1
Item 1. Business.
Overview
PART I
Genprex™ is a clinical stage gene therapy company developing potentially life-changing treatments for cancer and diabetes. Our cancer therapies
are based upon our novel proprietary technology platform, including our lead drug candidate, Oncoprex™ immunogene therapy, or Oncoprex, for non-
small cell lung cancer (NSCLC). Oncoprex consists of a tumor suppressor gene inserted into a patient’s cells that has immunomodulatory effects and is
thereby considered an “immunogene therapy.” The gene is one of a series of genes whose therapeutic use is covered by an exclusive worldwide license
from The University of Texas MD Anderson Cancer Center. We also are developing a pre-clinical gene therapy that is covered by an exclusive license from
the Rangos Research Center at UPMC Children’s Hospital of Pittsburgh that has the potential to cure type 1 and type 2 diabetes. This potential treatment
works by reprogramming beta cells in the pancreas to restore their function, allowing them to replenish insulin levels.
Oncology Platform Technologies
Our oncology platform technologies are designed to administer cancer fighting genes by encapsulating them into nanoscale hollow spheres called
nanovesicles, which are then administered intravenously and taken up by tumor cells where they express proteins that are missing or found in low
quantities. Oncoprex has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer
cells, re-establishes pathways for apoptosis, or programmed cell death, in cancer cells, and modulates the immune response against cancer cells. Oncoprex
has also been shown to block mechanisms that create drug resistance.
With Oncoprex, we are initially targeting NSCLC. According to the World Health Organization, lung cancer is the leading cause of cancer deaths
worldwide, causing more deaths than breast, colon, kidney, liver, prostate or skin cancers, and lung cancer is one of the most common types of cancer. Each
year, there are more than 2 million new lung cancer cases and 1.7 million deaths from lung cancer worldwide. According to the American Cancer Society’s
2020 report, each year in the United States there are more than 228,000 new cases of lung cancer and more than 135,000 deaths from lung cancer. NSCLC
represents 84 percent of all lung cancers and has a 23 percent five-year relative survival rate. However, according to the National Cancer Institute, 57
percent of lung cancer diagnoses are distant, or have metastasized, and the five-year relative survival rate for distant diagnoses is 5 percent. We believe that
there is a significant unmet medical need for new treatments for NSCLC in the United States and globally, and we believe that Oncoprex may be suitable
for a majority of NSCLC patients.
In January, 2020, we received a United States FDA Fast Track Designation for use of Oncoprex™ in combination with EGFR inhibitor
osimertinib (AstraZeneca’s Tagrisso®) for the treatment of NSCLC patients with EFGR mutations whose tumors progressed after treatment with
osimertinib alone. According to the FLAURA study sponsored by AstraZeneca, the median length of time that patients are treated with osimertinib before
their tumors progress is approximately 18 months.
The FDA may award Fast Track Designation if it determines that a product either alone or in combination with one or more products demonstrates
the potential to address unmet medical needs for a serious or life-threatening disease or condition. The Fast Track Designation is intended to facilitate the
development of and to expedite the review of products that may treat serious and life-threatening conditions so that such product can reach the market
expeditiously.
Fast Track drug candidates must show advantages over available therapies, such as superior effectiveness, avoiding serious side effects, improving
diagnosis and outcome, decreasing significant toxicity, and the ability to address public health needs. Fast Track Designation recipients may also be eligible
for accelerated approval or rolling review of the recipient’s Biologics License Application (BLA). In addition, Fast Track product candidates could be
eligible for priority review if supported by clinical data at the time of BLA submission.
In 2019, preclinical data was presented by MD Anderson collaborators for the combination of TUSC2, the active agent in Oncoprex, with
pembrolizumab (Merck’s Keytruda®), demonstrating that TUSC2 combined with the checkpoint blockade mechanism of action of pembrolizumab was
more effective than pembrolizumab alone in increasing the survival of mice with human immune cells (humanized mice) that had metastatic lung cancer.
Also presented in 2019 by MD Anderson was pre-clinical data for the combination of TUSC2, pembrolizumab and chemotherapy for the treatment of some
of the most resistant metastatic lung cancers. This study found that the addition of TUSC2, increases the effectiveness of pembrolizumab and
chemotherapy, and thus, may improve on first-line standard of care for lung cancer. Further, 2019 saw the publication in Nature by independent researchers
that the TUSC2 gene may prevent tumor growth in triple-negative breast cancer (TNBC), a cancer with very limited therapeutic options.
2
We believe that our platform technologies could allow delivery of a number of cancer fighting genes, alone or in combination with other cancer
therapies, to combat multiple types of cancer. Our research and development pipeline, discussed in “Our Pipeline” below, demonstrates our clinical and
preclinical progress to date. We believe that Oncoprex’s combination of pan-kinase inhibition, direct induction of apoptosis, anti-cancer immune
modulation and complementary action with targeted drugs and immunotherapies is unique, and positions Oncoprex to provide treatment for patients with
NSCLC and possibly other cancers, who are not benefitting from currently offered therapies.
Cancer results from genetic mutations. Mutations that lead to cancer are usually present in two major classes of genes: oncogenes, which are
involved in functions such as signal transduction and transcription; and tumor suppressor genes, which play a role in governing cell proliferation by
regulating transcription. Transduction is the process by which chemical and physical signals are transmitted through cells. Transcription is the process by
which a cell’s DNA sequence is copied to make RNA molecules, which then play a role in protein expression. In normal cells, mutations in oncogenes are
discovered and targeted for elimination by tumor suppressor genes. In cancer cells, the oncogene mutations may overwhelm the natural tumor suppression
processes, or those tumor suppression processes may be impaired or absent. Functional alterations due to mutations in oncogenes or tumor suppressor
genes may result in the abnormal and uncontrolled growth patterns characteristic of cancer. These genetic alterations facilitate such malignant growth by
affecting signal transduction pathways and transcription, thus inhibiting normal growth signaling in the cell, circumventing the natural process of apoptosis,
evading the immune system’s response to cancer, and inducing angiogenesis, which is the formation of new blood vessels that supply cancer cells.
The most common genetic alterations present in NSCLC are in tumor suppressor genes, against which few targeted small molecule drugs have
been developed. Each of the two sets of chromosomes in the cell nucleus includes two copies of each gene, called alleles, which may be identical or may
show differences. In most situations, tumor suppressor genes require both alleles of a gene to be deleted or inactivated to impair tumor suppression activity
and lead to tumor growth. The replacement of just one functional allele may therefore be enough to restore the normal cellular functions of growth
regulation and apoptosis.
Among the genetic conditions associated with lung cancer are the overexpression of epidermal growth factor receptors, or EGFRs, and mutations
of kinases. Kinases are enzymes that play an important role in signal transduction through the modification of proteins by adding or taking away phosphate
groups, a process called (de-)phosphorylation, to change the proteins’ function. When two EGFR transmembrane proteins are brought to proximity on the
cell membrane surface, or dimerize, either through a ligand, or binding molecule, that binds to the extracellular receptor, or through some other process, the
intracellular protein-kinase domains can autophosphorylate, and activate downstream processes, including cell signaling pathways that can lead to either
cell cycle arrest or cell growth and proliferation. EGFRs and kinases can act similarly to a switch that turns “on” and “off” when phosphate groups are
either added or taken away. Mutated kinases can have a malfunctioning on/off switch, causing the switch to be stuck in the “on” position or failing to turn
the switch “off,” leading to the loss of cell control.
A subset of NSCLC patients (approximately 7% of NSCLC patients of North American and European descent and approximately 30% to 50% of
NSCLC patients of Asian descent) carry an EGFR mutation that makes their tumors sensitive to tyrosine kinase inhibitors (TKIs). However, even for these
patients, tumor resistance to TKIs frequently develops within two to three years, resulting in eventual disease progression. EGFR TKIs generally do not
benefit NSCLC patients who do not have this activating EGFR mutation. However, our clinical and preclinical data have shown that the combination of
Oncoprex and erlotinib can increase anti-tumor activity even in cancers without the EGFR mutations, as well as in cancers that have become resistant to
erlotinib. For this reason, we believe Oncoprex may be suitable for the majority of NSCLC patients.
Cancer can spread when cells’ natural cancer suppression functions are impaired. The tumor suppressor gene called Tumor Suppressor Candidate
2, or TUSC2 (which was formerly known as FUS1) has been shown to affect both cell proliferation and apoptosis. TUSC2 is a pan-kinase inhibitor, which
means that it has the ability to inhibit multiple kinase receptors, such as EGFR and platelet-derived growth factor receptor, or PDGFR. TUSC2 is frequently
inactivated early in the development of lung cancer, and loss of TUSC2 expression in NSCLC is associated with significantly worse overall survival
compared to patients with normal TUSC2 expression. Many types of cancer cells, including approximately 80% of NSCLC cells, lack expression of
TUSC2.
Cancer can also spread when the body’s natural immune functions are impaired, including by the cancer cells themselves. PD-1, or Programmed
Death-1, is a receptor expressed on the surface of activated T cells, which are part of the body’s immune system. PD-L1, or Programmed Death Ligand-1,
is a protein/receptor expressed on the surface of cancer and other cells. The binding of PD-1 to PD-L1 has been speculated to contribute to cancer cells’
ability to evade the body’s immune response. PD-1 and molecules like it are called immune checkpoints, because they can impede the normal immune
response, for example by blocking the T cells from attacking the cancer cells. In many cancers, PD-L1 receptors are up-regulated, and substantial research
is now being performed in the emerging field of immuno-oncology to discover drugs or antibodies that could block PD-L1 and similar receptors. It is
believed that blocking the PD-1/PD-L1 interaction pathway and other similar checkpoints, such as cytotoxic T-lymphocyte-associated protein 4, or CTLA-
4, with drugs called checkpoint inhibitors can prevent cancer cells from inactivating T cells.
3
Our Oncoprex immunogene therapy is designed to interrupt cell signaling pathways that cause replication and proliferation of cancer cells, and to
target and kill cancer cells via receptor pathways, and also to stimulate the natural immune responses against cancer. Oncoprex combines features of gene
therapy and immunotherapy in that it up-regulates TUSC2 expression in the cell, and also increases the anti-tumor immune cell population and down-
regulates PD-L1 receptors, thereby potentially boosting the immune response to cancer.
Oncoprex consists of a TUSC2 gene encapsulated in a nanovesicle made from lipid molecules with a positive electrical charge. Oncoprex is
injected intravenously and can specifically target cancer cells, which generally have a negative electrical charge. Once Oncoprex is taken up into a cancer
cell, the TUSC2 gene is expressed into a protein that is capable of restoring certain defective functions arising in the cancer cell. Oncoprex nanovesicles are
designed to deliver the functioning TUSC2 gene to cancer cells while minimizing their uptake by normal tissue. Tumor biopsy studies conducted at MD
Anderson show that, in three patients, the uptake of TUSC2 in tumor cells after Oncoprex treatment was 10 to 25 times the uptake in normal cells. We
believe that Oncoprex, unlike other gene therapies, which either need to be delivered directly into tumors or require cells to be removed from the body, re-
engineered and then reinserted into the body, is the first systemic gene therapy to be used for cancer in humans.
Clinical data from the evaluation of 25 patients in our Phase I/II clinical trial, as well as our preclinical data, indicate that Oncoprex can be
combined with the widely used anti-cancer drug erlotinib (marketed as Tarceva® by Genentech, Inc.) in humans. Erlotinib is a tyrosine kinase inhibitor, or
TKI, which uses a mechanism of action similar to that of pan-kinase inhibitors to block the action of tyrosine kinases. Tyrosine kinases are a type of kinase
involved in many cell functions, including cell signaling, growth and division. In addition, MD Anderson researchers have conducted preclinical studies
combining Oncoprex with:
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the TKI gefitinib (marketed as Iressa® by AstraZeneca Pharmaceuticals) in animals and in human NSCLC cells;
third generation TKIs such as osimertinib (marketed as Tagrisso® by AstraZeneca Pharmaceuticals);
MK2206 in animals (MK2206 is an inhibitor of AKT kinases, which affect cell signaling pathways downstream from tyrosine kinases);
an anti-PD-1 antibody equivalent to the checkpoint inhibitor pembrolizumab (marketed as Keytruda® by Merck & Co.) in animals;
an anti-PD-1 antibody equivalent to the checkpoint inhibitor nivolumab (marketed as Opdivo® by Bristol-Myers Squibb Company) in
animals; and
an anti-CTLA4 antibody equivalent to ipilimumab (marketed as Yervoy® by Bristol-Myers Squibb Company) in animals.
The manufacturers of the marketed drugs were not involved in any of our clinical or preclinical studies. In studies involving marketed drugs, the
drugs were administered concurrently with Oncoprex without being modified in any way, and the antibodies used in our preclinical studies that did not use
the marketed drugs were the non-humanized equivalent to marketed drugs.
Data from these clinical and preclinical studies indicate that combining Oncoprex with these other therapies yields results more favorable than
either these therapies or Oncoprex alone, with minimal side effects relative to other lung cancer drugs, thereby potentially making Oncoprex a therapy
complementary to these cancer treatments. In addition, based on our clinical and preclinical studies and on preclinical studies conducted by others, we
believe that Oncoprex could be combined with other lung cancer drugs that have similar mechanisms of action to the drugs mentioned above, such as
nivolumab (marketed as Opdivo® by Bristol-Myers Squibb Company) and atezolizumab (marketed as Tecentriq® by Genentech/Roche). We have not
conducted preclinical or clinical studies combining Oncoprex with atezolizumab.
Researchers at MD Anderson have collaborated with other researchers to identify other genes, such as those in the 3p21.3 chromosomal region,
that may act as tumor suppressors or have other cancer fighting functions. We hold rights to certain of these genes under license agreements with MD
Anderson. Data from preclinical studies performed by MD Anderson researchers and others suggest that product candidates that could be derived from our
technology platform could be effective against other types of cancer, including glioblastoma, head and neck, breast (including triple-negative breast
cancer), renal cell (kidney), thyroid, and soft tissue sarcoma, as well as NSCLC. Therefore, our platform technologies may allow delivery of a number of
cancer fighting genes, alone or in combination with other cancer therapies, to combat multiple types of cancer.
In 2012, MD Anderson researchers completed a Phase I clinical trial of Oncoprex as a monotherapy. The primary objective of this Phase I trial
was to assess the toxicity of Oncoprex administered intravenously and to determine the maximum tolerated dose (MTD) and recommended Phase II dose
of Oncoprex alone. Secondary objectives were to assess the expression of TUSC2 following intravenous delivery of Oncoprex in tumor biopsies and also to
assess the anticancer activity of Oncoprex. This trial demonstrated that Oncoprex was well tolerated and established the MTD and the therapeutic dosage
for Oncoprex at 0.06 mg/kg administered every 21 days. Although this trial was not designed to show changes in outcomes, a halt in cancer growth was
observed in a number of patients, and tumor regressions occurred in primary lung tumors and metastatic cancers in the liver, pancreas, and lymph nodes. In
addition, pre- and post-treatment patient biopsies demonstrated that intravenous Oncoprex selectively and preferentially targeted patients’ cancer cells, and
suggested that clinical anti-cancer activity was mediated by TUSC2.
4
MD Anderson researchers have completed the first phase of a Phase I/II clinical trial of Oncoprex in combination with erlotinib in patients with
Stage IV (metastatic) or recurrent NSCLC that is not potentially curable by radiotherapy or surgery, whether or not they have received prior chemotherapy,
and whether or not they have an activating EGFR mutation. The Phase I portion of the trial was a dose-escalating study with primary endpoints of
establishing the safety and tolerability of the combination of Oncoprex and erlotinib, and establishing the MTD. The secondary endpoint of the Phase I
portion of the trial was to assess the toxicity of the combination of Oncoprex with erlotinib. In the Phase I portion of the trial, which began in 2014, 18
subjects were treated, and the MTD was determined to be the highest tested dose: 0.06 mg/kg of Oncoprex administered every 21 days and 150 mg of
erlotinib per day. Toxicities were found to compare favorably with those of other lung cancer drugs.
The Phase II portion of the trial was designed to include subjects treated with the combination of Oncoprex and erlotinib at the MTD with the
primary goal of measuring the response rate, and secondary endpoints of stable disease, time to progression and overall survival. The response rate for
cancer therapies is defined under the Response Evaluation Criteria in Solid Tumors, or RECIST, as Complete Response (CR) + Partial Response (PR);
disease control rate is defined under the RECIST criteria as Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)>8weeks.
Enrollment criteria for the second phase of the Phase I/II clinical trial were identical to those in the first phase. The Phase II portion of the trial
began in June 2015. Of the 39 patients allowed in the protocol for the Phase II portion of this trial, ten were enrolled and nine were evaluable for response
under the trial protocol, because they received two or more cycles of treatment. Interim results show that four of the patients had tumor regression and one
patient had a Complete Response (CR) under the RECIST criteria. The patient with the CR had disappearance of the lung primary tumor, as well as lung,
liver, and lymph node metastases. The median response duration for all patients, which is defined as the median time between when response is first noted
to the time when cancer progression is observed, was three months. The response rate for the nine patients evaluated was 11% and the disease control rate
for the nine patients was 78%.
The response rate and disease control rate in the Phase II portion of our Phase I/II clinical trial substantially exceeds the response rate of 7% (with
no CRs) and disease control rate of 58% reported for a clinical trial of the TKI afatinib (marketed as Gilotrif® by Boehringer Ingelheim Pharmaceuticals,
Inc.) in a study referred to as the LUX-Lung 1 clinical trial. A total of 585 patients were enrolled in that Phase IIB/III clinical trial, whose primary endpoint
was overall survival and whose secondary endpoints were progression-free survival, RECIST response, quality of life and safety. The LUX-Lung 1 clinical
trial was a randomized, double blinded Phase IIB/III clinical trial treating subjects with Stage IIIB or IV adenocarcinoma, a type of NSCLC. The Phase II
portion of our Phase I/II trial was not blinded, and was designed to treat NSCLC subjects regardless of EGFR status.
Preliminary analysis of the interim data from the Phase II portion of our Phase I/II trial supported our belief that Oncoprex may provide medical
benefit in several subpopulations of NSCLC patients for which there is an unmet medical need, and may provide pathways for accelerated approval by the
FDA. Data from our clinical trials, along with our preclinical data, provided the basis for our application for a Fast Track Designation, which was granted
by FDA on January 14, 2020. In granting our Fast Track Designation, the FDA found that Oncoprex may provide a benefit over existing therapies for
patients whose tumors progress on osimertinib. The FDA Fast Track Designation is for use of the combination of Oncoprex with osimertinib in patients
whose tumors progressed on osimertinb. Our original Phase I/II trial was designed to treat patients with Oncoprex combined with erlotinib rather than with
osimertinib. We believe that the Fast Track Designation provides a defined pathway toward FDA approval of the combination of Oncoprex with
osimertinib, thus we decided to allocate our resources toward a new Phase I/II clinical trial of Oncoprex combined with osimertinib, and we will not enroll
additional patients in our Phase I/II clinical trial of Oncoprex combined with erlotinib at this time. Instead we plan to open a new Phase I/II clinical trial of
Oncoprex combined with osimertinib.
Our Oncoprex immunogene therapy technology was discovered through a lung cancer research consortium from MD Anderson and The
University of Texas Southwestern Medical Center (UTSWMC) along with the NCI. The TUSC2 discovery teams included Jack A. Roth, MD, FACS,
chairman of our Scientific and Medical Advisory Board. We have assembled a team of experts in clinical and translational research, including laboratory
scientists, medical oncologists and biostatisticians, to pursue the development and commercialization of Oncoprex and other potential product candidates.
Our technology discoveries and research and development programs have been the subjects of numerous peer-reviewed publications and have
been supported by Small Business Innovation Research (SBIR) grants and grants from the National Institutes of Health, the United States Department of
Treasury, and the State of Texas. We hold a worldwide, exclusive license from MD Anderson to patents covering the therapeutic use of TUSC2 and other
genes that have been shown to have cancer fighting properties, as well as a number of related technologies, including 33 issued patents. The rights we have
obtained pursuant to our license agreement with MD Anderson are made subject to the rights of the U.S. government to the extent that the technology
covered by the licensed intellectual property was developed under a funding agreement between MD Anderson and the U.S. government.
5
Diabetes Gene Therapy
Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which leads over time to serious
damage to the heart, blood vessels, eyes, kidneys and nerves. The most common is type 2 diabetes, usually in adults, which occurs when the body becomes
resistant to insulin or doesn't make enough insulin. In the past three decades the prevalence of type 2 diabetes has risen dramatically. Type 1 diabetes, once
known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin by itself. According to
the World Health Organization, about 422 million people worldwide have diabetes and 1.6 million deaths are directly attributed to diabetes each year. Both
the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades.
Our diabetes gene therapy was developed by lead researcher Dr. George Gittes, at the Rangos Research Center at UPMC Children’s Hospital of
Pittsburgh. It works by reprogramming beta cells in the pancreas to restore their function, thereby replenishing levels of insulin. The infusion process uses
an endoscope and an adeno-associated virus (AAV) vector to deliver Pdx1 and MafA genes to the pancreas. The proteins these genes express have been
shown to transform alpha cells in the pancreas into functional beta-like cells, which can produce insulin but are distinct enough from beta cells to evade the
body’s immune system.
The diabetes gene therapy has been tested in vivo in mice and nonhuman primates. In studies of diabetic mice, the gene therapy approach restored
normal blood glucose levels for an extended period of time, typically around four months. According to Dr. Gittes, the duration of restored blood glucose
levels in mice could translate to decades in humans. If successful, this gene therapy could eliminate the need for insulin replacement therapy for diabetic
patients.
Recent Developments
License Agreement with University of Pittsburgh
On February 11, 2020, we signed an exclusive license agreement with the University of Pittsburgh - Of the Commonwealth System of Higher
Education for a potentially curative gene therapy for diabetes. The diabetes gene therapy candidate has the potential to treat Type 1 and Type 2 diabetes,
which, according to the Centers for Disease Control’s 2020 National Diabetes Statistics Report, together currently affect approximately 34.2 million people
in the U.S., or 10.5% of the population.
Financings
On February 19, 2020, we sold an aggregate of 5,000,000 shares of our common stock for a purchase price of $3.50 per share in a registered direct
offering. We received net proceeds of approximately $16.0 million after deducting estimated offering expenses.
On January 23, 2020, we sold an aggregate of 7,620,000 shares of our common stock for a purchase price of $1.05 per share in a registered direct
offering. We received net proceeds of approximately $7.2 million after deducting estimated offering expenses.
On January 16, 2020, we sold an aggregate of 961,000 shares of our common stock for a purchase price of $0.24 per share in a registered direct
offering. We received net proceeds of approximately $200,000 after deducting estimated offering expenses.
Appointments of Officers and Directors
On March 12, 2020, we appointed Catherine M. Vaczy, as Executive Vice President and Chief Strategy Officer, and Michael T. Redman, as
Executive Vice President and Chief Operating Officer. In addition, the executive officer title of Julien L. Pham, MD, MPH, has been changed to President
and Chief Scientific Officer.
On March 18, 2020, the board of directors of the Company appointed three independent directors to fill vacancies on the board. Brent Longnecker
was appointed as a Class I director and will serve until the 2021 annual meeting of stockholders, Will R. Wilson Jr. was appointed as a Class II director and
will serve until the 2022 annual meeting of stockholders, and Jose Antonio Moreno Toscano was appointed as a Class III director and will serve until the
2020 annual meeting of stockholders. In addition, each of Messrs. Longnecker, Toscano and Wilson were appointed to serve as members of the audit
committee, compensation committee, and nominating and corporate governance committee, of the board.
6
Our Pipeline
Our technologies are designed to administer disease-fighting genes to provide new treatment options for large patient populations with cancer and
diabetes who currently have limited treatment options. We are developing our lead product candidate to be administered with targeted therapies and with
immunotherapies for NSCLC. We have conducted a Phase I/II targeted therapy clinical trial evaluating Oncoprex in combination with EGFR inhibitor
erlotinib. We have conducted preclinical research evaluating Oncoprex in combination with EGFR inhibitor osimertinib as well as Oncoprex in
combination with checkpoint inhibitor pembrolizumab. We continue to conduct preclinical research to explore how Oncoprex may be administered with
targeted therapies and immunotherapies in other solid tumors. Additionally, we are researching how other tumor suppressor genes can be applied using our
unique, nanoparticle delivery platform. We also are developing our pre-clinical diabetes candidate. Our research and development pipeline is shown below:
Our Strategy
We intend to develop and commercialize treatments for cancer based on our proprietary gene therapy platform, alone or in combination with other
cancer therapies. We also intend to develop and commercialize our licensed gene therapy for diabetes. Key elements of our strategy include:
•
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Conduct Clinical Trials with Oncoprex for Cancer. We plan to conduct clinical trials of Oncoprex immunogene therapy in combination
with EGFR TKIs, such as osimertinib, and/or in combination with immunotherapies, such as pembrolizumab, for treatment of NSCLC,
while exploring pathways to accelerated FDA approval of these combinations in NSCLC patients. We also may pursue clinical trials using
multi-drug combinations of Oncoprex with additional targeted therapies and immunotherapies. Osimertinib is now considered a new
standard of care in the United States for NSCLC patients with an EGFR mutation. Given this and receipt of FDA’s Fast Track Designation
for use of Oncoprex combined with osimertinib in patients whose tumors progress on osimertinib, we have decided to prioritize this drug
combination and patient population. Therefore, we plan to initiate a Phase I/II clinical trial of Oncoprex combined with osimertinib in late
2020 or early 2021 and do not intend to reopen enrollment in the current Phase I/II trial using the combination of Oncoprex and erlotinib at
this time.
Investigate the Effectiveness of Oncoprex in Other Cancers We may also explore the combination of Oncoprex and other therapies in
other cancers such as soft tissue, kidney, head and neck, thyroid, and/or breast cancer. We may also pursue development of additional
proprietary cancer-fighting genes, alone or in combination with EGFR TKIs such as erlotinib or osimertinib and/or with immunotherapies.
Prepare to Commercialize Oncoprex. We plan to continue to develop the manufacturing, process development and other capabilities
needed to commercialize Oncoprex.
Pursue Strategic Partnerships. We plan to pursue strategic partnerships with other developers and providers of anti-cancer drugs to
investigate possible therapeutic combinations of Oncoprex with drugs manufactured by others, to accelerate the development of our current
and potential product candidates through co-development and to increase the commercial opportunities for our current and potential product
candidates.
Develop Our Platform Technology. We plan to investigate the applicability of our platform technology with additional anti-cancer drugs.
Acquire Additional Technologies. We are investigating other technologies for possible acquisition, and plan to add additional technologies
to our pipeline should we have the opportunity to do so on acceptable financial terms.
7
Current Treatment of Cancer
Chemotherapy is the standard treatment for the majority of NSCLC patients, as it is for many other cancer patients. Because it is a systemic, rather
than a targeted, approach to treating cancer, chemotherapy also kills healthy cells and has a number of other side effects.
A subset of NSCLC patients carry one or both of two EGFR mutations, referred to as exon 19 deletion and exon 21 substitution, which make their
tumors sensitive to TKIs. Because EGFR is frequently overexpressed in lung tumors, it has become a favored therapeutic target for pharmaceutical
companies. Several pharmacological and biological approaches, including TKIs, have been developed specifically to block activated EGFR for cancer
therapy. The class of drugs functioning as protein kinase inhibitors (KIs) comprises the majority of targeted therapies for lung cancer, accounting for most
sales and use. Of the KIs, the TKI drugs are the most common, with drugs targeting EGFR kinases ("EGFR TKIs") leading the sector growth. Several
EGFR TKI therapies are marketed commercially including osimertinib, erlotinib, gefitinib, and afatinib.
Approximately 7% of NSCLC patients of North American and European descent and approximately 30% to 50% of NSCLC patients of Asian
descent have the activating EGFR mutations. This means that the majority of NSCLC patients do not have activating EGFR mutations and are therefore
“EGFR negative” and not optimal candidates for EGFR TKIs.
However, while EGFR TKIs are most effective in patients who have an activating EGFR mutation and are therefore described as “EGFR
positive,” they are significantly less effective in overall NSCLC populations and are generally not effective in patients without an activating EGFR
mutation.
In addition, even among those patients who are EGFR positive and benefit from EGFR TKI therapy, nearly all eventually become resistant to and
ultimately no longer respond to TKI therapy, resulting in eventual disease progression. For example, according to the FLAURA study, sponsored by
AstraZeneca, the median time to tumor progression for lung cancer patients on osimertinib is approximately 18 months. Furthermore, clinical trials have
shown that combining EGFR TKIs with conventional chemotherapy does not increase survival for lung cancer patients.
Our clinical and preclinical data indicate that the combination of our lead product candidate, Oncoprex, with EGFR TKIs, may increase anti-tumor
activity in cancers with or without the EGFR mutations and in cancers that have become resistant to EGFR TKI therapy, thus expanding the number of
patients who could benefit from those drugs.
TUSC2, the Active Agent in Oncoprex
TUSC2, which is the active agent in Oncoprex, is a multifunctional gene that plays a vital role in cancer suppression and normal cell regulation.
Key TUSC2 anti-cancer mechanisms of action include the inactivation of multiple oncogenic kinases, the induction of apoptosis, the control of cell
signaling and inflammation, and modulation of the immune system to fight cancer. Oncoprex has also been shown to block mechanisms that create drug
resistance. Our data indicate that Oncoprex in combination with both EGFR TKIs and with immunotherapies achieve results more favorable than results
achieved with either Oncoprex or such other therapies alone, and may make those drugs effective for patients who would not otherwise benefit from them.
Normal TUSC2 function is inactivated at the early onset of cancer development, making TUSC2 a potential target for all stages of cancer,
including metastatic disease. The TUSC2 protein is reduced or absent in approximately 85% of lung cancers. In patients with NSCLC, the loss of TUSC2
expression has been associated with significantly worse overall survival than when TUSC2 expression is not impaired.
Studies show TUSC2 protein functions as a key mediator in the Apaf1-mediated mitochondrial apoptosis pathway by recruiting and directing
cytoplasmic Apaf1 protein to a critical cellular location and activating it in situ and by up-regulating activity of other proapoptotic effectors. Normal
TUSC2 function mediates apoptosis in cancer cells through interaction with Apaf1 and down-regulates multiple tyrosine kinases including EGFR, AKT,
PDGFR, c-Kit, and c-Abl. TUSC2 mediates apoptosis in cancer cells but not normal cells through its interaction with Apaf1 and down-regulates tyrosine
kinases including EGFR, PDGFR, c-Kit, and c-Abl.
In normal cells, the proteins involved in the PI3K/AKT pathway (also called the mTOR pathway), in which PI3K, a kinase, generates messenger
molecules required to translocate AKT, another protein kinase, to the cell’s plasma membrane where it is phosphorylated and activated, play an important
role in cellular function and cellular trafficking. These proteins are often found to be aberrantly active in cancers, causing cells to lose their ability to
control cell growth, proliferation, and differentiation. Thus, mutations in PI3K (overexpression) and its upstream receptors, EGFR, have been associated
with many forms of cancers.
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Similarly, proteins in the Ras/MAPK pathway, which is a signal transduction pathway that transduces signals to the cell nucleus where specific
genes are activated for cell growth, division and differentiation, play a critical role in cellular responses to various stress stimuli, including osmotic stress,
DNA damage, and proinflammatory factors. As shown in the figures below, the TUSC2 protein, a potent pan-kinase inhibitor, blocks multiple cell
signaling pathways downstream of the receptor (EGFR in the figures), leading to cell cycle interruption and thereby preventing cancer cell proliferation and
survival.
Additionally, under stress conditions, such as oncogenic stress, cells go through a regulated process of programmed cell death, or cellular suicide,
called apoptosis, in order to control cell development and replication. The TUSC2 protein interacts via various apoptotic signaling pathways to stimulate
programmed cell death via the release of caspases, enzymes that play a significant role in apoptosis.
Pan-Kinase Inhibition by TUSC2
Stimulation of Apoptotic Signaling by TUSC2
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Cancer and the Immune Response
When functioning normally, the body’s immune system recognizes and destroys cancer cells, as well as other mutated cells and foreign bodies. As
cancer develops over time, some mutations in cancer cells enable them to inhibit immune mechanisms, thus allowing the cancer cells to escape detection
and destruction by the immune system and leading to the cancer’s “immune tolerance.” Therapies are being developed to allow patients to overcome this
immune tolerance, some by stimulating the natural immune response and others by removing the inhibitions on the immune response created by the cancer.
For example, PD-1 is a protein found on certain types of T cells, which are part of the immune system. Because PD-1 prevents T cells from attacking other
cells, including in some cases cancer cells, inhibiting PD-L1 receptors, a process called PD-1 checkpoint inhibition, can facilitate the immune response to
cancer.
In addition to its pro-apoptotic cytotoxicity and tyrosine kinase inhibitory activity, TUSC2 enhances the immune response to cancer. Data from
preclinical studies at MD Anderson have shown a therapeutic benefit from the combination of TUSC2 and anti-PD-1 antibody and a key role for TUSC2 in
regulating immune cell subpopulations including cytokines, natural killer (NK) cells, and T lymphocytes. In addition, TUSC2 has been found to down-
regulate PD-L1 receptors on the surface of cancer cells.
NK cells, an important part of the innate immune system, have developed several mechanisms to distinguish healthy cells from target cells. These
mechanisms allow NK cells to kill cells that are deemed dangerous to the host, including cancer cells. However, one of the consequences of malignant
transformation is the ability of the cancer cell to evade the immune system. Cancer cells do so via the up-regulation and interplay of receptors, including
checkpoint inhibitors such as PD-1 and PD-L1.
As shown in the illustration below, TUSC2 has been found to stimulate the release of interleukin-15, or IL-15, resulting in up-regulation of mature
NK cells that circulate and target cancer cells.
Modulation by TUSC2 of the Immune Response to Cancer
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The Genprex Oncology Platform and Oncoprex
We are developing a novel approach to cancer treatment, based on our immunogene therapy platform, which is designed to deliver any of a
number of cancer fighting tumor-suppressor genes, alone or in combination with other cancer therapies, to combat multiple types of cancer. Our platform
consists of anti-cancer genes encapsulated in nanovesicles that can be delivered intravenously.
Our lead product candidate, Oncoprex, is the TUSC2 gene, as the active anti-cancer agent, encapsulated into nanovesicles made from fat
molecules with a positive electrical charge formulated for intravenous administration. In our clinical trials to date Oncoprex was injected intravenously
approximately every 21 days for as long as the patient continued to benefit, which is defined as tumor size stabilization or shrinkage.
Oncoprex has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer
cells, re-establishes pathways for programmed cell death, or apoptosis, in cancer cells, and modulates the immune response against cancer cells. Oncoprex
has also been shown to block mechanisms that create drug resistance.
Oncoprex is a pan-kinase inhibitor shown to simultaneously inhibit the EGFR and AKT oncogenic kinase pathways in vitro and in vivo. Once the
cancer cell takes up the nanovesicle containing TUSC2, it is reprogrammed to die. Resistance to targeted drugs and checkpoint inhibitors develop through
activation of alternate bypass pathways. For example, when PD-1 is blocked, the TIM-3 checkpoint is up-regulated. We believe that Oncoprex’ multimodal
activity will block emerging bypass pathways, reducing the probability that drug resistance develops.
Our cancer gene therapy platform and its delivery system are highly targeted. While the TUSC2 gene induces apoptosis in cancer cells which have
low or absent TUSC2 expression, TUSC2 delivered by nanovesicles to normal cells is not toxic. Moreover, the nanovesicles are taken up by tumor cells
after Oncoprex treatment at 10 to 25 times the rate at which they are taken up by normal cells, because of selective endocytosis, or enveloping by the cell,
of the nanovesicle lipid formulation and the enhanced permeability and retention, or EPR, characteristics of tumor vasculature, without the need for
external ligands, or binding molecules. Pre- and posttreatment biopsies following intravenous injection of Oncoprex in a Phase I clinical trial showed
robust TUSC2 protein expression in cancer cells at both primary and metastatic tumor sites.
Our preclinical and clinical data indicate that Oncoprex is well tolerated and may be effective alone or in combination with targeted small
molecule therapies, thereby facilitating the action of both drugs, allowing use in expanded populations of patients who may benefit from advanced therapy
regimens.
Data have shown that when Oncoprex is combined with EGFR TKI therapy, such as erlotinib, in EGFR mutated resistant cancers, the combination
therapy overcomes intrinsic and acquired therapeutic resistance by simultaneously inactivating the EGFR and the AKT signaling pathways to restore
apoptotic signaling. Overcoming EGFR resistance in a clinical setting could provide a path for approval of Oncoprex for patients who do not have an
activating EGFR mutation (90% of patients of American and European descent and 50% to 70% of those of Asian descent) and/or for patients who have an
activating EGFR mutation but who have become resistant to EGFR TKIs.
Clinical and preclinical data indicate that Oncoprex, when combined with EGFR TKIs such as osimertinib, erlotinib, and gefitinib, provides a
synergistic effect that could also benefit the larger population of NSCLC patients who are EGFR negative (which means they are not expected to benefit
from EGFR TKI drugs alone). Further, our data show that Oncoprex may re-sensitize EGFR positive patients who become resistant to, and therefore no
longer benefit from, EGFR TKIs alone. Thus, Oncoprex may both significantly expand the benefit of EGFR TKIs to the majority of patients (90% of those
of American and European descent and 50% to 70% of those of Asian descent) who do not have EGFR activating mutations and would therefore not
otherwise be expected to benefit from EGFR TKI drugs, and also extend the usefulness and benefit of EGFR TKIs for the population of NSCLC patients
who are EGFR positive, but whose tumors progress on EGFR TKIs. Our FDA Fast Track Designation was granted specifically for treatment of patients
whose tumors progress after receiving the EGFR TKI drug osimertinib.
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Many currently approved cancer therapeutics target only single molecules or a single specific genetic abnormality related to driving the
proliferation and survival of cancer cells. In contrast, Oncoprex works by targeting several molecules within the cancer cell to interrupt cell signaling
pathways that cause replication and proliferation of cancer cells, to target and kill cancer cells, to block mechanisms that create drug resistance and to
stimulate the natural immune response. Moreover, clinical and preclinical data show that Oncoprex works with other cancer drugs or their non-humanized
equivalents, to produce more effective anti-cancer effects than either produces alone. In conjunction with these other drugs and equivalents, Oncoprex has
been shown to mediate an anti-tumor response through up-regulation of NK cells, CD8+ T cells, and down-regulation of regulatory T cells, or Tregs, and
PD-L1 receptors, activate alternative immune mechanisms with the potential to complement checkpoint inhibitors. Published data indicate that
effectiveness of these kinase inhibitors and immunotherapy drugs is enhanced when they are combined with Oncoprex.
Oncology Delivery System
Our immunogene therapy platform consists of anti-cancer genes encapsulated in nanovesicles delivered intravenously. The Oncoprex TUSC2 gene
is encapsulated in a positively charged nanovesicle that binds to actively replicating (and therefore negatively charged) cancer cells, and then enters the
cancer cell through selective endocytosis. These nanoscale vesicles differ significantly from liposomes historically used for drug delivery in that they are
true particles encapsulating the therapeutic payload within a bilamellar lipid coat. Our collaborators at MD Anderson have optimized the characteristics of
lipids including N-(1-(2,3-Dioleoyloxy)propyl)-N,N,N-trimethylammonium methyl sulfate, or DOTAP:cholesterol and a DNA plasmid expressing the
TUSC2 tumor suppressor gene which form a spherical particle with a hollow center, nanoscale in size, which encapsulates the TUSC2 gene for delivery as
Oncoprex.
Operation of the Oncoprex TUSC2 Nanovesicle Delivery System
The particle size is small enough to allow Oncoprex to cross tight barriers in the lung, but large enough to avoid accumulation or clearance in the
liver, spleen and kidney. The cationic (positive) charge of the nanovesicle targets cancer cells, and direct nanovesicle fusion avoids target cell endocytosis.
A Phase I clinical trial showed that intravenous Oncoprex therapy selectively and preferentially targeted primary and metastatic tumor cells, resulting in
anticancer activity. The nanovesicles are non-immunogenic, allowing repetitive therapeutic dosing and providing extended half-life in the circulation.
We believe that the nanovesicles used in Oncoprex are applicable to delivery of a range of therapeutic and prophylactic plasmid DNAs and RNA
interference constructs. The nanovesicle manufacturing methods we and our collaborators have developed have been optimized and we believe they may be
useful for a wide array of disease treatments. Clinical outcomes demonstrated that the delivery system used in Oncoprex is well tolerated in humans and
can deliver high therapeutic doses. The nanovesicle delivery system and safety database may be attractive to drug developers because it overcomes
historical technological boundaries with lipid-based delivery systems.
Oncology Platform Technologies
We hold an exclusive worldwide license to patents covering the therapeutic use of a series of genes in the 3p21.3 region of the human
chromosome, including TUSC2, that have been shown in preclinical and clinical research to have cancer fighting properties. While we are initially
targeting NSCLC, data from preclinical studies conducted by MD Anderson researchers and others indicate that product candidates derived from our
immunogene therapy platform may also be effective with respect to other types of cancer, including soft tissue, kidney, head and neck, thyroid, and breast
cancer. Preclinical and clinical data also indicate that our current and potential product candidates are complementary to other successful cancer drugs.
Therefore, our platform technologies may allow delivery of any of a number of cancer fighting genes, alone or in combination with other cancer therapies,
to combat multiple types of cancer. In addition, we are investigating biomarkers to predict response and additional immunotherapies to combine with
Oncoprex.
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Preclinical and Clinical Development, Rationale and Strategy
Phase I Monotherapy Clinical Trial
In 2012, MD Anderson researchers completed a Phase I clinical trial of Oncoprex as a monotherapy. The primary objective of this Phase I trial
was to assess the toxicity of Oncoprex administered intravenously and to determine the MTD and recommended Phase II dose, of Oncoprex alone.
Secondary objectives were to assess the expression of TUSC2 following intravenous delivery of Oncoprex in tumor biopsies and also to assess the anti-
cancer activity of Oncoprex, although the study was not designed to show changes in outcomes. This trial demonstrated that Oncoprex was well tolerated
and established the MTD and the therapeutic dosage for Oncoprex at 0.06 mg/kg administered every 21 days. Although this trial was not designed to show
changes in outcomes, a halt in cancer growth was observed in some patients. Tumor regressions occurred in primary lung tumors and metastatic cancers in
the liver, pancreas, and lymph nodes. In addition, pre- and posttreatment patient biopsies demonstrated that intravenous Oncoprex selectively and
preferentially targeted patients’ cancer cells, and suggested that clinical anti-cancer activity was mediated by TUSC2.
In the Phase I Monotherapy Trial, Oncoprex was injected intravenously in stage IV (metastatic) lung cancer patients who had received traditional
platinum combination chemotherapy but still showed tumor progression at the time of entry into the study. Oncoprex was manufactured in Good
Manufacturing Process (GMP) facilities to meet specifications of size, appearance, and transfection efficiency. During the trial, manufacturing was
transferred from Baylor College of Medicine to MD Anderson, thus confirming reproducibility of the manufacturing process. Subjects received escalating
doses ranging from 0.01 mg/kg to 0.09 mg/kg at three-week intervals for a maximum of six cycles of a dose every three weeks. Fever is a common reaction
to intravenous drug administration; accordingly, dexamethasone, a steroid, and diphenhydramine, an antihistamine, were administered as a standard
treatment to prevent fever and eliminated the only clinically significant toxicity of fever.
In the Phase I Monotherapy Trial, 31 subjects were treated at six dose levels ranging from 0.01 to 0.09 mg/kg. Seventy percent of subjects had
received two or more prior chemotherapy regimens. Among four subjects treated without the fever-reducing premedications, all four subjects developed
grade 2 or higher fevers within 24 hours of treatment. Among the 27 subjects premedicated with the fever-reducing premedications, the highest fever was
grade 2, which occurred in two subjects. The only serious adverse events, defined as grade 3, 4 or 5 events under the Common Terminology Criteria for
Adverse Events published by the U.S. Department of Health and Human Services, were grade 3 fever (experienced by three patients) and grade 3
hypotension (experienced by 1 patient). The only dose-limiting toxicities were two episodes of transient grade 3 hypophosphatemia (abnormally low levels
of phosphate in the blood) resulting in an MTD of 0.06 mg/kg. Twenty-three subjects received two or more doses, of whom five subjects, or 22% of the 23
subjects, achieved disease control for periods ranging from 2.6 months to 10.8 months. The median disease control period for these subjects was 5.0
months (95% CI: 2.0-7.6), while the other 18 subjects’ cancer progressed during the Phase I Monotherapy Trial. Disease control for cancer therapies is
defined under the RECIST as Complete Response (CR) + Partial Response (PR) + Stable Disease (SD)>8weeks). Median survival for all subjects in the
Phase I Monotherapy Trial was 8.3 months (95% CI 6.0-10.5 months) and mean survival time was 13.2 months (95%CI 8.9-7.5 months) with a range of
two to 23+ months.
Two subjects had reductions in primary tumor size of 14% and 26%. One subject with stable disease, a 54-year-old female with a large cell
neuroendocrine carcinoma who received 12 cycles of Oncoprex therapy, had evidence of a durable metabolic response, which is a lasting reduction of
metabolic activity in the tumor, as shown by positron emission tomography (PET) imaging. The response was documented with PET scans performed after
the second, fourth and sixth doses, all showing decreased metabolic activity in the tumor with no changes in size or number of metastases by computed
tomography (CT) imaging. The illustration below is of the PET scan of this subject performed after the fourth dose. This subject had received six prior
chemotherapy regimens. Prior to entry in the Phase I Monotherapy Trial, two hepatic metastases were progressing on gemcitabine. The subject also had a
metastasis in the head of the pancreas and a peripancreatic lymph node, shown by the arrows in the illustration below. Illustration A shows the pretreatment
PET scan. The dose of Fluorodeoxyglucose (18F) was 8.8mCi. Illustration B shows the post treatment PET scan performed 20 days following the fourth
dose of Oncoprex. The dose of Fluorodeoxyglucose (18F) was 9.0mCi. All scans were performed within a 60 to 90 minute window after injection.
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Metabolic Tumor Response in a Metastatic Lung Cancer Subject
This subject survived after subsequent therapy more than seven years after the final treatment with Oncoprex, to our knowledge, without evidence
of cancer progression in the responding sites.
To test whether the TUSC2 gene introduced by Oncoprex therapy was expressed following Oncoprex therapy in the Phase I Monotherapy Trial,
pre-treatment and 24-hour post-treatment tumor biopsies were obtained from seven subjects by percutaneous CT guidance from a central tumor location. A
quantitative real time reverse transcriptase PCR, or RT-PCR, analysis using a plasmid TUSC2 sequence-specific probe was performed on samples blinded
to time of biopsy. The RT-PCR analysis detected high levels of TUSC2 plasmid expression in six of seven post-treatment tumor specimens but not in
pretreatment specimens or negative controls.
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In addition, an in situ proximity ligation assay (PLA) performed on paired biopsies from three subjects, demonstrated no TUSC2 protein staining
in pre-treatment tissues compared with intense TUSC2 protein staining in post-treatment tissues. For the PLA, anti-TUSC2 polyclonal antibodies were
developed to detect the presence of TUSC2. Pre-treatment and post-treatment biopsies were obtained from three patients. The top panel for each patient in
the illustration below represents the pre-treatment biopsy “controls” with DAPI, a type of blue stain. The bottom panel for each patient are post-treatment
biopsies, and represent overlays of blue DAPI staining and red anti-TUSC2 antibody staining. The blue stains in the top panels indicate the absence of
TUSC2 in the pre-treatment biopsies, and the red and purple (red overlaying blue) stains in the bottom panels indicate the presence of TUSC2 in robust
quantities in the post-treatment biopsies, showing that TUSC2 was successfully introduced into the tumors in the Phase I Monotherapy Trial.
Proximity Ligation Assay (PLA) for TUSC2 protein in tumor biopsies
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An RT-PCR gene expression profiling analysis of apoptotic pathway genes in a paired specimen showing high post-treatment levels of TUSC2
mRNA and protein in one subject also showed up-regulation and downregulation of certain genes involved in both the intrinsic and extrinsic apoptotic
pathways. Antibodies to single and double stranded DNA were not detected 14 months after completion of 12 cycles of therapy in the subject, indicating
that within that period no anti-DNA antibodies had developed. The conclusion from the Phase I Monotherapy Trial was that Oncoprex administered
intravenously in lung cancer patients was well tolerated with demonstrable gene delivery to tumors with protein expression and evidence of antitumor
activity. Although the number of biopsies was limited due to regulatory constraints, the consistent results across test platforms suggests that these
observations are reliable.
Based on the positive results from the Phase I Monotherapy Trial and preclinical data from studies of the combination of Oncoprex plus EGFR
TKI drugs, we proceeded to evaluate Oncoprex as a lung cancer therapeutic to be used in combination with the EGFR TKI erlotinib in a Phase I/II
Combination Therapy Trial.
Preclinical Studies
Investigators at MD Anderson conducted preclinical research showing that Oncoprex alone blocked the activation of the c-Abl tyrosine kinase. A
number of other studies at MD Anderson have demonstrated the complementary effects of Oncoprex combined with a variety of targeted kinase inhibitory
agents, both marketed and in various stages of clinical development, including erlotinib, gefitinib, osimertinib, MK2206, and others. Researchers
investigated the use of Oncoprex combined with commercially available EGFR TKI drugs erlotinib and gefitinib, and conducted preclinical in vitro and in
vivo studies combining Oncoprex with these drugs in a variety of human lung cancer cell lines, including cancers with activating EGFR mutations and
EGFR mutation negative cancers. Lung cancers known to have intrinsic and acquired resistance to erlotinib therapy were also studied, as were Kras-related
and other cancers. Notably, studies in xenograft animal models demonstrated that Oncoprex and either erlotinib or gefitinib showed synergistic anti-cancer
effects, superior to either agent used alone, in both EGFR mutation negative cancers (generally not candidates for erlotinib) and in EGFR mutation positive
cancers (optimal candidates for erlotinib), including cancers known to be resistant to erlotinib therapy. The addition of Oncoprex to either erlotinib or
gefitinib overcame drug-induced resistance by simultaneously inactivating EGFR and AKT signaling pathways and by inducing apoptosis in erlotinib- or
gefitinib-resistant cancers with EGFR mutations and with EGFR mutation-negative cancers.
In one study, MD Anderson researchers tested the combination of erlotinib and Oncoprex against five human NSCLC cell lines: H1299, H322,
A549, H460, and H1975, the latter of which has the L858R and T790M EGFR mutations and is highly resistant to erlotinib. The results showed that the
combination of Oncoprex and erlotinib significantly reduced NSCLC colony formation beyond the effect of erlotinib, Oncoprex or controls alone (p<0.01
at both 1 and 2.3 uM concentrations for all cell lines). The cooperative interaction between erlotinib and Oncoprex was confirmed in vivo using a lung
colony formation metastases model in nu/nu mice with A549 human lung cancer cells injected in the tail vein. Mice were treated with the combination of
Oncoprex and erlotinib and various controls including empty nanovesicles, erlotinib alone, Oncoprex alone, and other controls.
The greatest reduction in lung colonies occurred with the Oncoprex with erlotinib combination (90% reduction) which was reduced compared to
all control groups (p<0.0005). In terms of total tumor nodules, the cooperative effect is greater than 0.9999. This means that there is less than a 1 in 10,000
chance that the low dose erlotinib with TUSC2 combination does not have a cooperative effect and greater than 9,999 in 10,000 chance that the cooperative
effect exists. P-value is the probability that the difference between two data sets was due to chance. The smaller the p-value, the more likely the differences
are not due to chance alone. In general, if the pvalue is less than or equal to 0.05, the outcome is considered statistically significant. The FDA’s evidentiary
standard of efficacy generally relies on a p-value of less than or equal to 0.05.
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MD Anderson researchers also tested Oncoprex in TUSC2-deficient and erlotinib or gefitinib-resistant NSCLC cell lines. Treatment of the
NSCLC EGFR mutation negative cell lines H1299, H322, H358 and H460 cancer cell line showed that the Oncoprex combination significantly sensitized
(p<0.001) response of the cancer cell lines to both erlotinib or gefitinib treatment and synergistically induced apoptosis in vitro. The findings were
confirmed in vivo in an H322 orthotopic lung cancer mouse model. These studies included the K-ras mutant cell line H460, which is significant because
patients with K-ras mutant tumors are generally unresponsive to erlotinib or gefitinib. Synergistic induction of apoptosis was observed with the
combination of Oncoprex and concentrations of erlotinib or gefitinib similar to steady-state serum concentrations achievable with oral dosing. The
combination of Oncoprex and either erlotinib or gefitinib induced similar levels of tumor cell growth inhibition, apoptosis induction, and inactivation of
oncogenic protein kinases.
Data from these and other MD Anderson studies suggest a combination of Oncoprex with gefitinib or erlotinib can promote synergistic tumor cell
killing and overcome drug-induced resistance by simultaneously inactivating the EGFR and the AKT signaling pathways and by inducing apoptosis in
resistant cells with nonmutated EGFR. These data suggest that NSCLC patients with an activating EGFR mutation, whose cancer progresses on erlotinib,
may potentially benefit from Oncoprex with erlotinib combination therapy. These data also suggest that NSCLC patients without an activating EGFR
mutation (generally unresponsive to erlotinib) may potentially benefit from Oncoprex with erlotinib combination therapy.
In another study, MD Anderson researchers analyzed the effects of TUSC2 re-expression on the sensitivity of tumor cells to the AKT inhibitor
MK2206 in vitro and in mice. The AKT pathway is an important intracellular, converging positive regulator of apoptosis. AKT stimulates apoptosis and is
frequently dysregulated in cancers, and this has been associated with reduced sensitivity to anti-tumor drugs. The study showed that the combination of
TUSC2 transfection with MK2206 treatment suppressed tumor cell viability in vitro and effectively inhibited xenograft tumor growth in vivo more
effectively than either agent alone.
Preclinical Study Showing that the TUSC2-Erlotinib Combination Significantly Inhibits Tumor Cell Viability and Colony Formation in
NSCLC Cells Without an Activating EGFR Mutation
Previous research has shown that NSCLC in cells that lack the activating EGFR mutations exon 19 deficiency and exon 21 substitution is not
halted or inhibited by erlotinib at pharmacologically relevant doses. In one preclinical study, MD Anderson researchers tested a group of EGFR negative
NSCLC lines for sensitivity to erlotinib after restoration of TUSC2 expression, both transiently and stably, and found a significant benefit resulting from
the combination at micromolar ranges between 1uM and 2.3uM. These concentrations are achievable in patient serum with standard dosing regimens and
are pharmacologically relevant. Cell viability was evaluated in 3 TUSC2 Tet-On stable clones that had been treated with doxycycline to induce TUSC2,
and combined with erlotinib. As expected, the cells that had not had TUSC2 expression restored were not sensitive to erlotinib alone, and the viability of
cells in the A549, H1299, and H175 cancer cell lines was 92%, 90%, and 98%, respectively. Induction of TUSC2 with doxycycline alone showed more
cytoxicity than erlotinib alone, resulting in 16%, 22%, and 5% cell death, respectively. However, when cells were exposed to doxycycline and treated with
2.3 “M erlotinib for 48 hours, a growth inhibitory effect was observed for all three cell lines (p<0.05), with the relative survival of the A549, H1299, and
H175 cancer cells being reduced by 48%, 42%, and 38%, respectively. Similarly, as shown in the graphs below, colony formation was significantly
inhibited in cells transiently transfected with TUSC2 and treated with erlotinib. The ability of A549, H1299, H322, and H460 cells to form colonies was
reduced by 90%, 80%, 93%, and 85%, respectively. In dose titration experiments erlotinib also mediated increased inhibition of colony formation at
nanomolar concentrations. Taken together, the results clearly demonstrate the superiority of the TUSC2-erlotinib combination treatment over each agent
alone, and indicate that the effect is independent of the technique of exogenous gene expression. For both viability and colony formation assays the
probability of a cooperative effect was greater than 0.99, on a scale from 0 to 1. Zero means no probability of a true cooperative effect, and one means
100% probability of a cooperative effect given the observed data.
17
Inhibition of Colony Formation by a Combination of TUSC2 and Erlotinib
In the graphs above, “EV” means DOTAP: cholesterol (DC)—empty vector (EV) complex (the Oncoprex nanovesicle without the TUSC2 gene),
“PBS” means phosphate-buffered saline, and “EV + PBS” means EV and PBS, acting as a control; “ER” means erlotinib; “*” means p<0.05; and “**”
means p<0.01.
18
TUSC2-Erlotinib Combination Significantly Inhibits Tumor Growth and Metastasis and Induces Apoptotic Activity
In another preclinical study, MD Anderson researchers analyzed the effect of the combination of TUSC2 and erlotinib on inhibiting tumor growth
and metastasis in two NSCLC mouse xenograft models. Mice with established flank tumors of equal volumes were divided into different treatment groups:
PBS, used as a control; DC-TUSC2 complex (Oncoprex), referred to in the graphs below as “Fus1” or “TUSC2”; erlotinib alone, referred to in the graphs
as “Erlo” or “ER”; DOTAP:cholesterol (DC)—empty vector (EV) complex with erlotinib, referred to as “EV + Erlo” or “EV + ER”; and Oncoprex plus
erlotinib, referred to as “Combo,” “TUSC2 + ER” or “TUSC2 + Erlo.” In the H322 subcutaneous xenograft model, the combination of intravenous
Oncoprex and erlotinib was significantly superior (p<0.05) in reducing tumor volumes than either agent alone, as shown by graph A below. With
adjustment for multiple comparisons, the tumor growth rate of Oncoprex and erlotinib combination was the only group significantly smaller than the PBS
control group (p<0.01). The mean tumor volume was 421.25±89.27 mm3, compared with 1082.50±338.69 mm3, 801.25±144.60 mm3, 675.00±228.80
mm3, and 875.00±267.85 mm3, in their counterparts receiving PBS, Oncoprex, erlotinib, or EV + erlotinib, respectively. In terms of tumor size, the
posterior probability of cooperative effect was 0.9928, which means that there were less than 100 in 10,000 chances that the effect of TUSC2-erlotinib
combination was not cooperative.
MD Anderson researchers also developed a lung metastasis xenograft mouse model, using the human TUSC2-defective, EGFR negative A549
NSCLC cell line. Animals were treated with the same protocol as their subcutaneous counterparts. The number of tumor nodules on lung surfaces was
reduced by 82% after TUSC2-erlotinib treatment, compared to 41% and 54%, for TUSC2 alone or erlotinib treatment alone, respectively, as shown in
graph B below. The overall difference of the tumor nodule count among the five groups was significant (p<0.0001), as was the difference between the
Oncoprex and erlotinib combination group compared to each of the other groups (p<0.01).
As shown in graph C below, in resected tumor tissues assayed by TUNEL, the average number of apoptotic cells in the TUSC2 + erlotinib group
was many times higher than in any of the other groups, including the groups receiving erlotinib alone and USC2-nanovesicles alone.
These results show that the growth inhibitory benefit of TUSC2-erlotinib in vitro could be reproduced in vivo and validate the effects of this
combination.
Inhibition of Tumor Growth and Metastasis, and Induction of Apoptotic Activity, by a Combination of TUSC2 and Erlotinib
In graphs B and C above, “*” means p<0.05; the values in graph C above represent percentages from at least 1000 counted cells.
19
Phase I/II Combination Clinical Trial: TUSC2 Nanovesicles with Erlotinib
Phase I- Combination Trial
The Phase I Monotherapy Trial showed that Oncoprex is well tolerated, that high levels of TUSC2 expression are detected in the tumor post-
treatment, and that there is evidence of tumor growth suppression. Based on the positive results from the Phase I Monotherapy Trial and substantial
preclinical evidence that Oncoprex is complementary with EGFR TKIs, we obtained permission from FDA to begin a new Phase I/II trial (Phase I/II
Combination Trial) at MD Anderson combining Oncoprex with erlotinib in patients with Stage IV (metastatic) or recurrent NSCLC that is not potentially
curable by radiotherapy or surgery, whether or not they have received prior chemotherapy, and whether or not they have an activating EGFR mutation.
Enrollment in the Phase I portion of the Phase I/II Combination Trial, referred to as the Phase I Combination Trial, commenced in 2014 at MD Anderson
with Dr. Charles Lu as the Principal Investigator.
In the Phase I Combination Trial, 18 subjects were treated with the following dose levels:
Dose Level
1
2
3
4
Drug Doses
erlotinib (100 mg/day) + Oncoprex (0.045mg/kg)
erlotinib (100 mg/day) + Oncoprex (0.06mg/kg)
erlotinib (150 mg/day) + Oncoprex (0.045mg/kg)
erlotinib (150 mg/day) + Oncoprex (0.06mg/kg)
As in the Phase I Monotherapy Trial, subjects received a pre-treatment regimen of oral and intravenous dexamethasone and diphenhydramine to
reduce fever, along with an infusion of Oncoprex every three weeks. Subjects received oral erlotinib daily during each three-week cycle during the
treatment period.
The Phase I Combination Trial was also a dose escalation study with the primary purpose of determining the MTD. Dose Limiting Toxicities were
defined as grade 3, 4, or 5 events during the first cycle of treatment that were considered to be treatment related. At dose level 1 (Oncoprex .045 mg/kg plus
erlotinib 100 mg), one subject had grade 3 adverse events of fatigue, muscle weakness, and hyponatremia (low sodium level) considered to be related to the
study treatment (erlotinib); therefore, three additional subjects were treated at this dose level (six subjects total), none of whom suffered a Dose Limiting
Toxicity. At dose level 2 (Oncoprex .06 mg/kg plus erlotinib 100 mg), there were no Dose Limiting Toxicities. At dose level 3 (Oncoprex .45 mg/kg plus
erlotinib 150 mg), one subject had a grade 3 rash considered to be related to the study treatment (erlotinib); therefore, an additional three subjects were
treated at this dose level (six subjects total). No additional subjects suffered a Dose Limiting Toxicity at dose level 3. At dose level 4 (Oncoprex .06 mg/kg
plus erlotinib 150 mg), there were no Dose Limiting Toxicities; thus dose level 4 was determined to be the MTD.
Once the MTD for the study treatment combination was determined in the Phase 1 Combination Trial to be Dose Level 4, accrual proceeded on
the Phase II portion of the study. Since the eligibility criteria, drug administration details (other than dose) and evaluation details were identical for the
Phase I Combination trial and the Phase II Combination trial, three subjects in the Phase I Combination Trial who were treated at the MTD were included
in the Phase II Combination Trial.
Four patients in the Phase I portion of the Combination Trial had stable disease ranging from 12 weeks to 36 weeks. The following observations
from our preclinical studies and from the Phase I Combination Trial provided the rationale for proceeding with the Phase II Combination Trial combining
Oncoprex with erlotinib:
•
•
•
•
TUSC2 inhibits a variety of tyrosine kinases including EGFR, PDGFR, c-kit, and c-abl;
expression of TUSC2 in NSCLC cells combined with TKIs is complementary in vitro and in vivo;
intravenous administration of a nanoparticle encapsulated TUSC2 expression plasmid effectively delivers TUSC2 to distant tumor sites and
mediates an anti-tumor effect in orthotopic human lung cancer xenograft models; and
when the TUSC2-nanoparticle is combined with a TKI, the suppression of tumor growth in mouse xenograft models is synergistic.
20
Phase II Combination Trial
The Phase II Combination Trial is designed to include subjects treated with the combination of Oncoprex and erlotinib at the MTD with the
primary goal of measuring the response rate, and secondary endpoints of stable disease, time to progression and overall survival. The response rate for
cancer therapies is defined under the RECIST as Complete Response (CR) + Partial Response (PR); disease control rate is defined under the RECIST
criteria as Complete Response (CR) + Partial Response (PR) + Stable Disease (SD) > 8 weeks.
Enrollment criteria for the second phase of the Phase I/II clinical trial are identical to those in the first phase. The first subject enrolled in the Phase
II portion of the study began erlotinib on Day 8, and subsequently every other enrolled subject began erlotinib on Day 8. The rationale for delaying
erlotinib was to allow exploratory analyses of potential differential effects of Oncoprex nanoparticles alone and in combination with erlotinib on
downstream pathway activation and potential biomarkers of erlotinib resistance. In the Phase II Combination Trial, subjects received three-week cycles of
Oncoprex in combination with erlotinib until the occurrence of progressive disease (PD), unacceptable toxicity, withdrawal of consent, or study treatment
discontinuation for other reasons, whichever occured first.
Of the 39 patients allowed in the protocol for the Phase II portion of the trial, 10 were enrolled (three of whom were also subjects of the Phase I
Combination Trial) and nine were evaluable for response under the trial protocol, because they received 2 or more cycles of treatment. None of the 10
subjects treated in the Phase II portion of the Phase I/II trial suffered a Dose Limiting Toxicity. Interim results show that four of the patients had tumor
regression and one patient had a CR under the RECIST criteria. The median response duration for all patients, which is defined as the median time between
when response is first noted to the time when cancer progression is observed, was three months. The response rate for the nine patients evaluated to date
was 11% and the disease control rate for the nine patients was 78%.
The patient with the CR, a 58 year old female, upon enrollment in the study had metastatic NSCLC status following 6 cycles of pemetrexed and
carboplatin and two cycles of maintenance pemetrexed with cancer progression. The patient’s tumor has EGFR exon 18 and 20 missense mutations, which
are not sensitive to erlotinib. As shown in the illustrations below, this patient had disappearance of both the lung primary tumor and the lung, liver and
lymph node metastases.
Subject with RECIST Complete Response
21
Preliminary analysis of these data further supported our belief that Oncoprex may provide medical benefit in several subpopulations of NSCLC
patients for which there is an unmet medical need, and may provide pathways for accelerated FDA approval.
Based on preclinical data and the data from our Phase I monotherapy trial and our Phase I/II combination trial described above, as well as
additional preclinical data from experiments combining Oncoprex with osimertinib against NSCLC we applied for a Fast Track Designation from the
United States FDA. In January, 2020, we received a United States FDA Fast Track Designation for use of Oncoprex™ in combination with EGFR
inhibitor osimertinib (AstraZeneca’s Tagrisso®) for the treatment of NSCLC patients with EFGR mutations that progressed after treatment with osimertinib
alone. According to the FLAURA study sponsored by AstraZeneca, the median length of time that patients are treated with osimertinib before their tumors
progress is approximately 18 months.
We believe that the Fast Track Designation provides a defined pathway toward FDA approval of the combination of Oncoprex with osimertinib,
and therefore we have decided to allocate our resources toward a new Phase I/II clinical trial of Oncoprex combined with osimertinib, and will not enroll
additional patients in our Phase I/II clinical trial of Oncoprex combined with erlotinib at this time. Instead we plan to open a new Phase I/II clinical trial of
Oncoprex combined with osimertinib.
We plan to open enrollment in this new Phase I/II clinical trial at multiple clinical trial sites in the United States and possibly in other countries.
Opening the sites will require contracting with each site and approval of the IRB of each site where the trial is conducted. Any estimate of the duration of
the trial would also be subject to substantial uncertainty, because treatment generally continues under the clinical trial protocol until the patient dies,
experiences a serious adverse event or withdraws from the trial, or until cancer progresses. Even after completion of treatment, patients continued to be
monitored. We intend to use a portion of our available funds to open clinical trial sites.
Preclinical Studies of TUSC2 in the Immune Response to Cancer
Previous research has shown that TUSC2 regulates cytokine expression in vitro. Cytokines are proteins that stimulate inflammation as part of the
immune response. Stable expression of TUSC2 in H1299 NSCLC cells altered expression of a wide spectrum of cytokines including IL2, IL7, IL8 and 10,
GM-CSF and PDGF-beta. TUSC2 is a positive regulator of innate immunity via regulation of IL-15 expression. IL-15 induces NK cell differentiation.
The systemic effect of the TUSC2 and anti-PD1 antibody combination was examined in two immunecompetent, syngeneic mouse models of Kras
and p53 mutant lung cancer. C57BL/6 mice were subcutaneously injected with murine adenocarcinoma lung carcinoma CMT/167-luc cells (KrasG12V
mutation). CMT/167 cells do not express TUSC2. Tumors from untreated mice, isotype antibody control, or those treated with anti-PD1 were used as
controls. 344SQ (KrasG12D allele and a knock-in Trp53R172HÄG allele) adenocarcinomas which metastasize to the lung in 126S2 mice were also used.
When tumors reached 50-100 mm3, mice were either injected intravenously with DOTAP:cholesterol (DC)-TUSC2 complex alone (at a dose of 25 “g of
plasmid DNA and 10 nmol DC, every 48 hours for three injections), or (DC)-TUSC2 complex combined with anti-PD1 antibody (250 “g for four
injections) alone or combined with anti-CTLA4 (100ug for three injections). Tumor growth and development was monitored by scoring ex-vivo
luminescence using the IVIS Imaging System 200 Series. All tumor measurements were blinded to treatment and results were analyzed independently by
biostatisticians.
22
Preclinical Study Showing that the TUSC2 and Anti-PD1 Combination Cooperatively Inhibits Growth of CMT/167 Lung Adenocarcinomas
Mouse experiments showed combined treatment with TUSC2 and anti-PD1 antibody superior to anti-PD1 alone in five independent experiments
in two different tumor models. Results of a representative experiment is shown in the graph below. By week 3 the reduction in tumor image intensity by the
combination of TUSC2 and anti-PD1 and TUSC2, anti-PD1, plus anti-CTLA4 was greater than the reduction with TUSC2 alone, anti-PD1 combined with
anti-CTLA4, or the isotype control. Spleens and blood were collected for immunological analysis profiling by multicolor flow cytometry. Immune profiling
panels were designed to evaluate response and major changes of specific regulatory innate and adaptive immune cells to TUSC2 or anti-PD1 treatment in
peripheral blood and spleen.
12-Preclinical Study Showing Effect of TUSC2 Anti-PD1 Combo on T Lymphocytes
Preclinical Study Showing the Effect of the TUSC2 and Anti-PD1 Combination on T Lymphocytes
The population of NK cells, cytotoxic lymphocytes critical to innate immune function, was assessed in peripheral blood mononuclear cells
(PBMCs) in tumor bearing mice treated with anti-PD1, TUSC2 alone and the combination. As shown in the graph below, the NK cell population increased
strongly in the TUSC2 alone and TUSC2+PD1 groups which correlated with tumor regression. Anti-PD1 alone had no effect on NK cell proliferation.
Tumor free mice without mutations that lead to metastasis were injected intravenously with TUSC2 which caused a threefold up-regulation of NK
cells in the peripheral blood of TUSC2 injected mice as compared with non-injected mice. CD8 T cells, which are cytotoxic T cells (CTL) for tumor
killing, act as a prognostic marker of tumor regression. Increased numbers of CTL were found in the TUSC2 and TUSC2+PD1 groups as compared with
that of the control group which directly correlated with the anti-tumor effect, as shown in the graph below. Lower levels of CD62L expression on T
lymphocytes in TUSC2 treated mice suggests that TUSC2 regulates T cell activation. Moreover, TUSC2 induced down-regulation of regulatory T cells
(Treg, CD4+CD25+). TUSC2 was shown to down-regulate checkpoint markers such as PD-1, CTLA-4, Tim-3, and LAG-3.
23
13-Effect of TUSC2 with Anti-PD1 on Immune Cell Populations in Peripheral Blood (Large)
Preclinical Study Showing that TUSC2 Immunogene Therapy is Synergistic with Anti-PD1 in Lung Cancer Syngeneic Mouse Models
Based on the prolonged responses that were observed in TUSC2 clinical trials, which suggest that TUSC2 may modulate the immune response,
and on the fact that checkpoint blockade immunotherapy against PD1 and PD-L1 has yielded durable antitumor activity in a subset of NSCLC patients,
MD Anderson researchers conducted a preclinical study to investigate the immune response to TUSC2 in immune cell populations and the synergistic
antitumor effect of TUCS2 in combination with anti-PD1 checkpoint blockade in syngeneic mouse NSCLC models.
Two Kras-mutant syngeneic mouse models were used to explore the effect of TUSC2+anti-PD1 (+/- anti-CTLA-4) on immune cells infiltration
into the tumor micro-environment. Activating Kras mutations are the most common driver mutations in lung adenocarcinomas. Lung cancer with mutant
Kras has a poor prognosis, is often resistant to conventional therapy, and readily becomes resistant to targeted therapies with kinase inhibitors. Studies by
researchers not at MD Anderson have found that PD1 expression was highly associated with the presence of Kras mutations and that PD-L1 expression was
elevated in premalignant Kras-mutant cells, suggesting that Kras mutation may affect the function of the PD1/PD-L1 immune checkpoint pathway.
The first syngeneic mouse model used a murine lung carcinoma cell line CMT/167-luc with a Kras G12V mutation and a low level of TUSC2
expression, implanted subcutaneously in C57BL/6 mice. The second syngeneic mouse model optimized an aggressive experimental metastatic lung cancer
model using 129SvE mice injected with SQ344 lung cancer cells, which contained KrasG12D allele. The SQ344 tumor model was found to be less
sensitive to anti-PD1 single agent treatment.
24
The graph below shows the protocol for and results of this preclinical study, in which anti-PD-1, TUSC2 and anti-CTLA-4 treatments were
administered in the SQ344 metastatic lung tumor mouse model. Figure A shows that SQ344 tumor cells have less expression of PD-L1 than in the
CMT167 model, as determined by flow cytometry. The level of PD-L1 expression in SQ344 cells was only 4.5%, which was significantly lower than the
level found in the CMT 167 mouse tumor model (23.7% vs. 4.5%, p < 0.0001), suggesting that SQ344 would respond less strongly to an anti-PD1 agent
than the CMT167 model. Figure B shows the protocol for the experiment, in which treatments were administered every three or four days in the mouse
tumor cells. Figure C shows the survival of the mice with the lung tumor cells treated with (a) no treatment, (b) a combination of anti-PD-1 and anti-
CTLA-4, (c) TUSC2 alone, (d) a combination of TUSC2 and anti-PD-1, and (e) a combination of TUSC2, anti-PD-1 and anti-CTLA-4. Figure D shows
samples of untreated lung tissue and lung tissue treated with TUSC2. Figure E shows tumor sizes after each of the treatments shown in Figure C after two
weeks. Figures F, G and H shows the infiltration by NK cells, the concentration of T regulatory, or Treg, cells and the concentration of myeloid-derived
suppressor, or MDSC, cells, a type of immune cells, in each case after treatment with (a) no treatment, (b) TUSC2 alone, (c) a combination of TUSC2 and
anti-PD-1 and (d) a combination of anti-PD-1 and anti-CTLA-4.
The results of this preclinical study indicate that TUSC2-sensitization to anti-PD1 could be produced in both Kras-mutant lung cancer mouse
models.
14-Therapeutic Efficacy of TUSC2+Anti-PD1 in a Lung Metastasis Model (Large)
25
Preclinical Studies of Additional 3p21.3 Genes with Cancer-Fighting Properties
We have licensed rights to a group of candidate tumor suppressor genes, including 101F6, NPRL2, CACNA2D2, PL6, BLU, RASSF1, HYAL 1
and HYAL2, in addition to TUSC2 (which is also referred to as FUS1), all of which are located in a sub-region of human chromosome 3 known as 3p21.3.
Using a number of techniques, MD Anderson researchers and their collaborators have identified these genes as potentially having cancer-fighting
characteristics. MD Anderson researchers have subsequently conducted a number of preclinical studies on certain of these genes, particularly 101F6 and
NPRL2, as well as TUSC2, both alone and in combination with other compounds, in order to assess their actual effects on NSCLC. Three of these
preclinical studies are described below. We plan to support continuing research into the cancer-fighting properties of these and other genes in the 3p21.3
sub-region as an important part of our strategy.
Preclinical Study Showing Expression of Several Genes in the Human Chromosome 3p21.3 Sub-region by an Adenovirus Vector Results in Tumor
Suppressor Activities in Vitro and in Vivo
MD Anderson researchers conducted preclinical studies, both in vitro and in vivo, of several of the licensed genes located in the 3p21.3 sub-
region, in order to assess their effects on tumor cell proliferation and apoptosis in human lung cancer cells. The researchers used adenoviral vectors to
introduce individual wild-type genes into 3p-deficient tumor xenografts and tumor cell lines. This “forced expression” of the wild-type forms of TUSC2,
101F6, and NPRL2 resulted in inhibition of tumor cell growth by induction of apoptosis and/or alteration of cell cycle pathways in vitro, compared to
control. Intratumoral injection of 101F6, TUSC2 and NPRL2 with adenoviral vectors, as well as systemic administration of these genes in an experimental
mouse model, suppressed the growth of tumor xenografts (in this case, human tissue grafted onto the mouse model) and inhibited lung metastases. The
results of these studies showed that the genes 101F6, NPRL2 and TUSC2 had the most significant anti-cancer effects of the tested genes and were therefore
the most promising genes for further study.
Preclinical Study Showing that Tumor Suppressor 101F6 and Ascorbate Inhibit Non–Small Cell Lung Cancer Growth
One of the promising tumor suppressor gene candidates, 101F6, expresses a protein found in normal lung bronchial epithelial cells and fibroblasts
but whose function is impaired in most lung cancers. This protein is involved in the regeneration of ascorbate, a well-known antioxidant that has been
tested as a supplemental therapeutic agent for human cancer prevention and therapy. MD Anderson researchers studied the effect of 101F6 in combination
with ascorbate on human lung cancer tissue, both in vitro and in vivo. In the in vitro portion of the study, 101F6 was transferred via nanoparticles similar to
our Oncoprex nanovesicles, and in combination with ascorbate, selectively targeted cancer cells and inhibited lung cancer cell growth to a greater extent
than either 101F6 or ascorbate alone. In vivo, the systemic injection of 101F6 nanoparticles in mouse tail veins, together with the intra-abdominal injection
of ascorbate, inhibited both tumor formation and growth in human NSCLC H322 lung cancer xenograft mouse models (P < 0.001) with greater effect than
either 101F6 or ascorbate administered alone.
Preclinical Study Showing NPRL2 Sensitizes Human NSCLC Cells to Cisplatin Treatment by Regulating Key Components in the DNA Repair Pathway
Another of the promising tumor suppressor gene candidates, NPRL2, interacts with a kinase that is activated by cisplatin, an anti-cancer drug,
leading to downstream activation of apoptosis in response to the presence of intracellular high-molecular weight DNA fragments, which themselves result
from the breakup of DNA molecules induced by exposure to cisplatin. Mutations in the NPRL2 gene are associated with resistance to this cisplatin-
mediated apoptosis. MD Anderson researchers have conducted preclinical studies of NPRL2 with cisplatin in vitro in lung cancer cell cultures and in vivo
in an experimental mouse model of chest cavity cancer dissemination. Data from these studies suggest that the systemic introduction of the NPRL2 gene
and the resulting expression of the NPRL2 protein in cancer cells activates the DNA damage checkpoint pathway in cisplatin-resistant and NPRL2-negative
cells. These studies suggest that the combination of NPRL2 and cisplatin could resensitize cisplatin nonresponders to cisplatin treatment, helping to
overcome resistance to cisplatin.
26
Process Development and Manufacturing
We do not currently have nor do we plan to build the internal infrastructure or capability to manufacture Oncoprex or any future product
candidates for use in the conduct of our clinical trials or for commercial supply. We currently rely on third-party contract manufacturers to manufacture
clinical supplies of Oncoprex.
We are currently transferring the manufacturing process originally developed by MD Anderson to commercial contract manufacturers to facilitate
large, multi-center clinical trials.
Oncoprex is an immunogene therapy consisting of a DNA plasmid in nanovesicles, or lipid nanoparticles (LNPs), to restore a gene (TUSC2)
deficient in certain cancers, including NSCLC.
The production of Oncoprex is a multi-step process that first involves the growth of bacteria (also known as fermentation), the inducement of
production of the DNA plasmid (TUSC2) by the bacteria, and removal of impurities and process residuals. The purified plasmid is solubilized in water and
then filled into vials for storage. The vials are kept refrigerated until use. Furthermore, lipids are then combined to form lipid nanoparticles (LNPs), which
are dried into a thin film, hydrated, filled into vials and stored under refrigeration until use. The DNA plasmid is then transfected into the LNPs to produce
the drug product, which is a liquid suspension filled into small vials.
MD Anderson tested the shelf life of the final DOTAP:cholesterol formulation. A shelf life of at least one year was established by MD Anderson.
We currently plan to conduct shelf life studies with other vendors.
To treat cancer patients, we currently believe Oncoprex will be an intravenous (IV) infusion every three weeks during the treatment period.
Various contract manufacturers currently perform the manufacturing steps, including the production of the DNA plasmid and liposomes, DNA transfection
and vial filling.
Manufacturers of our products are required to comply with applicable FDA manufacturing requirements contained in the FDA’s GMP regulations.
GMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and
documentation. Pharmaceutical product manufacturers and other entities involved in the manufacture and distribution of approved pharmaceutical products
are required to register their establishments with governmental authorities, such as the FDA and/or Health Canada, and certain state agencies, and are
subject to periodic unannounced inspections by the governmental authorities and certain state agencies for compliance with GMP and other laws.
Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain GMP compliance.
Facilities used by contract manufacturers and their subcontractors must be approved by the respective governmental agencies after we submit a
request for marketing approval for Oncoprex. We do not control the manufacturing process and are completely dependent on contract manufacturers for
compliance with the applicable regulatory requirements for the manufacture of Oncoprex. If a contract manufacturer cannot successfully manufacture
material that conforms to the strict regulatory requirements of the FDA and any applicable foreign regulatory authority, they will not be able to secure the
applicable approval for their manufacturing facilities. If these facilities are not approved for commercial manufacture, we may need to find alternative
manufacturing facilities, which could result in delays in obtaining approval for the applicable product candidate as well as substantial additional expense.
In addition, contract manufacturers are subject to ongoing periodic unannounced inspections by the FDA and corresponding state and foreign
agencies for compliance with GMPs and similar regulatory requirements. Failure to comply with applicable GMPs or other regulatory requirements could
result in sanctions being imposed on us, including fines, injunctions, civil penalties, delays, suspensions or withdrawals of approvals, operating restrictions,
interruptions in supply and criminal prosecutions, any of which could significantly and adversely affect supplies of our Oncoprex and have a material
adverse impact on our business, financial condition and results of operations.
Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved marketing
authorization, including withdrawal of the product from the market. In addition, changes to the manufacturing process generally require prior FDA (or
other governmental agency) approval before being implemented and other types of changes to the approved product, such as adding new indications and
additional labeling claims, are also subject to further governmental review and approval.
In the event we develop or acquire additional product candidates, we expect to make similar arrangements with other third-party contract
manufacturers for such product candidates.
27
Oncology Intellectual Property
We hold a worldwide, exclusive license to including 33 issued patents for technologies developed at MD Anderson and UTSWMC. These patents
comprise various therapeutic, diagnostic, technical and processing claims.
The following table shows our families of issued patents and patent applications, together with information about the type of patent protection, the
jurisdiction and the patent expiration dates.
Patent
Family
1
Title and (Description)
Chromosome 3p21.3 genes are tumor
suppressors
(Use of our platform genes, including TUSC2,
and use of our non-viral nanovesicle delivery
system)
Type of Patent Protection
The patents in this family have claims
directed to compositions of matter, uses
of the compositions and processes for
preparing the compositions
2
3
4
Bioactive FUS1 Peptides and Nanoparticle-
Polypeptide Complexes (Pharmaceutical
formulation of TUSC2 (also referred to as FUS1)
nanoparticles, method of delivering TUSC2 to
cancer cells, and method of treating cancer
patients with TUSC2 nanoparticles)
Methods and Compositions of Non-Viral Gene
Therapy for Treatment of Hyperproliferative
Diseases
(Methods of delivery, including our nanovesicle
delivery system, of a series of genes that are
licensed to us, including TUSC2, and genes that
are not licensed to us)
Methods and Compositions Related to Novel
hTMC Promoter and Vectors for Tumor-
Selective and High-Efficient Expression of
Therapeutic Genes
(A genetic technology to improve the
effectiveness of gene therapy, relating to our
platform genes and other genes)
The patents in this family have claims
directed to compositions of matter, uses
of the compositions and processes for
preparing the compositions
The patents in this family have claims
directed to compositions of matter, uses
of the compositions and processes for
preparing the compositions
The patents in this family have claims
directed to compositions of matter, uses
of the compositions and processes for
preparing the compositions
28
Jurisdiction
United States (3 issued)
Australia (2 issued)
Japan (1 issued)
Canada (1 issued)
Europe (1 issued; validated in
Switzerland, Germany, Denmark,
Finland, France,
United Kingdom, Ireland,
Sweden, Netherlands)
United States (2 issued)
Korea (1 issued)
Patent Expiration Dates
7/10/2021, except for the
issued US patents,
which expire on
5/15/2024, 7/29/2022,
and 5/7/2022
3/14/2026, except for one
of the issued US patents,
which expires on 1/23/2030
United States (1 issued)
Canada (1 issued)
Europe (1 issued; validated in:
Belgium, France, Germany,
Italy, Liechtenstein, Spain,
Sweden, Switzerland, and
United Kingdom.
United States (1 issued)
5/24/2020
1/9/2030
Because the use of our platform genes, including TUSC2, and the use of our non-viral delivery system to deliver them, are covered by Family No.
1, we believe that expiration of the patents in Family 3 will not affect our intellectual property protection for use of the genes which are licensed to us and
are part of our platform.
We also hold a non-exclusive license from the National Institutes of Health (NIH) to 15 patents that expired on August 1, 2017. We are aware that
others have also licensed these technologies from the NIH. These patents relate to the DOTAP:cholesterol liposomes for delivery of therapeutic DNA,
which is the basic delivery system embodied in our nanovesicles. Through our license from MD Anderson, we have separate patent protection for the
combination of our nanovesicles with the genes we have licensed from MD Anderson, as well as for improvements that MD Anderson has made to the
nanovesicle delivery system. Because the license from the NIH is non-exclusive, we do not expect the expiration of the underlying patents to have a
material effect on our business. We have an ongoing obligation to pay the NIH a total of $240,000 (together with an additional $20,000 each year starting in
2018) upon our receipt of regulatory approval for our current or potential product candidates.
In addition to the current licensed patents, Genprex is currently evaluating additional patent licenses from MD Anderson to add to the patent
portfolio and expand our commercial potential. We expect to evaluate technology transfer opportunities to leverage the commercial potential of our
platform delivery system and also seek complementary oncology therapies.
We have filed a trademark application for our company name and for the drug name “Oncoprex” for added protection of future product branding.
Diabetes Intellectual Property
We hold a worldwide, exclusive license to an issued patent for diabetes technologies developed at the University of Pittsburgh. The following
table shows our issued patent with information about the type of patent protection, the jurisdiction and the patent expiration dates.
Patent
Family
1
Title and (Description)
Endogenous neogenesis of beta cells
Jurisdiction
United States (1 issued)
Patent Expiration Dates
4/17/2035
Type of Patent Protection
The patents in this family have claims
directed to compositions of matter, uses
of the compositions and processes for
preparing the compositions
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Licenses and Research Collaborations
Agreements with MD Anderson
We hold our Oncoprex technologies under a Patent and Technology License Agreement (MD Anderson License Agreement) with the Board of
Regents of The University of Texas System, MD Anderson. The MD Anderson License Agreement was originally entered into as of July 20, 1994 (and was
later amended on September 1, 1996, August 11, 1997, July 31, 1994 and October 4, 2001), between the Board of Regents of The University of Texas
System, MD Anderson and Intron Therapeutics, Inc. (which later changed its name to Introgen Therapeutics, Inc., or Introgen).
Pursuant to the MD Anderson License Agreement, as amended, we have rights to patents covering use of various genes, including the TUSC2
gene, for treatment of cancer, as well as know-how and related intellectual property.
The exclusive licenses under the MD Anderson License Agreement, will continue until the expiration of all patents covered by the agreement. The
last licensed patent under the MD Anderson License Agreement will expire in January 2030. Upon the expiration of the exclusive licenses, the licensee will
have a non-exclusive, fully paid-up right and license to use and otherwise exploit the technology rights licensed under the agreement. MD Anderson may
terminate the agreement in the event of the in the event of our voluntary or involuntary bankruptcy or if our business is placed in the hands of a receiver,
assignee or trustee. In addition, MD Anderson may terminate the agreement in the event of an uncured breach by us.
Pursuant to a Technology Sublicense Agreement dated March 7, 2007, referred to as the Sublicense Agreement, Introgen sublicensed its rights
under the MD Anderson License Agreement to Introgen Research Institute, Inc. (IRI) a company formed and owned by Rodney Varner, our current
President, CEO and Chairman of the board of directors.
Pursuant to an Assignment and Collaboration Agreement dated April 13, 2009, (IRI Collaboration Agreement) IRI assigned its rights under the
Sublicense Agreement to us, and we granted back to IRI a non-exclusive, royalty-free license to use and practice the licensed technology for non-
commercial research purposes. As consideration for this assignment, we agreed to assume all of IRI’s obligations to MD Anderson under the MD Anderson
License Agreement, including ongoing patent related expenses and royalty obligations.
The 2009 IRI Collaboration Agreement was amended by an Amended Collaboration and Assignment Agreement dated July 1, 2011 (2011 IRI
Collaboration Agreement). The 2011 Collaboration Agreement provided that IRI would provide additional licensing opportunities and services to us, in
return for monthly payments and our obligation to pay to IRI a royalty of 1% on sales of products licensed to us under the MD Anderson License
Agreement. In 2012, IRI’s obligation to provide those opportunities and services, and our obligation to make monthly payments to IRI, were terminated.
The 2011 IRI Collaboration Agreement had an initial term of two years and renews automatically for additional consecutive periods of one year each unless
either we or IRI gives prior written notice of termination to the other party. In addition, either we or IRI may terminate the agreement in the event of the
other party’s voluntary or involuntary bankruptcy or uncured default.
Pursuant to a Technology Sublicense Agreement dated June 1, 2011, we granted to IRI a non-exclusive sublicense, for non-commercial purposes,
to the rights under the Sublicense Agreement.
At the time that we entered into the 2011 IRI Collaboration Agreement, Mr. Varner was not an officer or director of Genprex, but he was deemed
to be an “affiliate” of the Company due to his beneficial ownership of approximately 39% of our issued and outstanding shares. At the time we acquired the
Oncoprex technologies under the 2009 IRI Collaboration Agreement, they were the subject of the Phase I Monotherapy Trial. We completed the Phase I
Monotherapy Trial and did substantial process development, manufacturing and regulatory work necessary to bring the technologies into a Phase I/II
Combination Trial.
30
Under the MD Anderson License Agreement, the Sublicense Agreement and the 2009 IRI Collaboration Agreement, we are obligated to pay all
fees, patent related expenses, royalties, and other amounts that become due with respect to the licensed patents, patent application and other technologies.
We are also obligated to pay to MD Anderson royalties of 1.5% of net sales attributed to sales of the licensed products, as well as 1.5% of advance
payments received by us (excluding amounts paid to us in reimbursement of development or other costs) from third parties pursuant to sublicense,
marketing, distribution or franchise arrangements. Under the 2011 IRI Collaboration Agreement, we are obligated to pay to IRI a royalty of 1.0% of net
sales of licensed products and 1.0% of certain other payments received by us. This royalty obligation continues for 21 years after the later of the
termination of the MD Anderson License Agreement and the termination of the Sublicense Agreement. We have no other payment obligations to IRI under
the 2009 IRI Collaboration Agreement or the 2011 IRI Collaboration Agreement. We were not required to make any up-front payments to MD Anderson or
IRI when we entered into the MD Anderson License Agreement, the Sublicense Agreement or the 2009 IRI Collaboration Agreement. Under the 2011 IRI
Collaboration Agreement, we were required to make payments of $30,000 per month to IRI. We made 14 of these monthly payments, totaling $420,000, to
IRI in 2011 and 2012, and our obligation to make such monthly payments was terminated in 2012.
Our rights under the MD Anderson License Agreement are made subject to the rights of the U.S. government to the extent that the technology
covered by the licensed intellectual property was developed under a funding agreement between MD Anderson and the U.S. government. Additionally, to
the extent there is any conflict between the MD Anderson License Agreement and applicable laws or regulations, applicable laws and regulations will
prevail. Similarly, to the extent there is any conflict between the MD Anderson License Agreement and MD Anderson’s funding agreement with the US
government, the terms of the funding agreement will prevail. Some, and possibly all, of our licensed intellectual property rights from MD Anderson have
been developed in the course of research funded by the U.S. government. As a result, the U.S. government may have certain rights to intellectual property
embodied in our current or future products pursuant to the Bayh-Dole Act of 1980. Government rights in certain inventions developed under a government-
funded program include a nonexclusive, non-transferable, irrevocable worldwide license to use inventions for any governmental purpose. In addition, the
U.S. government has the right to require us, or an assignee or exclusive licensee to such inventions, to grant licenses to any of these inventions to a third
party if the U.S. government determines that adequate steps have not been taken to commercialize the invention, that government action is necessary to
meet public health or safety needs, that government action is necessary to meet requirements for public use under federal regulations, or that the right to use
or sell such inventions is exclusively licensed to an entity within the U.S. and substantially manufactured outside the U.S. without the U.S. government’s
prior approval. Additionally, we may be restricted from granting exclusive licenses for the right to use or sell our inventions created pursuant to such
agreements unless the licensee agrees to additional restrictions (e.g., manufacturing substantially all of the invention in the U.S.). The U.S. government also
has the right to take title to these inventions if we fail to disclose the invention to the government and fail to file an application to register the intellectual
property within specified time limits. In addition, the U.S. government may acquire title in any country in which a patent application is not filed within
specified time limits. Additionally, certain inventions are subject to transfer restrictions during the term of these agreements and for a period thereafter,
including sales of products or components, transfers to foreign subsidiaries for the purpose of the relevant agreements, and transfers to certain foreign third
parties. If any of our intellectual property becomes subject to any of the rights or remedies available to the U.S. government or third parties pursuant to the
Bayh-Dole Act of 1980, this could impair the value of our intellectual property and could adversely affect our business. The U.S. government has not
exercised any of these rights or provided us with any notice of its intent to exercise any of these rights with respect to any of the intellectual property
licensed to us by MD Anderson. We are not aware of any instance in which the U.S. government has ever exercised any such rights with respect to any
technologies or other intellectual property developed under funding agreements with the U.S. government.
Our Phase I/II Clinical Trial combining Oncoprex with erlotinib is being conducted at MD Anderson pursuant to our Clinical Study Agreement
with MD Anderson dated February 10, 2014. Under this agreement, MD Anderson agreed to conduct the Phase I/II Combination Trial under the study
protocol, which includes treatment of up to 57 patients, and we agreed to pay up to $1,738,818 to MD Anderson for conducting the clinical trial. As of
December 31, 2019, we have paid approximately $530,000 to MD Anderson pursuant to this agreement, and a total of 28 patients have been enrolled in the
Phase I/II Combination Trial. This Clinical Study Agreement has a term of five years and may be terminated earlier by us upon thirty days’ notice, with due
regard for the health and safety of the study subjects. In addition, we and MD Anderson may terminate the Clinical Study Agreement immediately by
written agreement, MD Anderson may terminate the agreement immediately if the principal investigator of the Phase I/II Combination Trial is unable to
continue to serve and we and MD Anderson cannot agree on an acceptable successor, and either we or MD Anderson may terminate the agreement if
necessary for the safety, health or welfare of the clinical trial subjects. Given that we have received an FDA Fast Track Designation for the combination of
Oncoprex with osimertinib, we do not plan to continue enrolling patients in the Phase I/II clinical trial combining Oncoprex with erlotinib. This Clinical
Study Agreement remains in effect, however, as activities such and following patients and accumulating data are ongoing.
31
In January 2015, we entered into an option agreement with MD Anderson. This option agreement, which was renewed in July 2018, grants
exclusive rights to us to negotiate, until March 13, 2019, an exclusive license agreement related to patents covering both a method for treating cancer and
biomarker technology that would allow us to identify patients who might benefit from this treatment. We have paid MD Anderson a total of $35,000 for
this option agreement. We are negotiating with MD Anderson to extend the term of this option agreement.
In February 2017, we entered into a second option agreement with MD Anderson. This option agreement, which was renewed in July 2018, grants
exclusive rights to us to negotiate, until December 31, 2019, an exclusive license agreement related to technology that would provide patent protection for
the use of TUSC2 with checkpoint inhibitors. We paid MD Anderson a total of $37,803 for this option agreement. We are negotiating with MD Anderson
to extend the term of this option.
License Agreement with P53, Inc.
On February 26, 2010, IRI and P53, Inc. entered into a Technology License Agreement (P53 License Agreement) pursuant to which IRI granted to
P53, Inc. (P53) a worldwide, exclusive license under certain patents related to the nanovesicle delivery system that we are now using for the delivery of
TUSC2, but only for P53’s use in gene therapy products in which the sole active genes are p53 and MDA-7. As a result of the 2009 IRI Collaboration
Agreement, we are the licensor under the P53 License Agreement.
The P53 License Agreement authorizes P53 to develop, make and have made, use, offer for sale, sell, import and otherwise distribute the licensed
products. P53 agreed to submit quarterly reports of activities to IRI including at least such information as would allow IRI to calculate the amount owing to
IRI on account of such activities, as well as P53’s calculation of such amounts. As consideration for the P53 License Agreement, P53 agreed to pay IRI
one-half of all amounts invoiced by MD Anderson to IRI, up to a maximum of $15,000 to be paid by P53, for patent prosecution expenses incurred prior to
the effective date of the P53 License Agreement, as well as two-thirds of IRI’s ongoing patent prosecution expenses, in each case with respect to the
licensed patents. Additionally, P53 agreed to pay all amounts that become due to IRI as a result of the P53 License Agreement or the sales, licensing, or
other activities of P53 under the P53 License Agreement. Pursuant to the P53 License Agreement, P53 has granted to IRI a fully-paid license with respect
to improvements made by P53 to the technology licensed to P53 under the P53 License Agreement. The P53 License Agreement remains in effect until the
expiration of the last of the patents licensed under the agreement. The last licensed patent under the P53 License Agreement will expire in May 2020. We
may terminate the agreement for, among other things, P53’s breach of the agreement or if P53 challenges the validity or enforceability of any of the
licensed patents. P53 may terminate the agreement upon 90 days’ written notice.
License Agreement with University of Pittsburgh - Of the Commonwealth System of Higher Education
On February 11, 2020, we signed an exclusive license agreement (the “UP License Agreement”) with the University of Pittsburgh - Of the
Commonwealth System of Higher Education (“UP”) pursuant to which UP granted us a worldwide, exclusive license to certain Licensed Technology (as
defined in the UP License Agreement), and a worldwide, non-exclusive license to use certain related know-how, all related to diabetes gene therapy. The
UP License Agreement permits us to make, have made, use and sell the Licensed Technology and to practice the patent rights in the field of diabetes
therapy. We have agreed to sell the Licensed Technology to UP upon its request on terms and conditions as such products and/or processes are made
available to our most favored customer. As consideration for the UP License Agreement, we agreed to pay UP an initial license fee, annual maintenance
fees, running royalties minimum annual royalties beginning with the first commercial sale of the Licensed Technology, a share of non-royalty sublicense
income, and certain milestone payments, as well as patent prosecution expenses incurred prior to and after the effective date of the UP License Agreement.
The UP License Agreement shall remain in effect until the later of 20 years after the first commercial sale of the Licensed Technology or the expiration of
the last Valid Claim (as defined in the UP License Agreement). UP may terminate the agreement if, among other things, (i) we fail to cure a default, (ii) if
we fail to achieve the specified milestones within the specified time periods or (iii) our intentional practice of the licensed Patent Rights (as defined in the
UP License Agreement) or know-how outside the field of diabetes therapy. We may terminate the UP License Agreement upon six months’ prior written
notice to UP and payment of all amounts accrued or due to UP through the effective date of termination.
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Grants
We have received grants from the following entities: Texas Emerging Technology Fund, the SBIR, the NIH, and the United States Department of
the Treasury.
Competition
The biotechnology and pharmaceutical industries are intensely competitive and subject to rapid and significant technological change. We have
domestic and international competitors including major multinational pharmaceutical companies, established biotechnology companies, specialty
pharmaceutical and generic drug companies and universities and other research institutions. Smaller or early-stage companies may also prove to be
significant competitors, particularly through collaborative arrangements with large and established companies.
The unmet medical need for more effective cancer therapies is such that anticancer drugs are, by a significant margin, the leading class of drugs in
development. These include a wide array of products against cancer targeting many of the same indications as our drug candidates. There are a number of
drugs approved and under development for treatment of lung cancer. Treatments competitive with our primary product candidates generally fall into the
following categories: chemotherapies such as cisplatin, carboplatin, docetaxel and pemetrexed; targeted therapies such as erlotinib, gefitinib, afatinib and
osimertinib, and immunotherapies such as checkpoint inhibitors and CAR and CAR T cells, and oncolytic virus-based technology. Data indicate that
Oncoprex, when combined with targeted therapies and immunotherapies, may enhance the benefit of those therapies; therefore, we believe that Oncoprex
could be administered in combination with targeted therapies and immunotherapies and thus may not be a direct competitor of those drugs. In addition, new
drug candidates are constantly being conceived and developed. Any such competing therapy may be more effective and/or cost-effective than ours.
Many of our competitors have greater financial and other resources, such as larger research and development staff and more experienced
marketing and manufacturing organizations than we do. Large pharmaceutical companies, in particular, have extensive experience in clinical testing,
obtaining regulatory approvals, recruiting patients and manufacturing pharmaceutical products. These companies also have significantly greater research,
sales and marketing capabilities and collaborative arrangements in our target markets with leading companies and research institutions. Established
pharmaceutical companies may also invest heavily to accelerate discovery and development of novel compounds or to in-license novel compounds that
could make the product candidates that we develop obsolete. As a result of these factors, our competitors may succeed in obtaining patent protection and/or
FDA approval or discovering, developing and commercializing drugs for the cancer indications that we are targeting before we do or may develop drugs
that are deemed to be more effective or gain greater market acceptance than ours. Smaller or early-stage companies may also prove to be significant
competitors, particularly through collaborative arrangements with large, established companies. In addition, many universities and private and public
research institutes may become active in our target disease areas. Our competitors may succeed in developing, acquiring or licensing on an exclusive basis,
technologies and drug products that are more effective or less costly than any product candidates that we are currently developing or that we may develop,
which could render our products obsolete or noncompetitive. Any product candidates that we successfully develop and commercialize may compete with
existing and new therapies that may become available in the future. The availability of reimbursement from government and other third-party payers will
also significantly affect the pricing and competitiveness of our products.
Our commercial opportunities could be substantially limited in the event that our competitors develop and commercialize products that are more
effective, safer, less toxic, more convenient or less expensive than our comparable products. In geographies that are critical to our commercial success,
competitors may also obtain regulatory approvals before us, resulting in our competitors building a strong market position in advance of our product’s
entry. We believe the competitive factors that will determine the success of our programs will be the efficacy, safety, pricing and reimbursement, and
convenience of our current and potential product candidates.
33
Government Regulation
Government authorities in the U.S., at the federal, state and local level, and other countries extensively regulate, among other things, the research,
development, testing, manufacture, quality control, approval, labeling, packaging, storage, recordkeeping, promotion, advertising, distribution, post-
approval monitoring and reporting, marketing and export and import of products such as those we are developing. The pharmaceutical drug product
candidates that we develop must be approved by the FDA before they may be legally marketed.
In the United States, the FDA regulates pharmaceutical products under the Federal Food, Drug and Cosmetic Act and implementing regulations.
Pharmaceutical products are also subject to other federal, state and local statutes and regulations, including but not limited to the Public Health Service Act.
The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations
require the expenditure of substantial time and financial resources. Failure to comply with the applicable U.S. requirements at any time during the product
development process, the approval process or after approval, may subject an applicant to administrative or judicial sanctions. FDA sanctions could include
refusal to approve pending applications, withdrawal of an approval, a clinical hold, warning letters, product recalls, product seizures, total or partial
suspension of production or distribution injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties. Any
agency or judicial enforcement action could have a material adverse effect on us.
Within the FDA, the Center for Biologics Evaluation and Research (CBER) regulates gene therapy products. CBER works closely with the
NIH and its Novel and Exception Technology and Research Advisory Committee (NExTRAC) which makes recommendations to the NIH on gene therapy
issues and engages in a public discussion of scientific, safety, ethical and societal issues related to proposed and ongoing gene therapy protocols. The FDA
and the NIH have published guidance documents with respect to the development and submission of gene therapy protocols, including informed consent
documents. The FDA also has published guidance documents related to, among other things, gene therapy products in general, their preclinical assessment,
observing patients involved in gene therapy studies for delayed adverse events, potency testing, and chemistry, manufacturing and control information in
gene therapy Investigational New Drugs (INDs).
Ethical, social, and legal concerns about gene therapy, genetic testing, and genetic research could result in additional regulations restricting or
prohibiting the processes we may use. Federal and state agencies, congressional committees and foreign governments have expressed interest in further
regulating biotechnology. More restrictive regulations or claims that our products are unsafe or pose a hazard could prevent us from commercializing any
products. New government requirements may be established that could delay or prevent regulatory approval of our current and potential product candidates
under development. It is impossible to predict whether legislative changes will be enacted, regulations, policies, or guidance changed, or interpretations by
agencies or courts changed, or what the impact of such changes, if any, may be.
U.S. Biological Products Development Process
The process required by the FDA before a biological product, including our Oncoprex product candidate, may be marketed in the United States
generally involves the following:
•
•
•
•
•
•
•
completion of preclinical laboratory tests and animal studies according to Good Laboratory Practices (GLPs), and applicable requirements
for the humane use of laboratory animals or other applicable regulations;
submission to the FDA of an application for an IND, which must become effective before human clinical trials may begin;
performance of adequate and well-controlled human clinical trials according to the FDA’s regulations, commonly referred to as Good
Clinical Practices (GCPs) and any additional requirements for the protection of human research patients and their health information, to
establish the safety, purity, and potency of the proposed biological product for its intended use;
submission to the FDA of a BLA for marketing approval that includes substantive evidence of safety, purity, and potency from results of
nonclinical testing and clinical trials;
satisfactory completion of an FDA inspection of the manufacturing facility or facilities where the product is produced and tested to assess
compliance with GMP requirements to assure that the facilities, methods and controls are adequate to preserve the product’s identity,
strength, quality and purity;
potential FDA audit of the nonclinical and clinical trial sites that generated the data in support of the BLA; and
FDA review and approval, or licensure, of the BLA.
34
Before testing any product candidate, including a gene therapy product, in humans, the product candidate enters the preclinical testing stage.
Preclinical tests, also referred to as nonclinical studies, include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal
studies to assess the potential safety and activity of the product candidate. The conduct of certain preclinical tests must comply with federal regulations and
requirements, including GLPs.
Where a gene therapy study is conducted at, or sponsored by, institutions receiving NIH funding for recombinant DNA research, a protocol and
related documentation has to be submitted to and the clinical trial registered with the NIH Office of Biotechnology Activities, or OBA, pursuant to the NIH
Guidelines for Research Involving Recombinant DNA Molecules, or NIH Guidelines. Compliance with the NIH Guidelines is mandatory for investigators
at institutions receiving NIH funds for research involving recombinant DNA; however, many companies and other institutions not otherwise subject to the
NIH Guidelines voluntarily follow them. The NIH is responsible for convening the NExTRAC, a federal advisory committee, which discusses protocols
that raise novel or particularly important scientific, safety or ethical considerations at one of its quarterly public meetings. Current NIH guidelines specify
that, for experiments involving the deliberate transfer of recombinant or synthetic nucleic acid molecules, or DNA or RNA derived from recombinant or
synthetic nucleic acid molecules, into human research participants, no human gene transfer experiment shall be initiated until Institutional Biosafety
Committee approval (from the clinical trial site) has been obtained and all other applicable institutional and regulatory authorization(s) and approvals have
been obtained. The guidelines also specify that NExTRAC review of human gene transfer protocols should be limited to cases in which an oversight body,
such as an Institutional Biosafety Committee or an IRB determines that a protocol would significantly benefit from NExTRAC review, and has been
determined to meet certain additional criteria. The Office of Science Policy (OSP) will notify the FDA and the sponsor of the NExTRAC’s decision
regarding the necessity for full public review of a gene therapy protocol. NExTRAC proceedings and reports are posted to the OSP web site and may be
accessed by the public.
The clinical trial sponsor must submit the results of the preclinical tests, together with manufacturing information, analytical data, any available
clinical data or literature and a proposed clinical protocol, to the FDA as part of the IND. Some preclinical testing may continue even after the IND is
submitted. The IND automatically becomes effective 30 days after receipt by the FDA, unless the FDA places the clinical trial on a clinical hold within that
30-day time period. In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin. With gene
therapy protocols, if the FDA allows the IND to proceed, but the NExTRAC decides that full public review of the protocol is warranted, the FDA will
request at the completion of its IND review that sponsors delay initiation of the protocol until after completion of the NExTRAC review process. The FDA
may also impose clinical holds on a product candidate at any time before or during clinical trials due to safety concerns or non-compliance. If the FDA
imposes a clinical hold, trials may not recommence without FDA authorization and then only under terms authorized by the FDA. We are conducting a
Phase I/II clinical trial pursuant to an IND. However, we cannot be sure that issues will not arise that suspend or terminate our IND or that submission of
any new IND will result in the FDA allowing new clinical trials to begin, or that, once begun, issues will not arise that suspend or terminate such trials.
Clinical trials involve the administration of the product candidate to volunteers or patients under the supervision of qualified investigators,
generally physicians not employed by or under the clinical trial sponsor’s control. Clinical trials are conducted under protocols detailing, among other
things, the objectives of the clinical trial, dosing procedures, patient selection and exclusion criteria, and the parameters to be used to monitor patient safety,
including stopping rules that assure a clinical trial will be stopped if certain adverse events occur. Each protocol and any amendments to the protocol must
be submitted to the FDA as part of the IND. Clinical trials must be conducted and monitored in accordance with the FDA’s regulations comprising the GCP
requirements, including the requirement that all patients provide informed consent. Further, each clinical trial must be reviewed and approved by an
independent IRB at or servicing each institution at which the clinical trial will be conducted. An IRB is charged with protecting the welfare and rights of
clinical trial participants and considers such items as whether the risks to individuals participating in the clinical trials are minimized and are reasonable in
relation to anticipated benefits. The IRB also approves the form and content of the informed consent, which must be signed by each clinical trial patient or
his or her legal representative, and must monitor the clinical trial until completed. Clinical trials involving biological product candidates also must be
reviewed by an institutional biosafety committee (IBC) a local institutional committee that reviews and oversees basic and clinical research conducted at
that institution. The IBC assesses the safety of the research and identifies any potential risk to public health or the environment.
35
Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:
•
•
•
Phase I. The investigational product candidate is initially introduced into human patients and tested for safety. In the case of some products
for severe or life-threatening diseases, especially when the product candidate may be inherently too toxic to be ethically administered to
healthy volunteers, the initial human testing is often conducted in patients; gene therapy is usually administered to patients in Phase I trials.
This is also true in situations where toxicity can only be judged in patients with disease. An evaluation for preliminary evidence of efficacy
can be performed at this time.
Phase II. The investigational product candidate is evaluated in a limited patient population to identify possible adverse effects and safety
risks, to evaluate preliminarily the efficacy of the product candidate for specific targeted diseases, and to generate hypotheses for the dosage
tolerance, optimal dosage, and dosing schedule.
Phase III. Clinical trials are undertaken to evaluate further dosage, clinical efficacy, potency, and safety in an expanded patient population at
geographically dispersed clinical trial sites. These clinical trials are intended to establish the overall risk/benefit ratio of the product
candidate and provide an adequate basis for product labeling.
Post-approval clinical trials, sometimes referred to as Phase IV clinical trials, may be conducted after initial marketing approval. These clinical
trials are used to gain additional experience from the treatment of patients in the intended therapeutic indication, particularly for long-term safety follow-
up. The FDA recommends that sponsors observe patients for potential gene therapy-related delayed adverse events with agents such as those we are
developing for a period of up to 15 years, including a minimum of five years of annual examinations followed by ten years of annual queries, either in
person or by questionnaire, of clinical trial patients.
During all phases of clinical development, regulatory agencies require extensive monitoring and auditing of all clinical activities, clinical data, and
clinical trial investigators. Annual progress reports detailing the results of the clinical trials must be submitted to the FDA. Written IND safety reports must
be promptly submitted to the FDA, the NIH and the investigators for serious and unexpected adverse events, any findings from other trials, tests in
laboratory animals or in vitro testing that suggest a significant risk for human patients, or any clinically important increase in the rate of a serious suspected
adverse reaction over that listed in the protocol or investigator brochure. The sponsor must submit an IND safety report within 15 calendar days after the
sponsor determines that the information qualifies for expedited reporting. The sponsor must also notify the FDA of any unexpected fatal or life-threatening
suspected adverse reaction within seven calendar days after the sponsor’s initial receipt of the information. Phase I, Phase II and Phase III clinical trials
may not be completed successfully within any specified period, if at all. The FDA, the sponsor, or its data safety monitoring board may suspend a clinical
trial at any time on various grounds, including a finding that the patients are being exposed to an unacceptable health risk. Similarly, an IRB can suspend or
terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the
investigational product candidate has been associated with unexpected serious harm to patients.
There are also requirements governing the reporting of ongoing clinical trials and completed clinical trial results to public registries. Sponsors of
clinical trials of FDA-regulated products, including biologics, are required to register and disclose certain clinical trial information, which is publicly
available at www.clinicaltrials.gov. Information related to the product, patient population, phase of investigation, study sites and investigators, and other
aspects of the clinical trial is then made public as part of the registration. Sponsors are also obligated to discuss the results of their clinical trials after
completion. Disclosure of the results of these trials can be delayed until the new product or new indication being studied has been approved. The NIH and
the FDA have a publicly accessible database, the Genetic Modification Clinical Research Information System, which includes information on gene therapy
trials and serves as an electronic tool to facilitate the reporting and analysis of adverse events on these trials.
Concurrently with clinical trials, companies usually complete additional animal studies and also develop additional information about the physical
characteristics of the components of a product as well as finalize processes for manufacturing the components in commercial quantities in accordance with
GMP requirements. To help reduce the risk of the introduction of adventitious agents with use of biological products, the Public Health Service Act (PHS
Act), emphasizes the importance of manufacturing control for products whose attributes cannot be precisely defined. The manufacturing process must be
capable of consistently producing quality batches of the product candidate and, among other things, the sponsor must develop methods for testing the
identity, strength, quality, potency and purity of the final product. Additionally, appropriate packaging must be selected and tested and stability studies must
be conducted to demonstrate that the components of a product candidate do not undergo unacceptable deterioration over their shelf life.
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U.S. Review and Approval Processes
After the completion of clinical trials of an investigational biologic product, FDA approval of a BLA must be obtained before commercial
marketing of the product may begin. The BLA must include results of product development, laboratory, and animal studies, human trials, information on
the manufacture and composition of the product, proposed labeling and other relevant information. The testing and approval processes require substantial
time and effort and there can be no assurance that the FDA will accept the BLA for filing and, even if filed, that any approval will be granted on a timely
basis, if at all.
Under the Prescription Drug User Fee Act, as amended (PDUFA), each BLA must be accompanied by a significant user fee. The FDA adjusts the
PDUFA user fees on an annual basis. PDUFA also imposes annual product fees and annual establishment fees on facilities used to manufacture prescription
drugs or biologics. Fee waivers or reductions are available in certain circumstances, including a waiver of the application fee for the first application filed
by a small business. No user fees are assessed on BLAs for products designated as orphan drugs, unless the application also includes a non-orphan
indication.
Within 60 days following submission, the FDA reviews the BLA to determine if it is substantially complete before the agency accepts it for filing.
The FDA may refuse to file any BLA that it deems incomplete or not properly reviewable at the time of submission and may request additional
information.
In this event, the BLA must be resubmitted with the additional information. The resubmitted application also is subject to an initial filing review
before the FDA accepts it for filing. Once the submission is accepted for filing, the FDA begins an in-depth substantive review of the BLA. The FDA
reviews the BLA to determine, among other things, whether the proposed product is safe and potent, or effective, for its intended use, and has an acceptable
purity profile, and whether the product is being manufactured in accordance with GMP to assure and preserve the product’s identity, safety, strength,
quality, potency and purity. The FDA may refer applications for novel products or products that present difficult questions of safety or efficacy to an
advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application
should be approved and under what conditions. The FDA is not bound by the recommendations of an advisory committee, but it considers such
recommendations when making decisions. During the product approval process, the FDA also will determine whether a Risk Evaluation and Mitigation
Strategy (REMS) is necessary to assure the safe use of the product. If the FDA concludes that a REMS is needed, the sponsor of the BLA must submit a
proposed REMS; the FDA will not approve the BLA without a REMS, if required.
Before approving a BLA, the FDA will inspect the facilities at which the product is manufactured. The FDA will not approve the product unless it
determines that the manufacturing processes and facilities are in substantial compliance with GMP requirements and adequate to assure consistent
production of the product within required specifications. Additionally, before approving a BLA, the FDA will typically inspect one or more clinical sites, to
assure that the clinical trials were conducted in compliance with GCP requirements. To assure GMP, GLP and GCP compliance, an applicant must incur
significant expenditure of time, money, and effort in the areas of training, record keeping, production, and quality control.
Notwithstanding the submission of relevant data and information, the FDA may ultimately decide that the BLA does not satisfy its regulatory
criteria for approval and deny approval. Data obtained from clinical trials are not always conclusive and the FDA may interpret data differently from how
we interpret the same data. If the agency decides not to approve the BLA in its present form, the FDA will issue a complete response letter that usually
describes all of the specific deficiencies in the BLA identified by the FDA. The deficiencies identified may be minor, for example, requiring labeling
changes, or major, for example, requiring additional clinical trials. Additionally, the complete response letter may include recommended actions that the
applicant might take to place the application in a condition for approval. If a complete response letter is issued, the applicant may resubmit the BLA,
addressing all of the deficiencies identified in the letter, withdraw the application, or request a hearing.
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If a product candidate receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications
for use may otherwise be limited, which could restrict the commercial value of the product. Further, the FDA may require that certain contraindications,
warnings, or precautions be included in the product labeling. The FDA may impose restrictions and conditions on product distribution, prescribing, or
dispensing in the form of a risk management plan, or otherwise limit the scope of any approval. In addition, the FDA may require post marketing clinical
trials, sometimes referred to as Phase IV clinical trials, designed to assess further a biological product’s safety and effectiveness, and testing and
surveillance programs to monitor the safety of approved products that have been commercialized.
One of the performance goals agreed to by the FDA under the PDUFA is to review 90% of original standard BLAs within 10 months of the 60 day
filing date and 90% of original priority BLAs within six months of the 60 day filing date, whereupon a review decision is to be made. The FDA does not
always meet its PDUFA goal dates for standard and priority BLAs and its review goals are subject to change from time to time. The review process and the
PDUFA goal date may be extended by three months if the FDA requests or the BLA sponsor otherwise provides additional information or clarification
regarding information already provided in the submission within the last three months before the PDUFA goal date.
Orphan Drug Designation
Under the Orphan Drug Act, the FDA may grant orphan designation to a drug or biological product intended to treat a rare disease or condition,
which is generally a disease or condition that affects fewer than 200,000 individuals in the United States, or more than 200,000 individuals in the United
States for which there is no reasonable expectation that the cost of developing and making a drug or biological product available in the United States for
this type of disease or condition will be recovered from sales of the product. Orphan product designation must be requested before submitting a BLA. After
the FDA grants orphan product designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA. Orphan
product designation does not convey any advantage in or shorten the duration of the regulatory review and approval process. There can be no assurance that
we will receive Orphan-Drug Designation for any indications or for any of our current and potential product candidates.
If a product candidate that has orphan designation subsequently receives the first FDA approval for the disease or condition for which it has such
designation, the product is entitled to orphan product exclusivity, which means that the FDA may not approve any other applications to market the same
drug or biological product for the same indication for seven years, except in limited circumstances, such as a showing of clinical superiority to the product
with orphan exclusivity. Competitors, however, may receive approval of different products for the indication for which the orphan product has exclusivity
or obtain approval for the same product but for a different indication for which the orphan product has exclusivity. Orphan product exclusivity also could
block the approval of one of our product candidates for seven years if a competitor obtains approval of the same biological product as defined by the FDA
or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease. If a drug or biological product
designated as an orphan product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan productivity
exclusivity. Orphan drug status in the European Union has similar, but not identical benefits.
Expedited Development and Review Programs
The FDA has four programs in place intended to facilitate and expedite development and review of new drugs and biologics intended to address
unmet medical needs in the treatment of serious or life-threatening conditions. These are Fast Track Designation, Breakthrough Therapy Designation,
Accelerated Approval Program, and Priority Review Designation.
The Fast Track program is intended to expedite or facilitate the process for reviewing a new product if it is intended for the treatment of a serious
or life-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition. Fast Track
Designation applies to the combination of the product and the specific indication for which it is being studied. The sponsor of a new drug or biologic may
request the FDA to designate the drug or biologic as a Fast Track product at any time during the clinical development of the product. Unique to a Fast
Track product, the FDA may consider for review sections of the marketing application on a rolling basis before the complete application is submitted, if the
sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections of the application and determines that
the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application. In January, 2020, we
received a United States FDA Fast Track Designation for use of Oncoprex™ in combination with EGFR inhibitor osimertinib (AstraZeneca’s Tagrisso®)
for the treatment of NSCLC patients with EFGR mutations that progressed after treatment with osimertinib alone.
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A new product can receive Breakthrough Therapy Designation if it is intended, alone or in combination with one or more other drugs, to treat a
serious or life-threatening disease or condition and preliminary clinical evidence indicates that it may demonstrate substantial improvement over existing
therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. A Breakthrough
Therapy Designation conveys all of the features of Fast Track Designation in addition to more intensive FDA guidance on an efficient development
program, organizational commitment involving senior managers, and eligibility for priority review. Specifically, FDA intends to expedite the development
and review of a Breakthrough Therapy by, where appropriate, intensively involving senior managers and experienced review staff in a proactive
collaborative, cross-disciplinary review. Where appropriate, FDA also intends to assign a cross-disciplinary project lead for the review team to facilitate an
efficient review of the development program. The FDA notes that a compressed drug development program still must generate adequate data to
demonstrate that the drug or biologic meets the statutory standard for approval. Omitting components of the development program that are necessary for
such a determination can significantly delay, or even preclude, marketing approval.
Breakthrough Therapy Designation indicates that preliminary clinical evidence demonstrates the drug may have substantial improvement on one
or more clinically significant endpoints over available therapy. Breakthrough Therapy Designation intensifies FDA involvement to ensure an efficient drug
development program and is an organizational commitment from the FDA to involve its senior managers. A sponsor receiving Breakthrough Therapy
Designation has up to six months after receiving the Breakthrough Therapy Designation to request an Initial Comprehensive Multidisciplinary meeting to
discuss the drug development program. This initial meeting is a Type B meeting, used to discuss the overarching, high-level plan for drug development.
These discussions include topics such as planned clinical trials and endpoints, any resizing or adaptations to the trials, plans for expediting the
manufacturing development strategy and studies that potentially could be completed after approval. When Breakthrough Therapy Designation has been
granted, the FDA is encouraged to meet regularly with the sponsor and subsequent meetings are considered Type B meetings and are established based on
the needs of the program.
The FDA may grant accelerated approval under its Accelerated Approval Program to a product candidate for a serious or life-threatening
condition upon a determination that the product candidate has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or an
effect on a clinical endpoint that can be measured earlier than an effect on irreversible morbidity or mortality, that is reasonably likely to predict an effect
on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or
lack of alternative treatments. Accelerated approval is usually contingent on a sponsor’s agreement to conduct adequate and well-controlled additional post-
approval trials to verify and describe the product’s clinical benefit. In addition, the FDA currently requires as a condition for accelerated approval pre-
approval of promotional materials, which could adversely impact the timing of the commercial launch of the product.
Fast Track Designation, Breakthrough Therapy Designation, and Accelerated Approval do not change the standards for approval but may expedite
the development process.
An application for a product candidate may be eligible to obtain Priority Review Designation if it is intended to treat a serious condition and, if
approved, would provide a significant improvement in safety or effectiveness. The FDA will attempt to direct additional resources to the evaluation of an
application for a new product designated for priority review in an effort to facilitate the review. A Priority Review Designation means FDA’s goal is to take
action on the marketing application within six months (compared to 10 months under standard review) of the 60-day filing date. Priority Review
Designation does not change the standards for approval but may expedite the review process.
Post-Approval Requirements
Maintaining post-approval compliance with applicable federal, state, and local statutes and regulations requires the expenditure of substantial time
and financial resources. Rigorous and extensive FDA regulation of combination products continues after approval, particularly with respect to GMP. We
rely, and expect to continue to rely, on third parties for the production and distribution of clinical and commercial quantities of any products that we may
commercialize. Manufacturers of our products are required to comply with applicable requirements in the GMP regulations, including quality control and
quality assurance and maintenance of records and documentation. Other post-approval requirements include reporting of GMP deviations that may affect
the identity, potency, purity and overall safety of a distributed product, record-keeping requirements, reporting of adverse effects, reporting updated safety
and efficacy information, and complying with electronic record and signature requirements. After a BLA is approved, the product also may be subject to
official lot release. As part of the manufacturing process, the manufacturer is required to perform certain tests on each lot of the product before it is released
for distribution. If the product is subject to official release by the FDA, the manufacturer submits samples of each lot of product to the FDA together with a
release protocol showing a summary of the history of manufacture of the lot and the results of all of the manufacturer’s tests performed on the lot. The FDA
also may perform certain confirmatory tests on lots of some products before releasing the lots for distribution by the manufacturer.
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We also must comply with the FDA’s advertising and promotion requirements, such as those related to direct-to-consumer advertising, the
prohibition on promoting products for uses or in patient populations that are not described in the product’s approved labeling (known as “off-label use”),
industry-sponsored scientific and educational activities, and promotional activities involving the internet. Discovery of previously unknown problems or
the failure to comply with the applicable regulatory requirements may result in restrictions on the marketing of a product or withdrawal of the product from
the market as well as possible civil or criminal sanctions. Failure to comply with the applicable U.S. requirements at any time during the product
development process, approval process or after approval, may subject an applicant or manufacturer to administrative or judicial civil or criminal sanctions
and adverse publicity. FDA sanctions could include refusal to approve pending applications, withdrawal of an approval, clinical hold, warning or untitled
letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts,
mandated corrective advertising or communications with doctors, debarment, restitution, disgorgement of profits, or civil or criminal penalties. Any agency
or judicial enforcement action could have a material adverse effect on us.
Manufacturers and other entities involved in the manufacture and distribution of approved products are required to register the establishments
where the approved products are made with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and
certain state agencies for compliance with GMP and other laws. Accordingly, manufacturers must continue to expend time, money, and effort in the area of
production and quality control to maintain GMP compliance. Discovery of problems with a product after approval may result in restrictions on a product,
manufacturer, or holder of an approved BLA, including withdrawal of the product from the market. In addition, changes to the manufacturing process or
facility generally require prior FDA approval before being implemented. Other types of changes to the approved product, such as adding new indications
and additional labeling claims, are also subject to further FDA review and approval.
U.S. Patent Term Restoration
Depending upon the timing, duration, and specifics of the FDA approval of the use of our current and potential product candidates, some of our
U.S. patents may be eligible for limited patent term extension under the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman
Amendments). The Hatch-Waxman Amendments permit a patent restoration term of up to five years as compensation for patent term lost during product
development and the FDA regulatory review process. However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14
years from the product’s approval date. The patent term restoration period is generally one-half the time between the effective date of an IND and the
submission date of a BLA plus the time between the submission date of a BLA and the approval of that application. Only one patent applicable to an
approved biological product is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent. The
U.S. Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.
Biosimilars and Exclusivity
The Biologics Price Competition and Innovation Act of 2009 (BPCIA) created an abbreviated approval pathway for biological products shown to
be highly similar to, or interchangeable with, an FDA-licensed reference biological product. The FDA has issued several guidance documents outlining an
approach to review and approval of biosimilars.
Biosimilarity, which requires that there be no clinically meaningful differences between the biological product and the reference product in terms
of safety, purity, and potency, can be shown through analytical studies, animal studies, and a clinical study or studies. Interchangeability requires that a
product is biosimilar to the reference product and the product must demonstrate that it can be expected to produce the same clinical results as the reference
product in any given patient and, for products that are administered multiple times to an individual, the biologic and the reference biologic may be
alternated or switched after one has been previously administered without increasing safety risks or risks of diminished efficacy relative to exclusive use of
the reference biologic. However, complexities associated with the larger, and often more complex, structures of biological products, as well as the
processes by which such products are manufactured, pose significant hurdles to implementation of the abbreviated approval pathway that are still being
worked out by the FDA.
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The BPCIA includes, among other provisions:
•
•
•
A 12-year exclusivity period from the date of first licensure of the reference product, during which approval of a 351(k) application
referencing that product may not be made effective;
A four-year exclusivity period from the date of first licensure of the reference product, during which a 351(k) application referencing that
product may not be submitted; and
An exclusivity period for certain biological products that have been approved through the 351(k) pathway as interchangeable biosimilars.
The BPCIA also establishes procedures for identifying and resolving patent disputes involving applications submitted under section 351(k) of the
PHS Act.
A biological product can also obtain pediatric market exclusivity in the United States. Pediatric exclusivity, if granted, adds six months to existing
exclusivity periods and patent terms. This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted
based on the voluntary completion of a pediatric clinical trial in accordance with an FDA-issued “Written Request” for such a clinical trial.
The BPCIA is complex and its interpretation and implementation by the FDA remains unpredictable. In addition, government proposals have
sought to reduce the 12-year reference product exclusivity period. Other aspects of the BPCIA, some of which may impact the BPCIA exclusivity
provisions, have also been the subject of recent litigation. As a result, the ultimate effect, implementation, and meaning of the BPCIA is subject to
uncertainty.
Additional U.S. Regulation
In the United States, our activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA,
including but not limited to, the Centers for Medicare and Medicaid Services (CMS), other divisions of the U.S. Department of Health and Human
Services, for instance the Office of Inspector General, the U.S. Department of Justice (DOJ), and individual U.S. Attorney offices within the DOJ, and state
and local governments. For example, sales, marketing and scientific/educational grant programs must comply with the anti-fraud and abuse provisions of
the Social Security Act, the false claims laws, the physician payment transparency laws, the privacy and security provisions of the Health Insurance
Portability and Accountability Act (HIPAA), as amended by the Health Information Technology for Economic and Clinical Health Act (HITECH) and
similar state laws, each as amended.
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational
Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, may affect our business. These and other laws
govern our use, handling and disposal of various biological, chemical, and radioactive substances used in, and wastes generated by, our operations. If our
operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental
fines. We believe that we are in material compliance with applicable environmental laws and that continued compliance therewith is unlikely to have a
material adverse effect on our business. We cannot predict, however, how changes in these laws may affect our future operations.
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Federal and State Fraud and Abuse Laws
In the United States, our activities are potentially subject to regulation by various federal, state and local authorities in addition to the FDA,
including but not limited to, CMS, other divisions of the U.S. Department of Health and Human Services, for instance, the Office of Inspector General,
DOJ, and individual U.S. Attorney offices within the DOJ, and state and local governments. These federal and state laws, which generally will not be
applicable to us or our current and potential product candidates unless and until we obtain FDA marketing approval for any of our current and potential
product candidates, include, among others, anti-kickback statutes, the False Claims Act and related stated state and federal laws, the Stark Law and related
state and federal laws, transparency laws, privacy and regulation regarding providing drug samples, sales and marketing activities and our relationships
with customers and payors as follows.
The federal Anti-Kickback Statute prohibits, among other things, individuals and entities from knowingly and willfully offering, paying,
soliciting, or receiving any remuneration, directly or indirectly, overtly or covertly, to induce or in return for purchasing, leasing, recommending, ordering,
or arranging for the purchase, lease, recommendation or order of any health care item or service reimbursable, in whole or in part, under Medicare,
Medicaid, or other federally financed healthcare programs. This statute has been interpreted to apply to arrangements between pharmaceutical
manufacturers on one hand and prescribers, purchasers, and formulary managers on the other. Although there are a number of statutory exemptions and
regulatory safe harbors protecting certain common activities from prosecution, the exemptions and safe harbors are drawn narrowly, and practices that
involve remuneration that may be alleged to be intended to induce prescribing, purchases or recommendations may be subject to scrutiny if they do not
qualify for an exemption or safe harbor. Additionally, the intent standard under the Anti-Kickback Statute was amended by the Affordable Care Act to a
stricter standard such that a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed
a violation. Further, the Affordable Care Act codified case law that a claim including items or services resulting from a violation of the federal Anti-
Kickback Statute constitutes a false or fraudulent claim for purposes of the federal civil False Claims Act.
HIPAA created additional federal criminal statutes that prohibit, among other actions, knowingly and willfully executing, or attempting to execute,
a scheme to defraud or to obtain, by means of false or fraudulent pretenses, representations or promises, any money or property owned by, or under the
control or custody of, any healthcare benefit program, including private third-party payers, willfully obstructing a criminal investigation of a healthcare
offense, and knowingly and willfully falsifying, concealing or covering up by trick, scheme or device, a material fact or making any materially false,
fictitious or fraudulent statement in connection with the delivery of or payment for healthcare benefits, items or services. Similar to the federal Anti-
Kickback Statute, a person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have committed a
violation.
Federal false claims and civil monetary penalties laws, including the federal civil False Claims Act, prohibit, among other things, any person or
entity from knowingly presenting, or causing to be presented, a false, fictitious or fraudulent claim for payment to, or approval by, the federal government,
or knowingly making, using, or causing to be made or used, a false statement to get a false claim paid. Several pharmaceutical and other health care
companies have been prosecuted under these laws for allegedly providing free product to customers with the expectation that the customers would bill
federal programs for the product. Other companies have been prosecuted for causing false claims to be submitted because of the company’s marketing of
the product for unapproved, and thus non-reimbursable, uses.
The majority of states also have statutes or regulations similar to the federal Anti-Kickback Statute and false claims laws, which apply to items
and services, reimbursed under Medicaid and other state programs, or, in several states, apply regardless of the payer.
We may also be subject to data privacy and security regulations by both the federal government and the states in which we conduct our business.
HIPAA, as amended by HITECH, and their respective implementing regulations, including the final Omnibus Rule published in 2013, imposes
requirements on certain types of entities, including mandatory contractual terms, relating to the privacy, security, and transmission of individually
identifiable health information. Among other things, HITECH makes HIPAA’s security standards and certain privacy standards directly applicable to
business associates, which are independent contractors or agents of covered entities that create, receive, maintain or transmit protected health information
in connection with providing a service for or on behalf of a covered entity. HITECH also created four new tiers of civil monetary penalties, amended
HIPAA to make civil and criminal penalties directly applicable to business associates, and gave state attorneys general new authority to file civil actions for
damages or injunctions in federal courts to enforce the federal HIPAA laws and seek attorneys’ fees and costs associated with pursuing federal civil actions.
In addition, many state laws govern the privacy and security of health information in specified circumstances, many of which differ from each other and
from HIPAA in significant ways and may not have the same requirements, thus complicating compliance efforts.
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Additionally, the federal Physician Payments Sunshine Act under the Affordable Care Act, and its implementing regulations, require that certain
manufacturers of drugs, devices, biological and medical supplies for which payment is available under Medicare, Medicaid or the Children’s Health
Insurance Program, with certain exceptions, annually report to CMS information related to certain payments or other transfers of value made or distributed
to physicians and teaching hospitals, or to entities or individuals at the request of, or designated on behalf of, the physicians and teaching hospitals and to
report annually certain ownership and investment interests held by physicians and their immediate family members. Failure to submit timely, accurately,
and completely the required information may result in civil monetary penalties of up to an aggregate of $150,000 per year and up to an aggregate of $1
million per year for “knowing failures”. Certain states also mandate implementation of compliance programs, impose restrictions on pharmaceutical
manufacturer marketing practices, and/or require the tracking and reporting of gifts, compensation, and other remuneration to healthcare providers and
entities.
Because of the breadth of these laws and the narrowness of the exceptions and safe harbors, it is possible that some of our business activities could
be subject to challenge under one or more of such laws. Such a challenge could have a material adverse effect on our business, financial condition, and
results of operations. If our operations are found to be in violation of any of these or any other health regulatory laws that may apply to us, we may be
subject to, without limitation, significant penalties, including the imposition of significant civil, criminal and administrative penalties, damages, monetary
fines, disgorgement, individual imprisonment, possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs,
contractual damages, reputational harm, diminished profits and future earnings, and curtailment or restructuring of our operations, any of which could
adversely affect our ability to operate our business and our results of operations.
In addition, as part of the sales and marketing process, pharmaceutical companies frequently provide samples of approved products to physicians.
This practice is regulated by the FDA and other governmental authorities, including, in particular, requirements concerning record keeping and control
procedures. Any failure to comply with the regulations may result in significant criminal and civil penalties as well as damage to our credibility in the
marketplace.
Coverage and Reimbursement
In many of the markets where we may do business in the future, the prices of pharmaceutical products are subject to direct price controls (by law)
and to reimbursement programs with varying price control mechanisms. In the United States, significant uncertainty exists as to the coverage and
reimbursement status of any product candidates for which we obtain product approval. Often private payers follow the coverage and reimbursement
decisions of the Medicare program, and it is difficult to predict how CMS may decide to cover and reimburse approved products, especially novel products,
and those determinations are subject to change.
Moreover, the process for determining whether a third-party payer will provide coverage for a drug product may be separate from the process for
setting the price of a drug product or for establishing the reimbursement rate that such a payer will pay for the drug product. Third-party payers may limit
coverage to specific products on an approved list, also known as a formulary, which might not include all of the FDA-approved drugs for a particular
indication. A decision by a third-party payer not to cover our current and potential product candidates could reduce physician utilization of our products
once approved. A payer’s decision to provide coverage for a drug product does not imply that an adequate reimbursement rate will be approved. Further,
one payer’s determination to provide coverage for a drug product does not assure that other payers will also provide coverage for the drug product.
Coverage and reimbursement for new products can differ significantly from payer to payer. As a result, the coverage determination process will require us
to provide scientific and clinical support for the use of our products to each payer separately and will be a time-consuming process. Additionally, third-
party reimbursement may not be available or may not be adequate to enable us to maintain price levels sufficient to realize an appropriate return on our
investment in product development.
Federal, state and local governments in the United States and foreign governments continue to consider legislation to limit the growth of
healthcare costs, including the cost of prescription drugs. Specifically, there have been several recent U.S. Congressional inquiries and proposed federal and
state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the
relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs. Future
legislation could limit payments for pharmaceuticals such as the drug candidates that we are developing.
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Different pricing and reimbursement schemes exist in other countries. In the EU, governments influence the price of drug products through their
pricing and reimbursement rules and control of national health care systems that fund a large part of the cost of those products to consumers. Some
jurisdictions operate systems under which products may be marketed only after a reimbursement price has been agreed. To obtain reimbursement or pricing
approval, some of these countries may require the completion of studies or analyses of clinical trials that compare the cost-effectiveness of a particular
product candidate to currently available therapies. Other member states allow companies to set their own prices for medicines, but exert cost controls in
other ways, including but not limited to, placing revenue caps on product sales, providing reimbursement for only a subset of eligible patients, mandating
price negotiations after a set period of time, or mandating that prices not exceed an average basket of prices in other countries. The downward pressure on
health care costs in general, particularly treatments, has become very intense. As a result, increasingly high barriers are being erected to the entry of new
products. In addition, European governments may periodically review and decrease prices based on factors, including, but not limited to, years-on-market,
price in other countries, competitive entry, new clinical data, lack of supporting clinical data, or other factors.
The marketability of any product candidates for which we or our collaborators receive regulatory approval for commercial sale may suffer if the
government and third-party payers fail to provide adequate coverage and reimbursement. In addition, an emphasis on cost containment measures in the
United States has increased and we expect will continue to increase the pressure on pharmaceutical pricing. Third-party payers are increasingly challenging
the prices charged for medical products and services, examining the medical necessity and reviewing the cost-effectiveness of drugs, medical devices and
medical services, in addition to questioning safety and efficacy. If these third-party payers do not consider our products to be cost-effective compared to
other available therapies, they may not cover our products after FDA approval or, if they do, the level of payment may not be sufficient to allow us to sell
our products at a profit. Coverage policies and third-party reimbursement rates may change at any time. Even if favorable coverage and reimbursement
status is attained for one or more products for which we or our collaborators receive regulatory approval, less favorable coverage policies and
reimbursement rates may be implemented in the future.
Health Care Reform
In March 2010, the Affordable Care Act was enacted, which affected, and may further affect, health care financing and delivery by both
governmental and private insurers, and therefore the pharmaceutical and biotechnology industry. The Affordable Care Act has affected and may continue to
affect existing government healthcare programs and may result in the development of new programs.
Among the Affordable Care Act’s provisions of importance to the pharmaceutical and biotechnology industries, in addition to those otherwise
described above, are the following:
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an annual, nondeductible fee on any entity that manufactures or imports certain specified branded prescription drugs and biologic agents
apportioned among these entities according to their market share in some government healthcare programs;
an increase in the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program, to 23.1% and 13% of the
average manufacturer price for most branded and generic drugs, respectively and capped the total rebate amount for innovator drugs at
100% of the Average Manufacturer Price (AMP);
a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for certain drugs and
biologics, including our current and potential product candidates, that are inhaled, infused, instilled, implanted or injected;
extension of manufacturers’ Medicaid rebate liability to covered drugs dispensed to individuals who are enrolled in Medicaid managed care
organizations;
expansion of eligibility criteria for Medicaid programs by, among other things, allowing states to offer Medicaid coverage to additional
individuals and by adding new mandatory eligibility categories for individuals with income at or below 133% of the federal poverty level,
thereby potentially increasing manufacturers’ Medicaid rebate liability;
a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% point-of-sale discounts off
negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s
outpatient drugs to be covered under Medicare Part D;
expansion of the entities eligible for discounts under the Public Health Service pharmaceutical pricing program;
a new Patient-Centered Outcomes Research Institute to oversee, identify priorities in, and conduct comparative clinical effectiveness
research, along with funding for such research;
establishment of a Center for Medicare Innovation at CMS to test innovative payment and service delivery models to lower Medicare and
Medicaid spending, potentially including prescription drug spending that began on January 1, 2011; and
a licensure framework for follow on biologic products.
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There have been judicial and Congressional challenges to certain aspects of the Affordable Care Act. As a result, there have been delays in the
implementation of, and action taken to repeal or replace, certain aspects of the Affordable Care Act. In January 2017, President Trump signed an Executive
Order directing federal agencies with authorities and responsibilities under the Affordable Care Act to waive, defer, grant exemptions from or delay the
implementation of any provision of the Affordable Care Act that would impose a fiscal or regulatory burden on states, individuals, healthcare providers,
health insurers or manufacturers of pharmaceuticals or medical devices. In December 2018 a judge for the United States District Court for the Northern
District of Texas ruled that the entire Affordable Care Act is unconstitutional. The ruling, which is on hold pending appeal, was followed by a brief from
the Department of Justice stating that the district court’s ruling should be affirmed. While the Affordable Care Act remains in effect at the time of this
filing, its future is uncertain. With respect to repeal or revision of the Affordable Care and its replacement with new or revised legislation, it is unclear
when such legislation will be enacted, what it will provide and what impact it will have on the availability of healthcare and containing or lowering costs of
healthcare.
The Trump Administration’s proposed fiscal year, or FY, 2020 budget includes extensive health policy provisions, the impact of which is
unpredictable. Among other changes, the proposed FY 2020 budget would authorize an administrative penalty for providers for ordering high-risk, high-
cost items or services without proper documentation, authorize civil monetary penalties for failure to report changes to information provided during
Medicaid enrollment or revalidation, and extend the Affordable Care Act Cost-Sharing Reduction payments through calendar year 2020. It is unclear how
these and other provisions of the FY 2020 budget resolution may affect our business in the future.
Other legislative changes have been proposed and adopted in the United States since the Affordable Care Act was enacted. For example, in August
2011, the Budget Control Act of 2011, among other things, created measures for spending reductions by Congress. A Joint Select Committee on Deficit
Reduction, tasked with recommending a targeted deficit reduction of at least $1.2 trillion for the fiscal year 2012 through 2021, was unable to reach
required goals, thereby triggering the legislation’s automatic reduction to several government programs. This includes aggregate reductions of Medicare
payments to providers of up to 2% per fiscal year, which went into effect in April 2013 and, due to the Bipartisan Budget Act of 2015, will remain in effect
through 2025 unless additional Congressional action is taken. Further, in January 2013, President Obama signed into law the American Taxpayer Relief Act
of 2012, which, among other things, further reduced Medicare payments to several providers, including hospitals, imaging centers and cancer treatment
centers, and increased the statute of limitations period for the government to recover overpayments to providers from three to five years.
We anticipate that the Affordable Care Act and other legislative reforms will result in additional downward pressure on the price that we receive
for any approved product, if covered, and could seriously harm our business. Any reduction in reimbursement from Medicare and other government
programs may result in a similar reduction in payments from private payers. The implementation of cost containment measures or other healthcare reforms
may prevent us from being able to generate revenue, attain profitability, or commercialize our products. In addition, it is possible that there will be further
legislation or regulation that could harm our business, financial condition, and results of operations.
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Environmental Regulation
In addition to the foregoing, state and federal laws regarding environmental protection and hazardous substances, including the Occupational
Safety and Health Act, the Resource Conservancy and Recovery Act and the Toxic Substances Control Act, may affect our business. These and other laws
govern our use, handling and disposal of various biological, chemical, and radioactive substances used in, and wastes generated by, our operations. If our
operations result in contamination of the environment or expose individuals to hazardous substances, we could be liable for damages and governmental
fines. We believe that we are in material compliance with applicable environmental laws and that continued compliance therewith is unlikely to have a
material adverse effect on our business. We cannot predict, however, how changes in these laws may affect our future operations.
U.S. Foreign Corrupt Practices Act
The U.S. Foreign Corrupt Practices Act, to which we are subject, prohibits corporations and individuals from engaging in certain activities to
obtain or retain business or to influence a person working in an official capacity. It is illegal to pay, offer to pay or authorize the payment of anything of
value to any foreign government official, government staff member, political party, or political candidate in an attempt to obtain or retain business or to
influence otherwise a person working in an official capacity.
Other countries, including a number of EU member states, have laws of similar application, including anti-bribery or anti-corruption laws such as
the UK Bribery Act. The UK Bribery Act prohibits giving, offering, or promising bribes to any person, as well as requesting, agreeing to receive, or
accepting bribes from any person. Under the UK Bribery Act, a company that carries on a business or part of a business in the United Kingdom may be
held liable for bribes given, offered or promised to any person in any country by employees or other persons associated with the company in order to obtain
or retain business or a business advantage for the company. Liability under the UK Bribery Act is strict, but a defense of having in place adequate
procedures designed to prevent bribery is available.
Government Regulation Outside of the United States
In addition to regulations in the United States, we will be subject to a variety of regulations in other jurisdictions governing, among other things,
clinical trials and any commercial sales and distribution of our products. Because biologically-sourced raw materials are subject to unique contamination
risks, their use may be subjected to different types of restrictions in different countries.
Whether or not we obtain FDA approval for a product, we must obtain the required approvals from regulatory authorities in foreign countries prior
to the commencement of clinical trials or marketing of the product in those countries. Certain countries outside of the United States have a similar process
that requires the submission of a clinical trial application equivalent to an IND prior to the commencement of human clinical trials. In the European Union,
for example, a clinical trial authorization, or CTA, must be submitted to each country’s national health authority and an independent ethics committee,
much like the FDA and the IRB, respectively. Once the CTA is approved in accordance with a country’s requirements, clinical trials may start.
The requirements and process governing the conduct of clinical trials, product licensing, pricing, and reimbursement vary from country to country.
In all cases, the clinical trials are to be conducted in accordance with GCP, applicable regulatory requirements, and the ethical principles that have their
origin in the Declaration of Helsinki.
If we fail to comply with applicable foreign regulatory requirements, we may be subject to, among other things, fines, suspension, or withdrawal
of regulatory approvals, product recalls, seizure of products, operating restrictions and criminal prosecution in those countries.
Employees
As of March 20, 2020, we had eight full-time employees. We are not a party to any collective bargaining agreements. We believe that we maintain
good relations with our employees.
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Corporate Information
We were incorporated in Delaware in April 2009. Our principal executive offices are located at 1601 Trinity Street, Bldg B, Suite 3.322, Austin,
TX 78712, and our telephone number is (877) 774-4679. Our corporate website address is www.genprex.com.
Information contained on, or that can be accessed through, our website or social medial sites does not constitute part of this Annual Report on
Form 10-K or any other report or document we file with the SEC, and any references to our website and social media sites are intended to be inactive
textual references only.
This Annual Report on Form 10-K, our Quarterly Reports on Form 10-Q, Current Reports on Form 8-K, and any amendments to those reports
filed or furnished pursuant to Sections 13(a) and 15(d) of the Securities Exchange Act of 1934, as amended, or the Exchange Act, are available (free of
charge) on our website as soon as reasonably practicable after we electronically file such material with, or furnish it to, the Securities and Exchange
Commission, or SEC.
We have proprietary rights to a number of trademarks, including Oncoprex™, that are used in this Annual Report on Form 10-K. Solely for
convenience, the trademarks and trade names in this Annual Report on From 10-K are generally referred to without the ® and ™ symbols, but such
references should not be construed as any indicator that their respective owners will not assert, to the fullest extent under applicable law, their rights
thereto. All other trademarks, trade names and service marks appearing in this Annual Report on Form 10-K are the property of their respective owners.
We qualify as an “emerging growth company” as the term is used in The Jumpstart Our Business Startups Act of 2012 (JOBS Act), and therefore,
we may take advantage of certain exemptions from various public company reporting requirements, including:
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a requirement to only have two years of audited financial statements and only two years of related selected financial data and management’s
discussion and analysis;
exemption from the auditor attestation requirement on the effectiveness of our internal controls over financial reporting;
reduced disclosure obligations regarding executive compensation; and
exemptions from the requirements of holding a nonbinding advisory stockholder vote on executive compensation and any golden parachute
payments.
We may take advantage of these provisions for up to five years following the year in which we completed our initial public offering, or such
earlier time that we are no longer an emerging growth company. We will remain an “emerging growth company” until the earliest of (i) the last day of the
fiscal year in which we have total annual gross revenues of $1.07 billion or more; (ii) the last day of our fiscal year following the fifth anniversary of the
date of our initial public offering; (iii) the date on which we have issued more than $1 billion in nonconvertible debt during the previous three years; or
(iv) the date on which we are deemed to be a large accelerated filer under the rules of the SEC. We may choose to take advantage of some, but not all, of
the available benefits of the JOBS Act. We have taken advantage of some of the reduced reporting requirements in this Annual Report on Form 10-K.
Accordingly, the information contained herein may be different than the information you receive from other public companies in which you hold stock. In
addition, the JOBS Act provides that an emerging growth company can delay adopting new or revised accounting standards until such time as those
standards apply to private companies. We have irrevocably elected not to avail ourselves of this exemption from new or revised accounting standards and,
therefore, we will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies.
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Item 1A. Risk Factors.
An investment in our common stock involves a high degree of risk. You should carefully consider the following risk factors and the other
information in this Annual Report on Form 10-K before investing in our common stock. Our business and results of operations could be seriously harmed
by any of the following risks. The risks set out below are not the only risks we face. Additional risks and uncertainties not currently known to us or that we
currently deem to be immaterial also may materially adversely affect our business, financial condition and/or operating results. If any of the following
events occur, our business, financial condition and results of operations could be materially adversely affected. In such case, the value and trading price of
our common stock could decline, and you may lose all or part of your investment.
Risks Related to Our Financial Position and Need for Additional Capital
We will require substantial additional funding, which may not be available to us on acceptable terms, or at all, and, if not so available, may require us
to delay, limit, reduce or cease our operations.
We are using the proceeds from our recent sales of our securities to advance Oncoprex through clinical development, as well as for other corporate
purposes. Developing pharmaceutical products, including conducting preclinical studies and clinical trials, is expensive. We will require substantial
additional future capital in order to complete clinical development and commercialize Oncoprex and for preclinical and clinical development and
commercialization of our gene therapy for diabetes. If the FDA requires that we perform additional preclinical studies or clinical trials beyond what we
currently anticipate, our expenses will further increase beyond what we currently expect and the anticipated timing of any potential approval of Oncoprex
and our diabetes gene therapy would likely be delayed. Further, there can be no assurance that the costs we will need to incur to obtain regulatory approval
of these product candidates will not increase.
We will continue to require substantial additional capital to continue our preclinical and clinical development and commercialization activities.
Because successful development of our current and potential product candidates is uncertain, we are unable to estimate the actual amount of funding we
will require to complete research and development and commercialize our products under development.
The amount and timing of our future funding requirements will depend on many factors, including but not limited to:
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the progress, costs, results and timing of our preclinical and clinical trials for Oncoprex and our diabetes gene therapy;
the outcome, costs and timing of seeking and obtaining FDA and any other regulatory approvals;
the ability of third parties to deliver materials and provide services for us;
the costs associated with securing and establishing commercialization and manufacturing capabilities;
market acceptance of our current and potential product candidates;
the costs of acquiring, licensing or investing in businesses, products, product candidates and technologies;
our ability to maintain, expand and enforce the scope of our intellectual property portfolio, including the amount and timing of any
payments we may be required to make, or that we may receive, in connection with the licensing, filing, prosecution, defense and
enforcement of any patents or other intellectual property rights;
our need and ability to hire additional management and scientific and medical personnel;
the effect of competing drug candidates and new product approvals;
our need to implement additional internal systems and infrastructure, including financial and reporting systems; and
the economic and other terms, timing of and success of our existing licensing arrangements and any collaboration, licensing or other
arrangements into which we may enter in the future.
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Some of these factors are outside of our control. Although we expect that our existing cash, and marketable securities will be sufficient to fund our
current operations through at least the next 24 months, this period could be shortened if there are any significant increases in planned spending on
development programs or more rapid progress of development programs than anticipated. Furthermore, we believe that our existing capital will not be
sufficient to enable us to complete the development and commercialization of Oncoprex. Accordingly, we expect that we will need to raise additional funds
in the future.
We may seek additional funding through a combination of equity offerings, debt financings, government or other third-party funding,
commercialization, marketing and distribution arrangements and other collaborations, strategic alliances and licensing arrangements. Additional funding
may not be available to us on acceptable terms, if at all. In addition, the terms of any financing may adversely affect the holdings or the rights of our
stockholders. Any new equity securities we issue could have rights, preferences, and privileges superior to those of holders of our existing capital stock. In
addition, the issuance of additional shares by us, or the possibility of such issuance, may cause the market price of our shares to decline. Any debt financing
secured by us in the future could involve restrictive covenants relating to our capital-raising activities and other financial and operational matters, which
may make it more difficult for us to obtain additional capital and to pursue business opportunities.
If we are unable to obtain funding on a timely basis, we may be required to significantly curtail one or more of our research or development
programs, our ability to continue to support our business growth and to respond to business challenges could be significantly limited, and we may be
required to curtail or cease operations. Accordingly, our business may fail, in which case you would lose the entire amount of your investment in our
securities.
Furthermore, we also could be required to seek funds through arrangements with collaborative partners or otherwise that may require us to
relinquish rights to some of our technologies or product candidates or otherwise agree to terms unfavorable to us.
We have never been profitable, we have no products approved for commercial sale, and to date we have not generated any revenue from product sales.
As a result, our ability to reduce our losses and reach profitability is unproven, and we may never achieve or sustain profitability.
We have never been profitable and do not expect to be profitable in the foreseeable future. We have not yet submitted any drug candidates for
approval by regulatory authorities in the United States or elsewhere. From our inception on April 1, 2009, to December 31, 2019, we incurred an
accumulated deficit of approximately $40.5 million. We incurred net losses of approximately $10.7 million and approximately $12.4 million for the years
ended December 31, 2019 and 2018, respectively.
To date, we have devoted most of our financial resources to our corporate overhead and research and development, including our preclinical
development activities and clinical trials. We have not generated any revenues from product sales. We expect to continue to incur losses for the foreseeable
future, and we expect these losses to increase as we continue our development of, and seek regulatory approvals for our current and potential product
candidates, prepare for and begin the commercialization of any approved products, and add infrastructure and personnel to support our continuing product
development efforts. We anticipate that any such losses could be significant for the next several years. If Oncoprex or any of our other potential product
candidates fails in clinical trials or does not gain regulatory approval, or if our drug candidates do not achieve market acceptance, we may never become
profitable. As a result of the foregoing, we expect to continue to experience net losses and negative cash flows for the foreseeable future. These net losses
and negative cash flows have had, and will continue to have, an adverse effect on our stockholders’ equity and working capital.
Because of the numerous risks and uncertainties associated with pharmaceutical product development, we are unable to accurately predict the
timing or amount of increased expenses or when, or if, we will be able to achieve profitability. In addition, our expenses could increase if we are required
by the FDA to perform studies or trials in addition to those currently expected, or if there are any delays in completing our clinical trials or the development
of any of our drug candidates. The amount of future net losses will depend, in part, on the rate of future growth of our expenses and our ability to generate
revenues.
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We have a limited operating history and we expect a number of factors to cause our operating results to fluctuate on an annual basis, which may make
it difficult to predict our future performance.
We are a clinical stage company with a limited operating history. Our operations to date have been limited to conducting clinical and preclinical
research. We have not yet obtained any regulatory approvals for any of our drug candidates. Consequently, any predictions made about our future success
or viability may not be as accurate as they could be if we had a longer operating history or approved products on the market. Our operating results are
expected to significantly fluctuate from quarter to quarter and year to year due to a variety of factors, many of which are beyond our control. Factors
relating to our business that may contribute to these fluctuations include:
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any delays in regulatory review and approval (assuming that our data support approval) of our current and potential product candidates in
clinical development, including our ability to receive approval from the FDA for Oncoprex;
delays in the commencement, enrollment and timing of clinical trials;
the success of our clinical trials through all phases of clinical development;
potential side effects of our current and potential product candidates that could delay or prevent approval or cause an approved drug to be
taken off the market;
our ability to obtain additional funding to develop product candidates;
our identification and development of additional drug candidates beyond Oncoprex and our gene therapy in diabetes;
competition from existing products or new products that continue to emerge;
the ability of patients or healthcare providers to obtain coverage or sufficient reimbursement for our products;
our ability to adhere to clinical trial requirements directly or with third parties such as contract research organizations (CROs);
our dependency on third-party manufacturers to manufacture our products and key ingredients;
our ability to establish or maintain collaborations, licensing or other arrangements, particularly with MD Anderson;
our ability to defend against any challenges to our intellectual property including claims of patent infringement;
our ability to enforce our intellectual property rights against potential competitors;
our ability to secure additional intellectual property protection for our drug candidates in development and associated technologies;
our ability to attract and retain key personnel to manage our business effectively; and
potential product liability claims.
Accordingly, the results of any historical quarterly or annual periods should not be relied upon as indications of future operating performance.
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Risks Related to Development and Commercialization of Our Current and Potential Product Candidates
Our success depends greatly on the success of our development of Oncoprex for the treatment of NSCLC, and our other product candidates, including
our gene therapy for diabetes. Oncoprex and our other product candidates are based on novel technology, which makes it difficult to predict the time
and cost or the outcome of development and of subsequently obtaining regulatory approval.
At this time we are actively pursuing development of only two product candidates, Oncoprex for NSCLC, and a preclinical stage gene therapy for
diabetes. We are dependent on the success of Oncoprex in the near term. We cannot provide you any assurance that we will be able to successfully advance
Oncoprex or the diabetes gene therapy through the development process, or that any development problems we experience in the future will not cause
significant delays or unanticipated costs, or that such development problems can be solved. We may also experience delays in developing a sustainable,
reproducible and scalable manufacturing process or transferring that process to commercial partners, or developing or validating product release assays in a
timely manner, which may prevent us from completing our clinical trials or commercializing our products on a timely or profitable basis, if at all.
Immunotherapy, gene therapy and biopharmaceutical product development are highly speculative undertakings and involve a substantial degree of
uncertainty. Because Oncoprex and our other potential product candidates are based upon novel technology, it is difficult to predict whether, either as stand-
alone therapies or in combination with other drugs, they will show consistently favorable results and to predict the time and cost of their development and
of subsequently obtaining regulatory approval. We believe only a few gene therapy products have been approved in the United States or Europe. We have
found it difficult to enroll patients in our clinical studies and may, in the future, find it difficult to enroll patients in our clinical studies, which could delay
or prevent clinical studies of our current and potential product candidates. We may encounter delays in our clinical studies, or we may fail to demonstrate
safety and efficacy to the satisfaction of FDA and other regulatory authorities. We may not be successful in our efforts to identify or discover additional
product candidates, or to develop product candidates that we have identified.
In addition, the clinical trial requirements of FDA, the European Commission, the European Medicines Agency (EMA) the competent authorities
of the Member States of the European Union (EU) and other regulatory authorities and the criteria these regulators use to determine the safety and efficacy
of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of such product candidates. The regulatory
approval process for novel product candidates such as ours can be more expensive and take longer than for other, better known or more extensively studied
product candidates. Even if we are successful in developing additional product candidates, it is difficult to determine how long it will take or how much it
will cost to obtain regulatory approvals for these product candidates in either the United States or the EU, or how long it will take to commercialize any
other products for which we receive marketing approval. In addition, any future marketing authorization granted by the European Commission may not be
indicative of what FDA may require for approval and vice versa.
Negative public opinion and increased regulatory scrutiny of gene therapy and genetic research may damage public perception of our current and
potential product candidates or adversely affect our ability to conduct our business or obtain regulatory approvals for our current and potential product
candidates.
Public perception may be influenced by claims that gene therapy is unsafe, and gene therapy may not gain the acceptance of the public or the
medical community. In particular, our success will depend upon physicians specializing in the treatment of those diseases that our current and potential
product candidates target prescribing treatments that involve the use of our current and potential product candidates in lieu of, or in addition to, existing
treatments with which they are already familiar and for which greater clinical data may be available. More restrictive government regulations or negative
public opinion would have a negative effect on our business or financial condition and may delay or impair the development and commercialization of our
current and potential product candidates or demand for any products we may develop. Adverse events in our clinical trials, even if not ultimately
attributable to our current and potential product candidates, and the resulting publicity could lead to increased governmental regulation, unfavorable public
perception, potential regulatory delays in the testing or approval of our potential product candidates, stricter labeling requirements for those product
candidates that are approved and a decrease in demand for any such product candidates. Concern about the environmental spread of our product, whether
real or anticipated, could also hinder the commercialization of our products.
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Prior to receiving Oncoprex, patients are required to undergo genetic screening to detect EGFR mutations and other mutations relevant to
cancer. Genetic testing has raised concerns regarding the appropriate utilization and the confidentiality of information provided by genetic testing. Genetic
tests for assessing a person’s likelihood of developing a chronic disease have focused public attention on the need to protect the privacy of genetic
information. Genetic testing information is also subject to significant restrictions under both federal and state law. For example, concerns have been
expressed that insurance carriers and employers may use these tests to discriminate on the basis of genetic information, resulting in barriers to the
acceptance of genetic tests by consumers. This could lead to governmental authorities restricting genetic testing or calling for limits on or regulating the
use of genetic testing, particularly for diseases for which there is no known cure. Any of these scenarios could decrease demand for Oncoprex or any other
products for which we may obtain marketing approval.
Delays in the commencement, enrollment and completion of clinical trials could result in increased costs to us and delay or limit our ability to obtain
regulatory approval for Oncoprex and our other potential product candidates.
Oncoprex has been tested in only one prior Phase I clinical study, involving 31 patients. In that study, Oncoprex was tested as a monotherapy. We
believe that the best path for development is to develop a combination therapy of Oncoprex in combination with EGFR TKIs, immunotherapies, and
possibly other drugs. We were previously conducting a Phase I/II clinical trial testing Oncoprex in combination with erlotinib; however, we are not
currently enrolling, and do not plan to enroll additional patients in this trial because we received FDA Fast Track Designation for the combination of
Oncoprex with osimertinib in patients whose tumors progressed on osimertinib. Accordingly, we plan to initiate a new clinical trial for the combination of
Oncoprex with osimertinib in NSCLC. We also plan to commence a new clinical trial with the combination of Oncoprex with an immunotherapy,
pembrolizumab (marketed as Keytruda® by Merck & Co).
The favorable results observed in our clinical trials to date may not continue in these new clinical trials or be replicated in other clinical trials,
especially those involving larger numbers of patients. Even if the Phase I/II trial is successful, success in early clinical studies may not be indicative of
results obtained in later studies. The results from our clinical trials may not demonstrate sufficient safety and efficacy to support the submission of
marketing approval for Oncoprex. Before we request marketing approval, the FDA may require us to conduct additional clinical studies or evaluate
subjects for an additional follow-up. Unless an accelerated approval process is allowed by the FDA, one or more Phase III studies is normally required for
approval.
Delays in the commencement, enrollment and/or completion of clinical trials at any of our sites could increase our product development costs or
delay or limit the regulatory approval of our current and potential product candidates. We do not know whether any future trials or studies of our other
potential product candidates will begin on time or will be completed on schedule, if at all. The start or end of a clinical study is often delayed or halted due
to regulatory requirements, changes in the proposed regulatory approval pathway for a drug candidate, manufacturing challenges, including delays or
shortages in available drug product, required clinical trial administrative actions, slower than anticipated patient enrollment, changing standards of care,
availability or prevalence of use of a comparative drug or required prior therapy, clinical outcomes or financial constraints. For instance, delays or
difficulties in patient enrollment or difficulties in retaining trial participants can result in increased costs, longer development times or termination of a
clinical trial. Clinical trials of a new product candidate require the enrollment of a sufficient number of patients, including patients who are suffering from
the disease the product candidate is intended to treat and who meet other eligibility criteria. Rates of patient enrollment are affected by many factors,
including the size of the patient population, the eligibility criteria for the clinical trial, which include the age and condition of the patients and the stage and
severity of disease, the nature of the protocol, the proximity of patients to clinical sites and the availability of effective treatments and/or availability of
other investigational treatment options for the relevant disease.
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If we are unable to secure contract manufacturers with capabilities to produce the products that we require, we could experience delays in conducting
our planned clinical trials.
Manufacturing Oncoprex involves several manufacturing steps. Historically, part of our manufacturing process was conducted in manufacturing
facilities at MD Anderson Cancer Center. We are transferring this portion of the process to a third-party manufacturer. Although we have contracted with
contract manufacturers with capabilities to produce the products that we require, no assurance can be given that such contract manufacturers will be able to,
and receive all approvals to, produce product sufficient for our trials. In accordance with GMPs, changing manufacturers may require the re-validation of
manufacturing processes and procedures, and may require further preclinical studies or clinical trials to show comparability between the materials produced
by different manufacturers. Changing our current or future contract manufacturers may be difficult and could be costly, which could result in our inability
to manufacture our clinical product candidate and a delay in the development of our clinical product candidate. Further, in order to maintain our
development timelines in the event of a change in a third-party contract manufacturer, we may incur higher costs to manufacture our clinical product
candidate.
A product candidate can unexpectedly fail at any stage of preclinical and clinical development.
The historical failure rate for product candidates is high due to scientific feasibility, safety, efficacy, changing standards of medical care and other
variables. The results from preclinical testing or early clinical trials of a product candidate may not predict the results that will be obtained in later phase
clinical trials of the product candidate. We, the FDA or other applicable regulatory authorities may suspend clinical trials of a product candidate at any time
for various reasons, including, but not limited to, a belief that subjects participating in such trials are being exposed to unacceptable health risks or adverse
side effects, or other adverse initial experiences or findings. We may not have the financial resources to continue development of, or to enter into
collaborations for, a product candidate if we experience any problems or other unforeseen events that delay or prevent regulatory approval of, or our ability
to commercialize, product candidates, including:
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inability to obtain sufficient funds required for a clinical trial;
inability to reach agreements on acceptable terms with current or prospective CROs and trial sites, the terms of which can be subject to
extensive negotiation and may vary significantly among different CROs and trial sites;
negative or inconclusive results from our clinical trials or the clinical trials of others for product candidates similar to ours, leading to a
decision or requirement to conduct additional preclinical testing or clinical trials or abandon a program;
serious and unexpected side effects experienced by subjects in our clinical trials or by individuals using drugs similar to our current and
potential product candidates;
conditions imposed by the FDA or comparable foreign authorities regarding the scope or design of our clinical trials;
delays in enrolling research subjects in clinical trials;
high drop-out rates and high fail rates of research subjects;
inadequate supply or quality of product candidate components or materials or other supplies necessary for the conduct of our clinical trials;
greater than anticipated clinical trial costs;
poor effectiveness of our current and potential product candidates during clinical trials; or
unfavorable FDA or other regulatory agency inspection and review of a clinical trial site or vendor.
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We may have difficulty engaging or retaining clinical trial sites and/or enrolling patients in our clinical trials, which could delay or prevent
development of our current and potential product candidates.
Identifying and qualifying patients to participate in clinical trials of our current and potential product candidates is critical to our success. The
timing of our clinical trials depends on the speed at which we can engage and retain clinical trial sites and recruit patients to participate in testing our
current and potential product candidates. We have experienced delays in some of our clinical trials in the past due to difficulties with enrollment and we
may experience similar delays in the future. We plan to conduct additional clinical trials, and we may experience difficulties with enrollment. If patients are
unwilling to participate in our clinical trials because of negative publicity from adverse events in the industry or in the trials for other third party product
candidates, or for other reasons, including competitive clinical trials for similar patient populations, the timeline for engaging sites, recruiting patients,
conducting studies and obtaining regulatory approval of potential products may be delayed. These delays could result in increased costs, delays in
advancing our product development, delays in testing the effectiveness of our technology or termination of the clinical trials altogether.
We or our clinical trial sites may not be able to identify, recruit and enroll a sufficient number of patients, or those with the required or desired
characteristics in a clinical trial, to complete our clinical trials in a timely manner. Patient enrollment is affected by factors including:
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severity of the disease under investigation;
design of the clinical trial protocol, including the fact that certain of our clinical trials are randomized to current treatments;
size of the patient population;
eligibility criteria for the clinical trial in question;
perceived risks and benefits of the product candidate under study;
proximity and availability of clinical trial sites for prospective patients;
availability of competing therapies and clinical trials;
efforts to facilitate timely enrollment in clinical trials;
timely availability of the study drug;
patient referral practices of physicians; and
ability to monitor patients adequately during and after treatment.
We currently plan to seek initial marketing approval in the United States and subsequently in Europe. We may not be able to initiate or continue
clinical trials if we cannot enroll a sufficient number of eligible patients to participate in the clinical trials required by the FDA or the EMA, or other
regulatory agencies. Our ability to successfully initiate, enroll and complete a clinical trial in any foreign country is subject to numerous risks unique to
conducting business in foreign countries, including:
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difficulty in establishing or managing relationships with CROs and physicians;
different standards for the conduct of clinical trials;
our inability to locate qualified local consultants, physicians and partners; and
the potential burden of complying with a variety of foreign laws, medical standards and regulatory requirements, including the regulation of
pharmaceutical and biotechnology products and treatments.
If we have difficulty enrolling a sufficient number of patients to conduct our clinical trials as planned, we may need to delay, limit or terminate
ongoing or planned clinical trials, any of which would have an adverse effect on our business.
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Any product candidate we advance through clinical trials may not have favorable results in later clinical trials or receive regulatory approval. Even if
we complete the necessary clinical trials, we cannot predict when, or if, we will obtain regulatory approval to commercialize a product candidate, and
the approval may be for a narrower indication than we seek.
Clinical failure can occur at any stage of our clinical development. Clinical trials may produce negative or inconclusive results, and we may
decide, or regulators may require us, to conduct additional clinical trials or nonclinical studies. In addition, data obtained from trials and studies are
susceptible to varying interpretations, and regulators may not interpret our data as favorably as we do, which may delay, limit or prevent regulatory
approval. Additionally, our partners, clients, other vendors, and/or other stakeholders may not agree with our interpretation(s) of data obtained from our
clinical trials, which could potentially cause a variety of issues, including but not limited to, delays, the necessity for additional studies and analyses,
dependence on third-party validation, and/or other unforeseen challenges. Success in preclinical studies and early clinical trials does not ensure that
subsequent clinical trials will generate the same or similar results or otherwise provide adequate data to demonstrate the efficacy and safety of a product
candidate. A number of companies in the pharmaceutical industry, including those with greater resources and experience than ours, have suffered
significant setbacks in clinical trials, even after seeing promising results in earlier clinical trials.
In addition, the design of a clinical trial can determine whether its results will support approval of a product and flaws in the design of a clinical
trial may not become apparent until the clinical trial is well advanced. We may be unable to design and execute a clinical trial to support regulatory
approval. Further, clinical trials of potential products often reveal that it is not practical or feasible to continue development efforts.
If Oncoprex is found to be unsafe or lack efficacy, we will not be able to obtain regulatory approval for it and our business would be harmed.
In some instances, there can be significant variability in safety and/or efficacy results between different trials of the same product candidate due to
numerous factors, including changes in trial protocols, differences in composition of the patient populations, adherence to the dosing regimen and other
trial protocols and the rate of dropout among clinical trial participants. We do not know whether any clinical trials we or any of our potential future
collaborators may conduct will demonstrate the consistent or adequate efficacy and safety that would be required to obtain regulatory approval and market
any products. If we are unable to bring Oncoprex to market, or to acquire other products that are on the market or can be developed, our ability to create
stockholder value will be limited.
Regulatory authorities also may approve a product candidate for more limited indications than requested, or they may impose significant
limitations in the form of narrow indications. These regulatory authorities may require warnings or precautions with respect to conditions of use or they
may grant approval subject to the performance of costly post-marketing clinical trials. In addition, regulatory authorities may not approve the labeling
claims or allow the promotional claims that are necessary or desirable for the successful commercialization of our product candidates. Any of the foregoing
scenarios could materially harm the commercial prospects for our product candidates and materially and adversely affect our business, financial condition,
results of operations and prospects.
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Even if we obtain regulatory approval of our current and potential product candidates, the products may not gain market acceptance among
physicians, patients, hospitals, cancer treatment centers, third-party payors and others in the medical community.
Ethical, social and legal concerns about gene therapy and genetic research could result in additional regulations restricting or prohibiting the
products and processes we may use. Even with the requisite approvals, the commercial success of our current and potential product candidates will depend
in part on the medical community, patients, and third-party payors accepting gene therapy products in general, and our current and potential product
candidates in particular, as medically useful, cost-effective and safe. Any product that we bring to the market may not gain market acceptance by
physicians, patients, hospitals, cancer treatment centers, third-party payors and others in the medical community. If these products do not achieve an
adequate level of acceptance, we may not generate significant product revenue and may not become profitable. The degree of market acceptance of these
product candidates, if approved for commercial sale, will depend on a number of factors, including:
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the clinical indications for which our current and potential product candidates are approved;
physicians, hospitals, cancer treatment centers and patients considering our current and potential product candidates as a safe and effective
treatment;
the potential and perceived advantages of our current and potential product candidates over alternative treatments;
the prevalence and severity of any side effects;
product labeling or product insert requirements of the FDA or other regulatory authorities;
limitations or warnings contained in the labeling approved by the FDA;
the timing of market introduction of our current and potential product candidates as well as competitive products;
the cost of treatment – both in absolute terms and in relation to alternative treatments;
the availability of coverage, reimbursement and pricing by third-party payors and government authorities and the adequacy thereof;
the willingness of patients to pay out-of-pocket in the absence of coverage by third-party payors, including government authorities;
the willingness, ability and availability of healthcare providers that can comply with the transportation, handling, and temperature-
controlled storage requirements associated with our current and potential product candidates;
relative convenience and ease of administration, including as compared to alternative treatments and competitive therapies; and
the effectiveness of our sales and marketing efforts, which are subject to various limitations under applicable law.
Even if a potential product displays a favorable efficacy and safety profile in preclinical and clinical trials, market acceptance of the product will
not be known until after it is launched. Our efforts to educate the medical community and third-party payors about the benefits of our product candidates
may require significant resources and may never be successful. Such efforts to educate the marketplace may require more resources than are required by the
conventional technologies marketed by our competitors and may be restricted by the allowed label.
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Our current and potential product candidates may have undesirable side effects that may delay or prevent marketing approval, or, if approval is
received, require them to be taken off the market, require them to include safety warnings or otherwise limit their sales.
In our Phase I clinical trial of Oncoprex as a monotherapy, the only serious adverse events, defined as grade 3, 4 or 5 events under the Common
Terminology Criteria for Adverse Events, or CTCAE, published by the U.S. Department of Health and Human Services, were grade 3 fever and grade 3
hypotension, and the only dose-limiting toxicities were two episodes of transient grade 3 hypophosphatemia (abnormally low levels of phosphate in the
blood).
The Phase I portion of our Phase I/II trial combining Oncoprex with erlotinib was a dose escalation study with the primary purpose of determining
the MTD. Dose Limiting Toxicities were defined as grade 3, 4 or 5 events during the first cycle of treatment that were considered to be treatment related.
At dose level 1 (Oncoprex .045 mg/kg plus erlotinib 100 mg), one subject had grade 3 adverse events of fatigue, muscle weakness and hyponatremia (low
sodium level) considered to be related to the study treatment (erlotinib); therefore, three additional subjects were treated at this dose level (six subjects
total), none of whom suffered a Dose Limiting Toxicity. At dose level 2 (Oncoprex .06 mg/kg plus erlotinib 100 mg), there were no Dose Limiting
Toxicities. At dose level 3 (Oncoprex .45 mg/kg plus erlotinib 150 mg), one subject had a grade 3 rash considered to be related to the study treatment
(erlotinib); therefore, an additional three subjects were treated at this dose level (six subjects total). No additional subjects suffered a Dose Limiting
Toxicity at dose level 3. At dose level 4 (Oncoprex .06 mg/kg plus erlotinib 150 mg), there were no Dose Limiting Toxicities; thus dose level 4 was
determined to be the MTD. None of the 10 subjects treated to date in the Phase II portion of the Phase I/II trial suffered a Dose Limiting Toxicity.
Additional or unforeseen side effects from Oncoprex or any of our other potential product candidates could arise either during clinical
development or, if approved, after the approved product has been marketed. A showing that Oncoprex or any other product candidate causes undesirable or
unacceptable side effects could interrupt, delay or halt clinical trials and result in the failure to obtain or suspension or termination of marketing approval
from the FDA and other regulatory authorities, or result in marketing approval from the FDA and other regulatory authorities only with restrictive label
warnings.
If any of our current and potential product candidates receives marketing approval and we or others later identify undesirable or unacceptable side
effects caused by such products:
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regulatory authorities may require the addition of labeling statements, specific warnings, a contraindication or field alerts to physicians and
pharmacies;
we may be required to change instructions regarding the way the product is administered, conduct additional clinical trials or change the
labeling of the product;
we may be subject to limitations on how we may promote the product;
sales of the product may decrease significantly;
regulatory authorities may require us to take our approved product off the market;
we may be subject to litigation or product liability claims; and
our reputation may suffer.
Any of these events could prevent us or our potential future collaborators from achieving or maintaining market acceptance of the affected product
or could substantially increase commercialization costs and expenses, which in turn could delay or prevent us from generating significant revenues from the
sale of our products.
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Potential product liability lawsuits against us could cause us to incur substantial liabilities and could limit commercialization of our products.
In the event any of our product candidates is approved for marketing by the FDA and other regulatory authorities, we may face potential product
liability. If successful claims are brought against us, we may incur substantial liability and costs. If the use of our current and potential product candidates
harms patients, or is perceived to harm patients even when such harm is unrelated to our current and potential product candidates, our regulatory approvals
could be revoked or otherwise negatively affected, and we could be subject to costly and damaging product liability claims. Although we do not currently
maintain product liability insurance, we may not be able to obtain or maintain insurance coverage in the future at a reasonable cost or in an amount
adequate to satisfy any liability that may arise, if at all.
Security breaches and other disruptions could compromise our information and expose us to liability, which would cause our business and reputation
to suffer.
In the ordinary course of our business, we collect and store sensitive data, including intellectual property, our proprietary business information and
that of our suppliers and business partners, as well as personally identifiable information of clinical trial participants and employees. Similarly, our CROs,
contractors and consultants possess certain of our sensitive data. The secure maintenance of this information is critical to our operations and business
strategy. Despite our security measures our information technology and infrastructure may be vulnerable to attacks by hackers or breached due to employee
error, malfeasance or other disruptions. Any such breach could compromise our networks and the information stored there could be accessed, publicly
disclosed, lost or stolen. Any such access, disclosure or other loss of information, including our data being breached at our our CROs, contractors and
consultants, could result in legal claims or proceedings, liability under laws that protect the privacy of personal information, disrupt our operations, and
damage our reputation which could adversely affect our business. Furthermore, the loss of clinical trial data from completed or future clinical trials could
result in delays in our regulatory approval efforts and significantly increase our costs to recover or reproduce the data which could cause the development
and commercialization of our current and potential product candidates to be delayed.
Business disruptions could seriously harm our future revenue and financial condition and increase our costs and expenses.
Our operations, and those of our CROs, contractors and consultants, could be subject to power shortages, telecommunications failures, wildfires,
water shortages, floods, earthquakes, hurricanes, typhoons, fires, extreme weather conditions, medical epidemics and other natural or man-made disasters
or business interruptions. The occurrence of any of these business disruptions could seriously harm our operations and financial condition and increase our
costs and expenses. Our ability to obtain clinical supplies of our current and potential product candidates could be disrupted if the operations of our contract
manufacturers are affected by a man-made or natural disaster or other business interruption. Unfavorable global economic conditions could adversely affect
our business, financial condition, or results of operations.
We do not carry insurance for all categories of risk that our business may encounter. In particular, we do not carry product liability insurance
covering any clinical trials liability that we may incur. Although we intend to obtain such insurance before we market any product, there can be no
assurance that we will secure adequate insurance coverage or that any such insurance coverage will be sufficient to protect our operations to significant
potential liability in the future. Any significant uninsured liability may require us to pay substantial amounts, which would adversely affect our financial
position and results of operations.
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Our business may be adversely affected by the ongoing coronavirus pandemic .
The outbreak of the novel Coronavirus (COVID-19) has evolved into a global pandemic. The coronavirus has spread to many regions of the
world. The extent to which the coronavirus impacts our business and operating results will depend on future developments that are highly uncertain and
cannot be accurately predicted, including new information that may emerge concerning the coronavirus and the actions to contain the coronavirus or treat
its impact, among others.
Should the coronavirus continue to spread, our business operations could be delayed or interrupted. For instance, our clinical trials may be affected
by the pandemic. Site initiation, participant recruitment and enrollment, participant dosing, distribution of clinical trial materials, study monitoring and data
analysis may be paused or delayed due to changes in hospital or university policies, federal, state or local regulations, prioritization of hospital resources
toward pandemic efforts, or other reasons related to the pandemic. If the coronavirus continues to spread, some participants and clinical investigators may
not be able to comply with clinical trial protocols. For example, quarantines or other travel limitations (whether voluntary or required) may impede
participant movement, affect sponsor access to study sites, or interrupt healthcare services, and we may be unable to conduct our clinical trials. Further, if
the spread of the coronavirus pandemic continues and our operations are adversely impacted, we risk a delay, default and/or nonperformance under existing
agreements which may increase our costs. These cost increases may not be fully recoverable or adequately covered by insurance. Infections and deaths
related to the pandemic may disrupt the United States’ healthcare and healthcare regulatory systems. Such disruptions could divert healthcare resources
away from, or materially delay FDA review and/or approval with respect to, our clinical trials. It is unknown how long these disruptions could continue,
were they to occur. Any elongation or de-prioritization of our clinical trials or delay in regulatory review resulting from such disruptions could materially
affect the development and study of our product candidates.
We currently utilize third parties to, among other things, manufacture raw materials and to manufacture clinical product. If either any third-party
parties in the supply chain for materials used in the production of our product candidates or the third-party manufacturers of our product candidates
themselves are adversely impacted by restrictions resulting from the coronavirus outbreak our ability to manufacture our product candidates for our clinical
trials and research and development activities related thereto may be disrupted.
The spread of the coronavirus, which has caused a broad impact globally, including restrictions on travel and quarantine policies put into place by
businesses and governments, may have a material economic effect on our business. While the potential economic impact brought by and the duration of the
pandemic may be difficult to assess or predict, it has already caused, and is likely to result in further, significant disruption of global financial markets,
which may reduce our ability to access capital either at all or on favorable terms. In addition, a recession, depression or other sustained adverse market
event resulting from the spread of the coronavirus could materially and adversely affect our business and the value of our common stock.
The ultimate impact of the current pandemic, or any other health epidemic, is highly uncertain and subject to change. We do not yet know the full
extent of potential delays or impacts on our business, our clinical trials, our research programs, healthcare systems or the global economy as a whole.
However, these effects could have a material impact on our operations, and we will continue to monitor the situation closely.
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We face competition from other biotechnology and pharmaceutical companies and our operating results will suffer if we fail to compete effectively.
The biotechnology and pharmaceutical industries are intensely competitive and subject to rapid and significant technological change. We have
domestic and international competitors including major multinational pharmaceutical companies, established biotechnology companies, specialty
pharmaceutical and generic drug companies and universities and other research institutions. Many of our competitors have greater financial and other
resources, such as larger research and development staff and more experienced marketing and manufacturing organizations than we do. Large
pharmaceutical companies, in particular, have extensive experience in clinical testing, obtaining regulatory approvals, recruiting patients and manufacturing
pharmaceutical products. These companies also have significantly greater research, sales and marketing capabilities and collaborative arrangements in our
target markets with leading companies and research institutions. Established pharmaceutical companies may also invest heavily to accelerate discovery and
development of novel compounds or to in-license novel compounds that could make the product candidates that we develop obsolete. As a result of these
factors, our competitors may succeed in obtaining patent protection and/or FDA approval or in discovering, developing and commercializing drugs for the
cancer indications that we are targeting before we do or may develop drugs that are deemed to be more effective or gain greater market acceptance than
ours. Smaller or early-stage companies may also prove to be significant competitors, particularly through collaborative arrangements with large, established
companies. In addition, many universities and private and public research institutes may become active in our target disease areas. Our competitors may
succeed in developing, acquiring or licensing on an exclusive basis, technologies and drug products that are more effective or less costly than any product
candidates that we are currently developing or that we may develop, which could render our products obsolete or noncompetitive.
There are a number of drugs approved and under development for treatment of lung cancer. Treatments competitive with our primary product
candidates generally fall into the following categories: chemotherapies such as cisplatin, carboplatin, docetaxel and pemetrexed; targeted therapies such as
erlotinib, gefitinib, afatinib and osimertinib, and immunotherapies such as checkpoint inhibitors and CAR and CAR T cells, and oncolytic virus-based
technology. In addition, new drug candidates are constantly being conceived and developed. Any such competing therapy may be more effective and/or
cost-effective than ours.
If our competitors market products that are more effective, safer or less expensive or that reach the market sooner than our future products, if any,
we may not achieve commercial success. In addition, because of our limited resources, it may be difficult for us to stay abreast of the rapid changes in all
technologies that are or may become competitive with ours. If we fail to stay at the forefront of technological change, we may be unable to compete
effectively. Technological advances or products developed by our competitors may render our technologies or product candidates obsolete, less competitive
or not economical.
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Risks Related to Regulatory Approval and Marketing of Our Current and Potential Product Candidates and Other Legal Compliance Matters
We cannot be certain that our product candidates, including Oncoprex or our diabetes gene therapy, will receive regulatory approval, and without
regulatory approval we will not be able to market them.
Our business currently depends largely on the successful development and commercialization of our product candidates, including Oncoprex
and/or our diabetes gene therapy. Our ability to generate revenue related to product sales will depend on the successful development and regulatory
approval of Oncoprex for the treatment of cancer, or our diabetes gene therapy. Even if we complete the necessary clinical studies, we cannot predict when
or if we will obtain regulatory approval to commercialize a product candidate. Further, if we do obtain regulatory approval, it may only apply to a
narrower indication than we expect. Even if we obtain regulatory approval for a product candidate, our products will remain subject to regulatory scrutiny.
We currently have no products approved for sale and we cannot guarantee that we will ever have marketable products. The development of a
product candidate and issues relating to its approval and marketing are subject to extensive regulation by the FDA in the United States and regulatory
authorities in other countries, with regulations differing from country to country. We are not permitted to market our current and potential product
candidates in the United States until we receive approval of a BLA from the FDA. We have not submitted any marketing applications for any of our current
and potential product candidates.
BLAs must include extensive preclinical and clinical data and supporting information to establish the product candidate’s safety and effectiveness
for each desired indication. BLAs must also include significant information regarding the chemistry, manufacturing and controls for the product. Obtaining
approval of a BLA is a lengthy, expensive and uncertain process, and we may not be successful in obtaining approval. The FDA review processes can take
years to complete, and approval is never guaranteed. If we submit a BLA to the FDA, the FDA must decide whether to accept or reject the submission for
filing. We cannot be certain that any submissions will be accepted for filing and review by the FDA. Regulators in other jurisdictions have their own
procedures for approval of product candidates. Even if a product is approved, the FDA may limit the indications for which the product may be marketed,
require extensive warnings on the product labeling or require expensive and time-consuming clinical trials or reporting as conditions of approval.
Regulatory authorities in countries outside of the United States and Europe also have requirements for approval of drug candidates with which we must
comply prior to marketing in those countries. Obtaining regulatory approval for marketing of a product candidate in one country does not ensure that we
will be able to obtain regulatory approval in any other country. In addition, delays in approvals or rejections of marketing applications in the United States,
Europe or other countries may be based upon many factors, including regulatory requests for additional analyses, reports, data, preclinical studies and
clinical trials, regulatory questions regarding different interpretations of data and results, changes in regulatory policy during the period of product
development and the emergence of new information regarding our current and potential product candidates or other products. Furthermore, regulatory
approval for any of our current and potential product candidates may be withdrawn.
If we are unable to obtain approval from the FDA or other regulatory agencies for Oncoprex, or if, subsequent to approval, we are unable to
successfully commercialize Oncoprex or our other potential product candidates, we will not be able to generate sufficient revenue to become profitable or
to continue our operations.
In addition, the clinical trial requirements of the FDA, the EMA, and other regulatory agencies and the criteria these regulators use to determine
the safety and efficacy of a product candidate vary substantially according to the type, complexity, novelty and intended use and market of the potential
products. The regulatory approval process for novel product candidates such as ours can be more expensive and take longer than for other, better known or
extensively studied pharmaceutical or other product candidates.
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Regulatory requirements governing gene therapy products have changed frequently and may continue to change in the future. For example, in
January 2017, the FDA Oncology Center of Excellence, or the Center of Excellence, was created to leverage the combined skills of regulatory scientists
and reviewers with expertise in drugs, biologics, and devices (including diagnostics). While the Center of Excellence is designed to help expedite the
development of oncology and malignant hematology-related medical products and support an integrated approach in the clinical evaluation of drugs,
biologics and devices for the treatment of cancer, the Center of Excellence may, at times, create confusion within the FDA and especially in the Center of
Biologics and Research, which is the primary review division for Oncoprex. Gene therapy clinical trials conducted at institutions that receive funding for
recombinant DNA research from the NIH, are also subject to review by the Novel and Exceptional Technology and Research Advisory Committee, or
NExTRAC, formerly known as the NIH Office of Biotechnology Activities’ Recombinant DNA Advisory Committee, or the RAC. In August 2018, the
NIH Director issued a statement describing a proposal intended to streamline the federal framework for oversight of gene therapy. The proposal, which the
NIH developed in conjunction with the FDA, included amending the NIH Guidelines for Research Involving Recombinant or Synthetic Nucleic Acid
Molecules, or NIH Guidelines, to eliminate duplicative review and reporting requirements for human gene transfer protocols. The statement also described
NIH’s effort to refocus the role of the RAC to be closer to its original mandate – a transparent forum for science, safety, and ethics of emerging
biotechnologies. Accordingly, the NIH Guidelines have been updated to reflect these changes and the RAC has been renamed the Novel and Exceptional
Technology and Research Advisory Committee, or NExTRAC. Although the FDA decides whether individual gene therapy protocols may proceed, the
NExTRAC review process can impede the initiation of a clinical trial, even if the FDA has reviewed the study and approved its initiation. Conversely, the
FDA can put an Investigational New Drug application, or IND, on a partial or complete clinical hold even if the NExTRAC has provided a favorable
review. Additionally, before a clinical trial can begin at an NIH-funded institution, that institution’s institutional review board, or IRB, and its Institutional
Biosafety Committee will have to review the proposed clinical trial to assess the safety of the study. In addition, adverse developments in clinical trials of
gene therapy products conducted by others may cause the FDA or other regulatory bodies to change the requirements for performing studies or for
obtaining approval of any of our current and potential product candidates. The regulatory changes discussed herein as well as other existing and future
regulatory developments may cause unexpected delays and challenges for companies seeking approval of gene therapy products, like Oncoprex.
These regulatory review committees and advisory groups, and the new guidelines they promulgate, may lengthen the regulatory review process,
require us to perform additional studies, increase our development costs, lead to changes in regulatory positions and interpretations, delay or prevent
approval and commercialization of our current and potential product candidates or lead to significant post-approval limitations or restrictions. As we
advance our current and potential product candidates, we will be required to consult with these regulatory and advisory groups and comply with applicable
guidelines. Any delay or failure to obtain, or unexpected costs in obtaining, the regulatory approval necessary to bring a potential product to market could
decrease our ability to generate sufficient revenue to maintain our business.
Even if we obtain regulatory approval for our product candidates, our products will remain subject to regulatory oversight.
Our product candidates for which we obtain regulatory approval will be subject to ongoing regulatory requirements for manufacturing, labeling,
packaging, storage, advertising, promotion, record-keeping and submission of safety and other post-market information. Any regulatory approvals that we
receive for our product candidates also may be subject to the specific obligations imposed as a condition for marketing authorization by equivalent
authorities in a foreign jurisdiction, particularly by the European Commission, limitations on the approved indicated uses for which the product may be
marketed or to the conditions of approval, or contain requirements for potentially costly post-marketing testing, including Phase IV clinical trials, and
surveillance to monitor the quality, safety and efficacy of the product.
For example, in the United States, the holder of an approved BLA is obligated to monitor and report adverse events and any failure of a product to
meet the specifications in the BLA. The holder of an approved BLA also must submit new or supplemental applications and obtain FDA approval for
certain changes to the approved product, product labeling or manufacturing process. Advertising and promotional materials must comply with the Federal
Food, Drug, and Cosmetic Act (FDCA) and implementing regulations and are subject to FDA oversight and post-marketing reporting obligations, in
addition to other potentially applicable federal and state laws.
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In the EU, any future advertising and promotion of our products will be subject to EU laws governing promotion of medicinal products,
interactions with physicians, misleading and comparative advertising and unfair commercial practices. In addition, other legislation adopted by individual
EU Member States may apply to the advertising and promotion of medicinal products. These laws may limit or restrict the advertising and promotion of
our products to the general public and may impose limitations on our promotional activities with health care professionals. These laws require that
promotional materials and advertising for medicinal products are consistent with the product’s Summary of Product Characteristics (SmPC) as approved by
the competent authorities. The SmPC is the document that provides information to physicians concerning the safe and effective use of the medicinal
product. It forms an intrinsic and integral part of the marketing authorization granted for the medicinal product. Promotion of a medicinal product that does
not comport with the SmPC is considered to constitute off-label promotion, which is prohibited in the EU. The applicable laws at EU level and in the
individual EU Member States also prohibit the direct-to-consumer advertising of prescription-only medicinal products. Violations of the rules governing
the promotion of medicinal products in the EU could be penalized by administrative measures, fines and imprisonment.
In addition, product manufacturers and their facilities may be subject to payment of application and program fees and are subject to continual
review and periodic inspections by FDA and other regulatory authorities for compliance with current GMP, requirements and adherence to commitments
made in the BLA or foreign marketing application. If we, or a regulatory authority, discover previously unknown problems with a product, such as adverse
events of unanticipated severity or frequency, or problems with the facility where the product is manufactured or disagree with the promotion, marketing or
labeling of that product, a regulatory authority may impose restrictions relative to that product, the manufacturing facility or us, including requiring recall
or withdrawal of the product from the market or suspension of manufacturing.
If we fail to comply with applicable regulatory requirements for any product following approval, a regulatory authority may:
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issue a warning letter asserting that we are in violation of the law;
seek an injunction or impose administrative, civil or criminal penalties or monetary fines;
suspend or withdraw regulatory approval;
suspend any ongoing clinical trials;
refuse to approve a pending BLA or comparable foreign marketing application (or any supplements thereto) submitted by us or our strategic
partners;
restrict the marketing or manufacturing of the product;
seize or detain the product or otherwise demand or require the withdrawal or recall of the product from the market;
refuse to permit the import or export of products;
request and publicize a voluntary recall of the product; or
refuse to allow us to enter into supply contracts, including government contracts.
Any government investigation of alleged violations of law could require us to expend significant time and resources in response and could
generate negative publicity. The occurrence of any event or penalty described above may inhibit our ability to commercialize our product candidates and
adversely affect our business, financial condition, results of operations and prospects.
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If the FDA does not find the manufacturing facilities of our future contract manufacturers acceptable for commercial production, we may not be able
to commercialize any of our current and potential product candidates.
We do not intend to manufacture the pharmaceutical products that we plan to sell. We are currently utilizing contract manufacturers for the
production of the active pharmaceutical ingredients and the formulation of drug product for the trials of Oncoprex currently being conducted or that will
need to be conducted prior to seeking regulatory approval. However, we do not have agreements for supplies of Oncoprex or any of our other potential
product candidates, and we may not be able to reach agreements with these or other contract manufacturers for sufficient supplies to commercialize
Oncoprex if it is approved. Additionally, the facilities used by any contract manufacturer to manufacture Oncoprex or any of our other potential product
candidates must be the subject of a satisfactory inspection before the FDA approves the product candidate manufactured at that facility. We are completely
dependent on these third-party manufacturers for compliance with the requirements of U.S. and non-U.S. regulators for the manufacture of our finished
products. If our manufacturers cannot successfully manufacture materials that conform to our specifications and the FDA’s GMP standards and other
requirements of any governmental agency to whose jurisdiction we are subject, our current and potential product candidates will not be approved or, if
already approved, may be subject to recalls. Reliance on third-party manufacturers entails risks to which we would not be subject if we manufactured our
current and potential product candidates, including:
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the possibility that we are unable to enter into a manufacturing agreement with a third party to manufacture our current and potential
product candidates;
the possible breach of the manufacturing agreements by the third parties because of factors beyond our control; and
the possibility of termination or nonrenewal of the agreements by the third parties before we are able to arrange for a qualified replacement
third-party manufacturer.
Any of these factors could cause the delay of approval or commercialization of our current and potential product candidates, cause us to incur
higher costs or prevent us from commercializing our current and potential product candidates successfully. Furthermore, if any of our current and potential
product candidates are approved and contract manufacturers fail to deliver the required commercial quantities of finished product on a timely basis at
commercially reasonable prices, and we are unable to find one or more replacement manufacturers capable of production at a substantially equivalent cost,
in substantially equivalent volumes and quality and on a timely basis, we would likely be unable to meet demand for our products and could lose potential
revenue. It may take several years to establish an alternative source of supply for our current and potential product candidates and to have any such new
source approved by the government agencies that regulate our products.
We may be subject, directly or indirectly, to federal and state healthcare fraud and abuse laws, false claims laws and other federal and state healthcare
laws, and the failure to comply with such laws could result in substantial penalties. Our employees, independent contractors, consultants, principal
investigators, CROs, commercial partners and vendors may engage in misconduct or other improper activities, including noncompliance with
regulatory standards and requirements.
State and federal regulatory and enforcement agencies continue actively to investigate violations of health care laws and regulations, and the
United States Congress continues to strengthen the arsenal of enforcement tools. The Bipartisan Budget Act of 2018 increased the criminal and civil
penalties that can be imposed for violating certain federal health care laws, including the Anti-Kickback Statute. Enforcement agencies also continue to
pursue novel theories of liability under these laws. Government agencies have increased regulatory scrutiny and enforcement activity with respect to
programs supported or sponsored by pharmaceutical companies, including reimbursement and co-pay support, funding of independent charitable
foundations and other programs that offer benefits for patients. Several investigations into these types of programs have resulted in significant civil and
criminal settlements.
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We are exposed to the risk of fraud, misconduct or other illegal activity by our employees, independent contractors, consultants, principal
investigators, CROs, commercial partners and vendors. Misconduct by these parties could include intentional, reckless and/or negligent conduct that fails
to: comply with the laws of the FDA and similar foreign regulatory bodies; provide true, complete and accurate information to the FDA and similar foreign
regulatory bodies; comply with manufacturing standards we have established; comply with federal and state data privacy, security, fraud and abuse and
other healthcare laws and regulations in the United States and similar foreign fraudulent misconduct laws; or report financial information or data accurately
or to disclose unauthorized activities to us. If we obtain FDA approval for any of our current and potential product candidates and begin commercializing
those products in the United States, our potential exposure under such laws would increase significantly, and our costs associated with compliance with
such laws would likely also increase. These laws may impact, among other things, our current activities with principal investigators and research patients,
as well as proposed and future sales, marketing and education programs and interactions with physicians and other health care providers. In particular, the
promotion, sales and marketing of healthcare items and services, as well as certain business arrangements in the healthcare industry, are subject to
extensive laws and regulations intended to prevent fraud, misconduct, kickbacks, self-dealing and other abusive practices. These laws and regulations may
restrict or prohibit a wide range of pricing, discounting, marketing and promotion, including off-label uses of our products, structuring and commission(s),
certain customer incentive programs and other business arrangements generally. Activities subject to these laws also involve the improper use or
misrepresentation of information obtained in the course of patient recruitment for clinical trials, creating fraudulent data in our preclinical studies or clinical
trials or illegal misappropriation of drug product, which could result in regulatory sanctions and cause serious harm to our reputation. It is not always
possible to identify and deter misconduct by employees and other third parties, and the precautions we take to detect and prevent this activity may not be
effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits stemming
from a failure to comply with these laws or regulations. Additionally, we are subject to the risk that a person or government could allege such fraud or other
misconduct, even if none occurred. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights,
those actions could have a significant impact on our business, including the imposition of fines or other sanctions. The laws that may affect our ability to
operate include, but are not limited to:
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the Federal Anti-Kickback Statute, which prohibits, among other things, individuals and entities from knowingly and willfully soliciting,
receiving, offering or paying any remuneration (including any kickback, bribe, or rebate), directly or indirectly, overtly or covertly, in cash
or in kind, to induce, or in return for, either the referral of an individual for, or the purchase, lease, order or recommendation of, any good,
facility, item or service for which payment may be made, in whole or in part, under a federal healthcare program, such as the Medicare and
Medicaid programs. A person or entity does not need to have actual knowledge of the statute or specific intent to violate it in order to have
committed a violation;
federal civil and criminal false claims laws and civil monetary penalty laws, including the civil False Claims Act, which impose criminal
and civil penalties, through government, civil whistleblower or qui tam actions, on individuals and entities for, among other things,
knowingly presenting, or causing to be presented, claims for payment or approval from Medicare, Medicaid, or other third-party payors that
are false, fictitious or fraudulent, or knowingly making, using or causing to be made or used, a false statement to avoid, decrease or conceal
an obligation to pay money to the federal government. In addition, the government may assert that a claim including items and services
resulting from a violation of the federal Anti-Kickback Statute constitutes a false or fraudulent claim for purposes of the False Claims Act;
HIPAA imposes criminal and civil liability for, among other things, knowingly and willfully executing, or attempting to execute, a scheme
to defraud or to obtain any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any
of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public
or private), willfully obstructing a criminal investigation of a healthcare offense, and knowingly and willfully falsifying, concealing or
covering up by any trick or device a material fact or making any materially false, fictitious or fraudulent statements in connection with the
delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters;
HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009 (HITECH) and their respective
implementing regulations, which impose requirements on certain covered healthcare providers, health plans, and healthcare clearinghouses,
as well as their respective business associates that perform services for them that involve the creation, use, maintenance or disclosure of,
individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information
without appropriate authorization;
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the federal physician payment transparency requirements, sometimes referred to as the “Physician Payments Sunshine Act,” created under
the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act (the Affordable Care
Act) and its implementing regulations, which require certain manufacturers of drugs, devices, biologics and medical supplies for which
payment is available under Medicare, Medicaid or the Children’s Health Insurance Program (with certain exceptions) to report annually to
the United States Department of Health and Human Services information related to payments or other transfers of value made to physicians
(defined to include doctors, dentists, optometrists, podiatrists and chiropractors) and teaching hospitals, as well as ownership and
investment interests held by physicians and their immediate family members;
the U.S. FDCA, which prohibits, among other things, the adulteration or misbranding of drugs and medical devices;
the Foreign Corrupt Practices Act and similar worldwide anti-bribery laws, which generally prohibit companies and their intermediaries
from making improper payments to non-U.S. officials for the purpose of obtaining or retaining business;
federal consumer protection and unfair competition laws, which broadly regulate marketplace activities and activities that potentially harm
consumers; and
state and foreign equivalents of each of the healthcare laws described above, among others, some of which may be broader in scope and
may apply regardless of the payor.
It is not always possible to identify and deter employee misconduct, and the precautions we take to detect and prevent inappropriate conduct may
not be effective in controlling unknown or unmanaged risks or losses or in protecting us from governmental investigations or other actions or lawsuits
stemming from a failure to be in compliance with such laws or regulations. Efforts to ensure that our business arrangements will comply with applicable
healthcare laws and regulations will involve substantial costs. It is possible that governmental and enforcement authorities will conclude that our business
practices may not comply with current or future statutes, regulations or case law interpreting applicable fraud and abuse or other healthcare laws and
regulations. If any such actions are instituted against us, and we are not successful in defending ourselves or asserting our rights, those actions could have a
significant impact on our business, including the imposition of civil, criminal and administrative penalties, damages, disgorgement, monetary fines,
possible exclusion from participation in Medicare, Medicaid and other federal healthcare programs, contractual damages, reputational harm, diminished
profits and future earnings, and curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and
our results of operations. In addition, the approval and commercialization of any of our current and potential product candidates outside the United States
will also likely subject us to foreign equivalents of the healthcare laws mentioned above, among other foreign laws.
Coverage and reimbursement may be limited or unavailable in certain market segments for our current and potential product candidates, if approved,
which could make it difficult for us to sell our current and potential product candidates profitably.
The commercial success of any current or future product candidate will depend upon the degree of market acceptance by physicians, patients,
insurance companies and other third-party payors, and others in the medical community. Even if we obtain approval to commercialize our current and
potential product candidates outside of the United States, a variety of risks associated with international operations could materially affect our business.
Due to the novel nature of our technology, we face uncertainty related to pricing and reimbursement for our current and potential product candidates. The
insurance coverage and reimbursement status of newly approved products is uncertain. Failure to obtain or maintain adequate coverage and reimbursement
for new or current products could limit our ability to market those products and decrease our ability to generate revenue. If market opportunities for our
current and potential product candidates are smaller than we believe they are, our revenues may be adversely affected and our business may suffer.
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Successful sales of our products, if our current and potential product candidates are approved, depend on the availability of coverage and adequate
reimbursement from third-party payors. In addition, because our current and potential product candidates represent new approaches to the treatment of
cancer and diabetes, we cannot be sure that coverage and reimbursement will be available for, or accurately estimate the potential revenue from, our current
and potential product candidates. Patients who are provided medical treatment for their conditions generally rely on third-party payors to reimburse all or
part of the costs associated with their treatment. Coverage and adequate reimbursement from governmental healthcare programs, such as Medicare and
Medicaid, and commercial payors are critical to new product acceptance.
Government authorities and other third-party payors, such as private health insurers and health maintenance organizations, decide which drugs and
treatments they will cover and the amount of reimbursement. Coverage and reimbursement by a third-party payor may depend upon a number of factors,
including, but not limited to, the third-party payor’s determination that use of a product is:
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a covered benefit under its health plan;
safe, effective and medically necessary;
appropriate for the specific patient;
cost-effective; and
neither experimental nor investigational.
In the United States, no uniform policy of coverage and reimbursement for products exists among third-party payors, and coverage and
reimbursement for products can differ significantly from payor to payor. As a result, obtaining coverage and reimbursement approval of a product from a
government or other third-party payor is a time-consuming and costly process that could require us to provide to each payor supporting scientific, clinical
and cost-effectiveness data for the use of our products and to justify the level of coverage and reimbursement relative to other therapies, with no assurance
that coverage and adequate reimbursement will be obtained. Third party payors may also have difficulty in determining the appropriate coverage of
Oncoprex and our other potential product candidates that are combination products, if approved, due to the fact that they are combination products that
include another drug. To the extent there are any delays in determining such coverage or inadequate coverage and reimbursement for all aspects of our
combination therapies, it would adversely affect the market acceptance, demand and use of our current and potential product candidates. Any denial in
coverage or reduction in reimbursement from Medicare or other government programs may result in a similar denial or reduction in payments from private
payors, which may adversely affect our future profitability.
We intend to seek approval to market our current and potential product candidates in both the United States and in selected foreign jurisdictions. If
we obtain approval in one or more foreign jurisdictions for our current and potential product candidates, we will be subject to rules and regulations in those
jurisdictions. In some foreign countries, particularly those in the European Union, the pricing of biologics is subject to governmental control and other
market regulations which could put pressure on the pricing and usage of our current and potential product candidates. In these countries, pricing
negotiations with governmental authorities can take considerable time after obtaining marketing approval of a product candidate. In addition, market
acceptance and sales of our current and potential product candidates will depend significantly on the availability of coverage and adequate reimbursement
from third-party payors for our current and potential product candidates and may be affected by existing and future health care reform measures.
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Healthcare legislative reform measures may have a material adverse effect on our business and results of operations.
Third-party payors, whether domestic or foreign, or governmental or commercial, are developing increasingly sophisticated methods of
controlling healthcare costs. In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to
the health care system that could affect our ability to sell our products profitably. In particular the Affordable Care Act and its implementing regulations,
among other things, subjected biological products to potential competition by lower-cost biosimilars, revised the methodology by which rebates owed by
manufacturers to the state and federal government for covered outpatient drugs and certain biologics, including our current and potential product
candidates, under the Medicaid Drug Rebate Program are calculated, increased the minimum Medicaid rebates owed by most manufacturers under the
Medicaid Drug Rebate Program, extended the Medicaid Drug Rebate program to utilization of prescriptions of individuals enrolled in Medicaid managed
care organizations, subjected manufacturers to new annual fees and taxes for certain branded prescription drugs, and provided incentives to programs that
increase the federal government’s comparative effectiveness research. The current Presidential Administration and U.S. Congress may seek to modify,
repeal, or otherwise invalidate all, or certain provisions of, the Affordable Care Act. There have been judicial and Congressional challenges to certain
aspects of the Affordable Care Act. As a result, there have been delays in the implementation of, and action taken to repeal or replace, certain aspects of the
Affordable Care Act. While the extent to which any such changes may affect our business is uncertain, steps have been taken to repeal and replace certain
aspects of the Affordable Care Act.
Since January 2017, President Trump has signed two Executive Orders designed to delay the implementation of certain provisions of the
Affordable Care Act or otherwise circumvent some of the requirements for health insurance mandated by the Affordable Care Act. Concurrently, Congress
has considered legislation that would repeal or repeal and replace all or part of the Affordable Care Act. While Congress has not passed comprehensive
repeal legislation, two bills affecting the implementation of certain taxes under the Affordable Care Act have been signed into law. The Tax Cuts and Jobs
Act of 2017 includes a provision repealing, effective January 1, 2019, the tax-based shared responsibility payment imposed by the Affordable Care Act on
certain individuals who fail to maintain qualifying health coverage for all or part of a year that is commonly referred to as the “individual
mandate.” Additionally, on January 22, 2018, President Trump signed a continuing resolution on appropriations for fiscal year 2018 that delayed the
implementation of certain Affordable Care Act-mandated fees, including the so-called “Cadillac” tax on certain high cost employer-sponsored insurance
plans, the annual fee imposed on certain health insurance providers based on market share, and the medical device excise tax on non-exempt medical
devices. Further, the Bipartisan Budget Act of 2018, among other things, amends the Affordable Care Act, effective January 1, 2019, to close the coverage
gap in most Medicare drug plans, commonly referred to as the “donut hole.” Congress also could consider subsequent legislation to repeal or repeal and
replace other elements of the Affordable Care Act. We continue to evaluate the possible impact of the Affordable Care Act, as amended, and the possible
repeal and/or replacement of the Affordable Care Act on our business.
In late 2018, the Centers for Medicare & Medicaid Services, or CMS, issued an advance notice of proposed rulemaking describing a potential
mandatory model to test Medicare reimbursement based on an “International Pricing Index,” or IPI. At the time CMS was considering issuing a proposed
rule that would describe the model in more detail in spring 2019, with the goal of starting the model in spring 2020. As of February 1, 2020, the proposed
rule has yet to be released; however, if such model proceeds as described, we cannot predict the requisite infrastructure and reporting requirements, existing
and new data sources required to establish an IPI and the impact on price reporting and reporting mechanics.
There have been, and likely will continue to be, legislative and regulatory proposals at the foreign, federal and state levels directed at broadening
the availability of healthcare and containing or lowering the cost of healthcare. We cannot predict the initiatives that may be adopted in the future. The
continuing efforts of the government, insurance companies, managed care organizations and other payors of healthcare services to contain or reduce costs
of healthcare and/or impose price controls may adversely affect:
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the demand for our current and potential product candidates, if we obtain regulatory approval;
our ability to set a price that we believe is fair for our products;
our ability to generate revenue and achieve or maintain profitability;
the level of taxes that we are required to pay; and
the availability of capital.
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We and our contract manufacturers are subject to significant regulation with respect to manufacturing our products. The manufacturing facilities on
which we rely may not continue to meet regulatory requirements and have limited capacity.
We are currently utilizing contract manufacturers for the production of the active pharmaceutical ingredients and the formulation of drug product
for our trials of Oncoprex. However, we do not have agreements for supplies of Oncoprex or any of our other potential product candidates. Each supplier
may require licenses to manufacture such components if such processes are not owned by the supplier or in the public domain and we may be unable to
transfer or sublicense the intellectual property rights we may have or later obtain with respect to such activities.
All entities involved in the preparation of therapeutics for clinical trials or commercial sale, including our existing contract manufacturers for
Oncoprex, are subject to extensive regulation. Components of a finished therapeutic product approved for commercial sale or used in late-stage clinical
trials must be manufactured in accordance with GMP. These regulations govern manufacturing processes and procedures (including record keeping) and the
implementation and operation of quality systems to control and assure the quality of investigational products and products approved for sale. Poor control
of production processes can lead to the introduction of contaminants, or to inadvertent changes in the properties or stability of our current and potential
product candidates that may not be detectable in final product testing. We or our contract manufacturers must supply all necessary documentation in
support of a BLA on a timely basis and must adhere to the FDA’s GLP and GMP regulations enforced by the FDA through its facilities inspection program.
Our facilities and quality systems and the facilities and quality systems of some or all of our third-party contractors must pass a pre-approval inspection for
compliance with the applicable regulations as a condition of regulatory approval of our current and potential product candidates or any of our other
potential products. In addition, the regulatory authorities may, at any time, audit or inspect a manufacturing facility involved with the preparation of our
current and potential product candidates or our other potential products or the associated quality systems for compliance with the regulations applicable to
the activities being conducted. If these facilities do not pass a pre-approval plant inspection, FDA approval of the products may not be granted.
The regulatory authorities also may, at any time following approval of a product for sale, audit our manufacturing facilities or those of our third-
party contractors. If any such inspection or audit identifies a failure to comply with applicable regulations or if a violation of our product specifications or
applicable regulations occurs independent of such an inspection or audit, we or the relevant regulatory authority may require remedial measures that may
be costly and/or time-consuming for us or a third party to implement and that may include the temporary or permanent suspension of a clinical trial or
commercial sales or the temporary or permanent closure of a facility. Any such remedial measures imposed upon us or third parties with whom we contract
could materially harm our business.
If we or any of our third-party manufacturers fail to maintain regulatory compliance, the FDA can impose regulatory sanctions including, among
other things, refusal to approve a pending application for a new drug product or biologic product or revocation of a pre-existing approval. As a result, our
business, financial condition and results of operations may be materially harmed.
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Additionally, if supply from one approved manufacturer is interrupted, there could be a significant disruption in commercial supply. An alternative
manufacturer would need to be qualified through a BLA supplement which could result in further delay. The regulatory agencies may also require
additional studies if a new manufacturer is relied upon for commercial production. Switching manufacturers may involve substantial costs and is likely to
result in a delay in our desired clinical and commercial timelines.
These factors could cause the delay of clinical trials, regulatory submissions, required approvals or commercialization of our current and potential
product candidates, cause us to incur higher costs and prevent us from commercializing our products successfully. Furthermore, if our suppliers fail to meet
contractual requirements, and we are unable to secure one or more replacement suppliers capable of production at a substantially equivalent cost, our
clinical trials may be delayed or we could lose potential revenue.
If we obtain approval to commercialize any of our product candidates outside the United States, a variety of risks associated with international
operations could materially adversely affect our business.
We expect that we will be subject to additional risks in commercializing any of our product candidates outside the United States, including the
following, any one or combination of which could have a material adverse effect on our business:
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different regulatory requirements for approval of drugs and biologics in foreign countries;
reduced protection for intellectual property rights;
unexpected changes in tariffs, trade barriers and regulatory requirements;
economic weakness, including inflation, or political instability in particular foreign economies and markets;
compliance with tax, employment, immigration and labor laws for employees living or traveling abroad;
foreign currency fluctuations, which could result in increased operating expenses and reduced revenues, and other obligations incident to
doing business in another country;
workforce uncertainty in countries where labor unrest is more common than in the United States;
production shortages resulting from any events affecting raw material supply or manufacturing capabilities abroad; and
business interruptions resulting from geopolitical actions, including war and terrorism or natural disasters including earthquakes, typhoons,
floods, fires and medical epidemics.
If we fail to comply with environmental, health and safety laws and regulations, we could become subject to fines or penalties or incur costs that could
have a material adverse effect on the success of our business.
We may become subject to federal, state and local laws and regulations governing the use, manufacture, storage, handling and disposal of
hazardous materials and certain waste products, including numerous environmental, health and safety laws and regulations, such as those governing
laboratory procedures and the handling, use, storage, treatment and disposal of hazardous materials and wastes. Our operations may in the future involve
the use of hazardous materials, including chemicals and biological materials. Our operations may also produce hazardous waste products. We generally
contract with third parties for the disposal of these materials and wastes. We cannot eliminate the risk of contamination or injury from these materials. In
the event of contamination or injury resulting from our use of hazardous materials, we could be held liable for any resulting damages, and any liability
could exceed our resources. We also could incur significant costs associated with civil or criminal fines and penalties. In addition, we may incur substantial
costs in order to comply with current or future environmental, health and safety laws and regulations. These current or future laws and regulations may
impair our research, development or production efforts. Failure to comply with these laws and regulations also may result in substantial fines, penalties or
other sanctions.
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Risks Related to Our Dependence on Third Parties
We may not be successful in establishing and maintaining development and commercialization collaborations, which could adversely affect our ability
to develop certain of our current and potential product candidates and our financial condition and operating results.
Because developing pharmaceutical products, conducting clinical trials, obtaining regulatory approval, establishing manufacturing capabilities and
marketing approved products are expensive, we may enter into collaborations with companies that have the required expertise. Additionally, if any of our
current and potential product candidates receives marketing approval, we may enter into sales and marketing arrangements with third parties. If we are
unable to enter into arrangements on acceptable terms, if at all, we may be unable to effectively market and sell our products in our target markets. We
expect to face competition in seeking appropriate collaborators. Moreover, collaboration arrangements are complex and time consuming to negotiate,
document and implement and they may require substantial resources to maintain. We may not be successful in our efforts to establish and implement
collaborations or other alternative arrangements for the development of our current and potential product candidates.
When we collaborate with a third party for development and commercialization of a product candidate, we can expect to relinquish some or all of
the control over the future success of that product candidate to the third party.
One or more of our collaboration partners may not devote sufficient resources to the commercialization of our current and potential product
candidates or may otherwise fail in their commercialization. The terms of any collaboration or other arrangement that we establish may contain provisions
that are not favorable to us. In addition, any collaboration that we enter into may be unsuccessful in the development and commercialization of our current
and potential product candidates. In some cases, we may be responsible for continuing preclinical and initial clinical development of a product candidate or
research program under a collaboration arrangement, and the payment we receive from our collaboration partner may be insufficient to cover the cost of
this development. If we are unable to reach agreements with suitable collaborators for our current and potential product candidates, we would face
increased costs, we may be forced to limit the number of our current and potential product candidates we can commercially develop or the territories in
which we commercialize them. As a result, we might fail to commercialize products or programs for which a suitable collaborator cannot be found. If we
fail to achieve successful collaborations, our operating results and financial condition could be materially and adversely affected.
We rely, and expect to continue to rely, on third parties to conduct, supervise and monitor our clinical trials, and if these third parties perform in an
unsatisfactory manner, it may harm our business.
We rely on CROs and clinical trial sites to ensure our clinical trials are conducted properly and on time. While we have agreements governing
their activities, we may have limited influence over their actual performance. We control only certain aspects of our CROs’ activities. Nevertheless, we are
responsible for ensuring that each of our clinical trials is conducted in accordance with the applicable protocol, legal, regulatory and scientific standards,
and our reliance on the CROs does not relieve us of our regulatory responsibilities.
We and our CROs are required to comply with the GCPs for conducting, recording and reporting the results of clinical trials to assure that the data
and reported results are credible and accurate and that the rights, integrity and confidentiality of clinical trial participants are protected. The FDA enforces
these GCPs through periodic inspections of study sponsors, principal investigators and clinical trial sites. If we or our CROs fail to comply with applicable
GCPs, the clinical data generated in our future clinical trials may be deemed unreliable, and the FDA may require us to perform additional clinical trials
before approving any marketing applications. Upon inspection, the FDA may determine that our clinical trials did not comply with GCPs. In addition, our
ongoing and future clinical trials will require a sufficient number of test subjects to evaluate the safety and effectiveness of our current and potential
product candidates. Accordingly, if our CROs fail to comply with these regulations or fail to recruit a sufficient number of patients, we may be required to
repeat such clinical trials, which would delay the regulatory approval process.
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Our CROs are not our employees, and we are not able to directly monitor whether or not they devote sufficient time and resources to our clinical
and nonclinical programs. These CROs may also have relationships with other commercial entities, including our competitors, for whom they may also be
conducting clinical trials or other drug development activities that could harm our competitive position. If our CROs do not successfully carry out their
contractual duties or obligations, fail to meet expected deadlines, or if the quality or accuracy of the clinical data they obtain is compromised due to their
failure to adhere to our clinical protocols or regulatory requirements, or for any other reasons, our clinical trials may be extended, delayed or terminated,
and we may not be able to obtain regulatory approval for or successfully commercialize our current and potential product candidates. As a result, our
financial results and the commercial prospects for our current and potential product candidates would be harmed, our costs could increase and our ability to
generate revenues could be delayed.
We rely, and expect to continue to rely, on third parties to distribute, manufacture and perform release testing for our current and potential product
candidates and other key materials and if such third parties do not carry out their contractual duties or meet expected deadlines, we may not be able to
obtain regulatory approvals for our current and potential product candidates.
We rely, and intend to continue to rely on third-party contract manufacturing organizations, or CMOs, to produce our current and potential product
candidates and other key materials and on third-party contract testing organizations, or CTOs, for the establishment and performance of validated product
release assays, but we have not entered into binding agreements with any such CMOs or CTOs to support commercialization. Additionally, any CMO may
not have experience producing our current and potential product candidates at commercial levels and may not achieve the necessary regulatory approvals or
produce our products at the quality, quantities, locations and timing needed to support commercialization. We may not have full control of these CMOs, and
they may prioritize other customers or be unable to provide us with enough manufacturing capacity to meet our objectives. We may change our
manufacturing process, and there can be no guarantee that the regulatory authorities will approve any new process in a timely manner or ever. Also, as a
consequence of the manufacturing change, there may be a requirement to conduct additional preclinical safety or efficacy studies, develop new
manufacturing and release assays and/or repeat all or part of the ascending dose safety study in animals or humans. Regulatory requirements ultimately
imposed could adversely affect our ability to test, manufacture or market products.
Historically, part of our manufacturing process was conducted in manufacturing facilities at MD Anderson Cancer Center. We are transferring this
portion of the process to a third-party manufacturer. Although we have contracted with contract manufacturers with capabilities to produce the products that
we require, no assurance can be given that such contract manufacturers will be able to, and receive all approvals to, produce product sufficient for our
trials. In accordance with current GMPs, changing manufacturers may require the re-validation of manufacturing processes and procedures, and may
require further preclinical studies or clinical trials to show comparability between the materials produced by different manufacturers. Changing our current
or future contract manufacturers may be difficult and could be costly if we do make such a change, which could result in our inability to manufacture our
clinical product candidate and a delay in the development of our clinical product candidate. Further, in order to maintain our development timelines in the
event of a change in a third-party contract manufacturer, we may incur higher costs to manufacture our clinical product candidate. There can be no
guarantee that the regulatory authorities will approve any new process in a timely manner or ever. Regulatory requirements ultimately imposed could
adversely affect our ability to test, manufacture or market products.
We intend to rely on third-party manufacturers for our clinical trials and commercialization. We may be unable to negotiate binding agreements
with manufacturers to support our commercialization activities at commercially reasonable terms.
No manufacturer we know of currently has the experience or ability to produce our current and potential product candidates at reasonable
commercial levels or under full commercial requirements. We may encounter technical or scientific issues related to manufacturing or development that we
may be unable to resolve in a timely manner or with available funds. Further, we have not fully completed the characterization and validation activities
necessary for commercial and regulatory approvals. If our manufacturing and testing partners do not enable such regulatory approvals, our
commercialization efforts may be harmed.
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Even if we timely develop a manufacturing process for Oncoprex and successfully transfer it to third-party manufacturers, if such third-party
manufacturers are unable to produce our current and potential product candidates in the necessary quantities, or in compliance with GMP or in compliance
with pertinent regulatory requirements, and within our planned time frame and cost parameters, the development and sales of our products, if approved,
may be materially harmed. The facilities used by our contract manufacturers to manufacture our current and potential product candidates must be approved
by the FDA as part of our BLA package, pursuant to inspections that will be conducted after we submit our BLA to the FDA. Although we provide
specifications, we do not control the manufacturing process of, and are completely dependent on, our contract manufacturing partners for compliance with
GMPs for the manufacture of our current and potential product candidates. If our contract manufacturers cannot successfully manufacture material that
conforms to our specifications and the strict regulatory requirements of the FDA or others, we will not be able to secure and/or maintain regulatory
approval covering their manufacturing facilities. In addition, we have limited control over the ability of our contract manufacturers to maintain adequate
quality control, quality assurance and qualified personnel. If the FDA or a comparable foreign regulatory authority does not approve these facilities for the
manufacture of our current and potential product candidates or if it withdraws any such approval in the future, we may need to find alternative
manufacturing facilities, which would significantly affect our ability to develop, obtain regulatory approval for or market our current and potential product
candidates, if approved. In addition, any failure to achieve and maintain compliance with these laws, regulations and standards could subject us to the risk
that we may have to suspend the manufacturing of our current and potential product candidates or that obtained approvals could be revoked, which would
adversely affect our business and reputation.
In addition, any significant disruption in our supplier relationships could harm our business. We source key materials, devices and equipment from
third parties, either directly through agreements with suppliers or indirectly through our manufacturers who have agreements with suppliers. There is a
small number of suppliers for certain key materials and components that are used to manufacture our current and potential product candidates. Such
suppliers may not sell these key materials to our manufacturers at the times or quantities we need them or on commercially reasonable terms. We may not
have any control over the process or timing of the acquisition of these key materials by our manufacturers.
We also expect to rely on other third parties to store and distribute our products for our clinical trials. Any performance failure on the part of these
third parties could delay clinical development or marketing approval of our current and potential product candidates or commercialization of our products,
if approved, producing additional losses and depriving us of potential product revenue.
We have completed and may in the future complete related party transactions that were not and may not be conducted on an arm’s length basis.
Our leading drug candidate, Oncoprex, is based upon patents and related technology covered by a patent and technology license agreement
between MD Anderson and Introgen Therapeutics, Inc. (such technology license agreement is referred to as the “MD Anderson License Agreement”),
under which we have rights to patents covering use of various genes, including the TUSC2 gene, for treatment of cancer, as well as know-how and related
intellectual property. In 2007, the MD Anderson License Agreement was sublicensed by Introgen Therapeutics, Inc. to Introgen Research Institute, Inc., a
Texas corporation (IRI) and in 2009 this sublicense was assigned by IRI to us, and we granted back to IRI a nonexclusive, royalty-free license to use and
practice the licensed technology for non-commercial research purposes. As consideration for this assignment, we agreed to assume all of IRI’s obligations
to MD Anderson under the MD Anderson License Agreement, including ongoing patent related expenses and royalty obligations. IRI also agreed in 2011
to provide additional technology licensing opportunities and services to us in return for monthly payments and our obligation to pay to IRI a royalty of
1% on sales of products licensed to us under the MD Anderson License Agreement. We also granted a non-exclusive, royalty-free sublicense to IRI in 2011
for non-commercial research purposes. IRI’s obligations to provide additional technology licensing opportunities and services to us, and our obligation to
make monthly payments to IRI, were terminated in 2012; however, our obligation to pay the 1% royalty to IRI upon sales of products licensed to us under
the MD Anderson License Agreement is ongoing. This royalty obligation continues for 21 years after the later of the termination of the MD Anderson
License Agreement and the termination of the sublicense assigned by IRI to us. IRI is controlled by Rodney Varner and his immediate family members. Mr.
Varner is currently Chairman of our board of directors, having joined our board of directors on August 15, 2012, and has been our Chief Executive Officer
since August 29, 2012; accordingly, in 2009 and 2011, when the above referenced agreements between IRI and Genprex were entered into, Mr. Varner was
neither a member of our board of directors nor an executive officer of Genprex. When the 2011 agreement was entered into, Mr. Varner was deemed to be
an “affiliate” of the Company due to his beneficial ownership of approximately 39% of our issued and outstanding shares at that time. Although we believe
that these transactions were conducted on an arm’s length basis, it is possible that the terms were less favorable to us than they might have been in a
transaction with an unrelated party.
We have adopted a written related-person transactions policy that sets forth our policies and procedures regarding the identification, review, consideration
and oversight of related-person transactions.
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Risks Related to Our Intellectual Property
If we fail to obtain or protect our intellectual property, our business will be impaired.
If we are unable to obtain or protect intellectual property rights related to our current and potential product candidates, we may not be able to
compete effectively in our markets. Third party claims of intellectual property infringement may prevent or delay our development and commercialization
efforts. We may not be successful in obtaining or maintaining necessary rights to product components and processes for our development pipeline through
acquisitions and licenses.
If we fail to comply with our obligations in the agreements under which we license intellectual property rights from third parties or otherwise
experience disruptions to our business relationships with our licensors, we could lose license rights that are important to our business. We may be involved
in lawsuits to protect or enforce our patents or the patents or our licensors, which could be expensive, time-consuming, and/or unsuccessful.
Obtaining and maintaining patent protection depends upon compliance with various procedural, document submission, fee payment, and other
requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for noncompliance with these
requirements. Issued patents covering our current and potential product candidates could be found invalid or unenforceable if challenged in court, or could
expire before we obtain product approval. The scope of our issued patents could be found to be narrower and provide less protection than we anticipate.
If we fail to comply with our obligations in the agreements under which we license intellectual property, we could lose license rights that are important
to our business.
Under our license agreement with MD Anderson, we hold a worldwide, exclusive license to, among other things, manufacture and market
products utilizing certain inventions that are critical to our business. In addition, under the UP License Agreement, UP granted us a worldwide, exclusive
license to certain Licensed Technology (as defined in the UP License Agreement), and a worldwide, non-exclusive license to use certain related know-how,
all related to diabetes gene therapy. In addition, we expect to enter into additional license agreements in the future. Our existing and future license
agreements may impose various payment and other obligations on us. If we fail to comply with our obligations under these agreements, our licensors may
have the right to terminate our licenses, in which event we would not be able to market products covered by such licenses.
Moreover, we may need to obtain licenses from third parties to advance our research or allow commercialization of our current and potential
product candidates; however, we may fail to obtain any of such licenses at a reasonable cost or on reasonable terms, if at all. In that event, we may be
required to expend significant time and resources to develop or license replacement technology. If we are unable to develop or license replacement
technology, we may be unable to develop or commercialize the affected product candidates, which could harm our business significantly. We cannot
provide any assurances that third-party patents do not exist which might be enforced against our current product candidates or future products, resulting in
either an injunction prohibiting our sales, or, with respect to our sales, an obligation on our part to pay royalties and/or other forms of compensation to third
parties.
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In certain cases, patent prosecution of our licensed technology may be controlled solely by the licensor. If our licensors fail to obtain and maintain
patent or other protection for the proprietary intellectual property we license from them, we could lose our rights to the intellectual property or our
exclusivity with respect to those rights, and our competitors could market competing products using the intellectual property. In addition, in certain cases,
we control the prosecution of patents resulting from licensed technology. In the event we breach any of our obligations related to such prosecution, we may
incur significant liability to our licensing partners. Licensing of intellectual property is of critical importance to our business and involves complex legal,
business and scientific issues and is complicated by the rapid pace of scientific discovery in our industry. Disputes may arise regarding intellectual property
subject to a licensing agreement, including, but not limited to:
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the scope of rights granted under the license agreement and other interpretation-related issues;
the extent to which our technology and processes infringe intellectual property of the licensor that is not subject to the licensing agreement;
the sublicensing of patent and other rights under our collaborative development relationships;
our diligence obligations under the license agreement and what activities satisfy those diligence obligations;
the ownership of inventions and know-how resulting from the joint creation or use of intellectual property by our licensors and us and our
partners; and
the priority of invention of patented technology.
If disputes over intellectual property that we have licensed prevent or impair our ability to maintain our current licensing arrangements on
acceptable terms, we may be unable to successfully develop and commercialize the affected product candidates.
The intellectual property rights we have licensed from MD Anderson and the UP are subject to the rights of the U.S. government.
The rights we have obtained pursuant to our license agreement with MD Anderson and the UP are made subject to the rights of the U.S.
government to the extent that the technology covered by the licensed intellectual property was developed under a funding agreement between such
institution and the U.S. government. Additionally, to the extent there is any conflict between our license agreement and applicable laws or regulations,
applicable laws and regulations will prevail. Similarly, to the extent there is any conflict between our license agreement with one of these institutions and
the institution’s funding agreement with the US government, the terms of the funding agreement will prevail. Some, and possibly all, of our licensed
intellectual property rights have been developed in the course of research funded by the U.S. government. As a result, the U.S. government may have
certain rights to intellectual property embodied in our current or future products pursuant to the Bayh-Dole Act of 1980. Government rights in certain
inventions developed under a government-funded program include a non-exclusive, non-transferable, irrevocable worldwide license to use inventions for
any governmental purpose. In addition, the U.S. government has the right to require us, or an assignee or exclusive licensee to such inventions, to grant
licenses to any of these inventions to a third party if the U.S. government determines that adequate steps have not been taken to commercialize the
invention, that government action is necessary to meet public health or safety needs, that government action is necessary to meet requirements for public
use under federal regulations, or that the right to use or sell such inventions is exclusively licensed to an entity within the U.S. and substantially
manufactured outside the U.S. without the U.S. government’s prior approval. Additionally, we may be restricted from granting exclusive licenses for the
right to use or sell our inventions created pursuant to such agreements unless the licensee agrees to additional restrictions (e.g., manufacturing substantially
all of the invention in the U.S.). The U.S. government also has the right to take title to these inventions if we fail to disclose the invention to the
government and fail to file an application to register the intellectual property within specified time limits. In addition, the U.S. government may acquire
title in any country in which a patent application is not filed within specified time limits. Additionally, certain inventions are subject to transfer restrictions
during the term of these agreements and for a period thereafter, including sales of products or components, transfers to foreign subsidiaries for the purpose
of the relevant agreements, and transfers to certain foreign third parties. If any of our intellectual property becomes subject to any of the rights or remedies
available to the U.S. government or third parties pursuant to the Bayh-Dole Act of 1980, this could impair the value of our intellectual property and could
adversely affect our business. The U.S. government has not exercised any of these rights or provided us with any notice of its intent to exercise any of these
rights with respect to any of the intellectual property licensed to us by MD Anderson or UP.
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If we are unable to protect our intellectual property rights or if our intellectual property rights are inadequate for our technology and product
candidates, our competitive position could be harmed.
Our commercial success will depend in part on our ability and the ability of our licensors to obtain and maintain patent and other intellectual
property protection in the United States and other countries with respect to our proprietary technology and products. We rely on trade secret, patent,
copyright and trademark laws, and confidentiality, licensing and other agreements with employees and third parties, all of which offer only limited
protection. We seek to protect our proprietary position by filing and prosecuting patent applications in the United States and abroad related to our novel
technologies and products that are important to our business.
The patent positions of biotechnology and pharmaceutical companies generally are highly uncertain, involve complex legal and factual questions
and have in recent years been the subject of much litigation. As a result, the issuance, scope, validity, enforceability and commercial value of our patents,
including those patent rights licensed to us by third parties, are highly uncertain. The steps we or our licensors have taken to protect our proprietary rights
may not be adequate to preclude misappropriation of our proprietary information or infringement of our intellectual property rights, both inside and outside
of the United States. Further, the examination process may require us or our licensors to narrow the claims for our pending patent applications, which may
limit the scope of patent protection that may be obtained if these applications issue. The rights already granted under any of our currently issued patents or
those licensed to us and those that may be granted under future issued patents may not provide us with the proprietary protection or competitive advantages
we are seeking. If we or our licensors are unable to obtain and maintain patent protection for our technology and products, or if the scope of the patent
protection obtained is not sufficient, our competitors could develop and commercialize technology and products similar or superior to ours, and our ability
to successfully commercialize our technology and products may be adversely affected. It is also possible that we or our licensors will fail to identify
patentable aspects of inventions made in the course of our development and commercialization. It is also possible that as research and development
progresses, the direction of our intellectual property strategy and patent portfolio will change, resulting in strategic business decisions to allow certain
patents or patent applications to be abandoned or lapse.
With respect to patent rights, we do not know whether any of the pending patent applications relating to any of our current and potential product
candidates will result in the issuance of patents that effectively protect our technology or products, or if any of our licensors’ issued patents will effectively
prevent others from commercializing competitive technologies and products. Publications of discoveries in the scientific literature often lag behind the
actual discoveries, and patent applications in the United States and other jurisdictions are typically not published until 18 months after filing or in some
cases not at all, until they are issued as a patent. Therefore, we cannot be certain that we or our licensors were the first to make the inventions claimed in
our owned or licensed patents or pending patent applications, or that we or our licensors were the first to file for patent protection of such inventions.
Our pending applications cannot be enforced against third parties practicing the technology claimed in such applications unless and until a patent
issues from such applications. Because the issuance of a patent is not conclusive as to its inventorship, scope, validity or enforceability, issued patents that
we have licensed from third parties may be challenged in the courts or patent offices in the United States and abroad. Such challenges may result in the loss
of patent protection, the narrowing of claims in such patents or the invalidity or unenforceability of such patents, which could limit our ability to stop others
from using or commercializing similar or identical technology and products, or limit the duration of the patent protection for our technology and products.
Protecting against the unauthorized use of our or our licensor’s patented technology, trademarks and other intellectual property rights is expensive, difficult
and may in some cases not be possible. In some cases, it may be difficult or impossible to detect third-party infringement or misappropriation of our
intellectual property rights, even in relation to issued patent claims, and proving any such infringement may be even more difficult.
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Third-party claims of intellectual property infringement may prevent or delay our development and commercialization efforts.
Our commercial success depends in part on our avoiding infringement of the patents and proprietary rights of third parties. There is a substantial
amount of litigation, both within and outside the United States, involving patent and other intellectual property rights in the biotechnology and
pharmaceutical industries, including patent infringement lawsuits, interferences, oppositions and inter partes reexamination proceedings before the US
Patent and Trademark Office (US PTO) and corresponding foreign patent offices. Numerous US and foreign issued patents and pending patent applications,
which are owned by third parties, exist in the fields in which we are pursuing development candidates. As the biotechnology and pharmaceutical industries
expand and more patents are issued, the risk increases that our current and potential product candidates may be subject to claims of infringement of the
patent rights of third parties.
Third parties may in the future assert that we are employing their proprietary technology without authorization. There may be third-party patents
or patent applications with claims to materials, formulations, methods of manufacture or methods for treatment related to the use or manufacture of our
current and potential product candidates. Because patent applications can take many years to issue, there may be currently pending patent applications
which may later result in issued patents that our current and potential product candidates may infringe. In addition, third parties may obtain patents in the
future and claim that use of our technologies infringes upon these patents. If any third-party patents were held by a court of competent jurisdiction to cover
the manufacturing process of any of our current and potential product candidates, or any final product itself, the holders of any such patents may be able to
block our ability to commercialize such product candidate unless we obtained a license under the applicable patents, or until such patents expire.
Similarly, if any third-party patents were held by a court of competent jurisdiction to cover aspects of our formulations, processes for manufacture
or methods of use, including combination therapy, the holders of any such patents may be able to block our ability to develop and commercialize the
applicable product candidate unless we obtained a license or until such patent expires. In either case, such a license may not be available on commercially
reasonable terms or at all.
Parties making claims against us may obtain injunctive or other equitable relief, which could effectively block our ability to further develop and
commercialize one or more of our current and potential product candidates. Defense of these claims, regardless of their merit, may involve substantial
litigation expense and would be a substantial diversion of employee resources from our business. In the event of a successful claim of infringement against
us, we may have to pay substantial damages, including treble damages and attorneys’ fees for willful infringement, pay royalties, redesign our infringing
products or obtain one or more licenses from third parties, which may be impossible or require substantial time and monetary expenditure.
We may not be successful in obtaining or maintaining necessary rights to product components and processes for our development pipeline through
acquisitions and in-licenses.
Presently we believe that we have rights to the intellectual property, through licenses from third parties to develop our current and potential
product candidates. Because our programs may involve additional product candidates that may require the use of proprietary rights held by third parties, the
growth of our business may depend in part on our ability to acquire, in-license or use these proprietary rights. In addition, our current and potential product
candidates may require specific formulations to work effectively and efficiently and these rights may be held by others. We may be unable to acquire or in-
license any compositions, methods of use, processes or other third-party intellectual property rights from third parties on reasonable terms, if at all. The
licensing and acquisition of third-party intellectual property rights is a competitive area, and a number of more established companies are also pursuing
strategies to license or acquire third-party intellectual property rights that we may consider attractive. These established companies may have a competitive
advantage over us due to their size, cash resources and greater clinical development and commercialization capabilities.
If we are unable to successfully obtain rights to required third-party intellectual property rights, our business, financial condition and prospects for
growth could suffer.
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Confidentiality agreements with employees and others may not adequately prevent disclosure of trade secrets and other proprietary information and
may not adequately protect our intellectual property.
We rely on trade secrets to protect our proprietary technologies, especially where we do not believe patent protection is appropriate or obtainable.
However, trade secrets are difficult to protect. We rely in part on confidentiality agreements with our employees, consultants, outside scientific
collaborators, sponsored researchers and other advisors to protect our trade secrets and other proprietary information. These agreements may not effectively
prevent disclosure of confidential information and may not provide an adequate remedy in the event of unauthorized disclosure of confidential information.
In addition, others may independently discover our trade secrets and proprietary information. Costly and time-consuming litigation could be necessary to
enforce and determine the scope of our proprietary rights, and failure to obtain or maintain trade secret protection could adversely affect our competitive
business position.
Our reliance on third parties may require us to share our trade secrets, which increases the possibility that a competitor will discover them or that our
trade secrets will be misappropriated or disclosed.
Because we rely on third parties to manufacture our current and potential product candidates, and because we collaborate with various
organizations and academic institutions on the advancement of our current and potential product candidates, we must, at times, share trade secrets with
them. We seek to protect our proprietary technology in part by entering into confidentiality agreements and, if applicable, material transfer agreements,
collaborative research agreements, consulting agreements or other similar agreements with our manufacturers, collaborators, advisors, employees and
consultants prior to beginning research or disclosing proprietary information. These agreements typically limit the rights of the third parties to use or
disclose our confidential information, such as trade secrets. Despite the contractual provisions employed when working with third parties, the need to share
trade secrets and other confidential information increases the risk that such trade secrets become known by our competitors, are inadvertently incorporated
into the technology of others, are used inappropriately to create new inventions or are disclosed or used in violation of these agreements. Given that our
proprietary position is based, in part, on our know-how and trade secrets, a competitor’s discovery of our trade secrets or other unauthorized use or
disclosure would impair our competitive position and may have a material adverse effect on our business.
In addition, these agreements typically restrict the ability of our collaborators, advisors, employees and consultants to publish data potentially
relating to our trade secrets. Our academic collaborators typically have rights to publish data, provided that we are notified in advance and may delay
publication for a specified time in order to secure our intellectual property rights arising from the collaboration. In other cases, publication rights are
controlled exclusively by us, although in some cases we may share these rights with other parties. We may also conduct joint research and development
programs that may require us to share trade secrets under the terms of research and development partnerships or similar agreements. Despite our efforts to
protect our trade secrets, our competitors may discover our trade secrets through breach of these agreements, independent development or publication of
information including our trade secrets in cases where we do not have proprietary or otherwise protected rights at the time of publication. A competitor’s
discovery of our trade secrets may impair our competitive position and have an adverse impact on our business.
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We may be involved in lawsuits to protect or enforce our patents or the patents of our licensors, which could be expensive, time-consuming and
unsuccessful.
Competitors may infringe our patents or the patents of our licensors. To counter infringement or unauthorized use, we may be required to file
infringement claims, which can be expensive and time-consuming. In addition, in an infringement proceeding, a court may decide that a patent of ours or
our licensors is not valid, is unenforceable and/or is not infringed, or may refuse to stop the other party from using the technology at issue on the grounds
that our patents do not cover the technology in question. An adverse result in any litigation or defense proceedings could put one or more of our patents at
risk of being invalidated or interpreted narrowly and could put our patent applications at risk of not issuing.
Interference proceedings provoked by third parties or brought by us may be necessary to determine the priority of inventions with respect to our
patents or patent applications or those of our licensors. An unfavorable outcome could require us to cease using the related technology or to attempt to
license rights to it from the prevailing party. Our business could be harmed if the prevailing party does not offer us a license on commercially reasonable
terms. Our defense of litigation or interference proceedings may fail and, even if successful, may result in substantial costs and distract our management
and other employees. We may not be able to prevent, alone or with our licensors, misappropriation of our intellectual property rights, particularly in
countries where the laws may not protect those rights as fully as in the United States.
Furthermore, because of the substantial amount of discovery required in connection with intellectual property litigation, there is a risk that some of
our confidential information could be compromised by disclosure during this type of litigation. There could also be public announcements of the results of
hearings, motions or other interim proceedings or developments. If securities analysts or investors perceive these results to be negative, it could have a
material adverse effect on the price of our common stock.
Obtaining and maintaining our patent protection depends on compliance with various procedural, document submission, fee payment and other
requirements imposed by governmental patent agencies, and our patent protection could be reduced or eliminated for non-compliance with these
requirements.
Periodic maintenance fees, renewal fees, annuity fees and various other governmental fees on patents and/or applications will be due to be paid to
the US PTO and various governmental patent agencies outside of the United States in several stages over the lifetime of the patents and/or applications. We
employ an outside firm and rely on our outside counsel to pay these fees due to non-US patent agencies. The US PTO and various non-US governmental
patent agencies require compliance with a number of procedural, documentary, fee payment and other similar provisions during the patent application
process. Although an inadvertent lapse can be cured by payment of a late fee or by other means in accordance with the applicable rules, there are situations
in which non-compliance can result in abandonment or lapse of the patent or patent application, resulting in partial or complete loss of patent rights in the
relevant jurisdiction. In such an event, our competitors might be able to enter the market which would have a material adverse effect on our business.
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Issued patents covering our current and potential product candidates could be found invalid or unenforceable if challenged in court.
If we or one of our licensing partners, including MD Anderson or UP, initiated legal proceedings against a third party to enforce a patent covering
one of our current and potential product candidates, the defendant could counterclaim that the patent covering our product candidate is invalid and/or
unenforceable. In patent litigation in the United States, defendant counterclaims alleging invalidity and/or unenforceability are commonplace. Grounds for
a validity challenge could be an alleged failure to meet any of several statutory requirements, including lack of novelty, obviousness or non-enablement.
Grounds for an unenforceability assertion could be an allegation that someone connected with prosecution of the patent withheld relevant information from
the US PTO, or made a misleading statement, during prosecution. Third parties may also raise similar claims before administrative bodies in the United
States or abroad, even outside the context of litigation. Such mechanisms include re-examination, post grant review and equivalent proceedings in foreign
jurisdictions (e.g., opposition proceedings). Such proceedings could result in revocation or amendment to our patents in such a way that they no longer
cover our current and potential product candidates. The outcome following legal assertions of invalidity and unenforceability is unpredictable. With respect
to the validity question, for example, we cannot be certain that there is no invalidating prior art, of which we and the patent examiner were unaware during
prosecution. If a defendant were to prevail on a legal assertion of invalidity and/or unenforceability, we would lose at least part, and perhaps all, of the
patent protection on our current and potential product candidates. Such a loss of patent protection would have a material adverse impact on our business.
We may be subject to claims that our employees, consultants or independent contractors have wrongfully used or disclosed confidential information of
third parties or that our employees have wrongfully used or disclosed alleged trade secrets of their former employers.
We now and in the future may employ individuals who were previously employed at universities or other biotechnology or pharmaceutical
companies, including our competitors or potential competitors. Although we try to ensure that our employees, consultants and independent contractors do
not use the proprietary information or know-how of others in their work for us, we may be subject to claims that we or our employees, consultants or
independent contractors have inadvertently or otherwise used or disclosed intellectual property, including trade secrets or other proprietary information, of
any of our employee’s former employer or other third parties. Litigation may be necessary to defend against these claims. If we fail in defending any such
claims, in addition to paying monetary damages, we may lose valuable intellectual property rights or personnel, which could adversely impact our business.
Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and other
employees.
We may be subject to claims challenging the inventorship or ownership of our patents and other intellectual property.
We may be subject to claims that former employees, collaborators or other third parties have an ownership interest in our patents or other
intellectual property. We may have potential ownership disputes arising, for example, from conflicting obligations of consultants, collaborators or others
who are involved in developing our current and potential product candidates. Litigation may be necessary to defend against these and other claims
challenging inventorship or ownership. If we fail in defending any such claims, in addition to paying monetary damages, we may lose valuable intellectual
property rights, such as exclusive ownership of, or right to use, valuable intellectual property. Such an outcome could have a material adverse effect on our
business. Even if we are successful in defending against such claims, litigation could result in substantial costs and be a distraction to management and
other employees.
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Changes in U.S. patent law could diminish the value of patents in general, thereby impairing our ability to protect our products.
The United States has enacted and is currently implementing wide-ranging patent reform legislation. Recent U.S. Supreme Court rulings have
narrowed the scope of patent protection available in certain circumstances and weakened the rights of patent owners in certain situations. In addition to
increasing uncertainty with regard to our ability to obtain patents in the future, this combination of events has created uncertainty with respect to the value
of patents, once obtained. Depending on decisions by the U.S. Congress, the federal courts and the U.S. PTO, the laws and regulations governing patents
could change in unpredictable ways that would weaken our ability to obtain new patents or to enforce our existing patents and patents that we might obtain
in the future.
We have not yet registered the trademark for Oncoprex, and failure to secure such registration could adversely affect our business.
While we have submitted trademark applications for the marks “GENPREX” and “ONCOPREX”, these marks have not yet been approved by the
U.S. Patent and Trademark Office. During trademark registration proceedings, our application may be rejected. Although we would be given an
opportunity to respond to the rejection of a trademark application, we may be unable to overcome such rejection. In addition, with respect to the US PTO
and comparable agencies in many foreign jurisdictions, third parties are given an opportunity to oppose pending trademark applications and to seek to
cancel registered trademarks. Opposition or cancellation proceedings may be filed against our trademarks, and our trademarks may not survive such
proceedings. Moreover, any name we propose to use with our current and potential product candidates in the United States must be approved by the FDA,
regardless of whether we have registered it, or applied to register it, as a trademark. The FDA typically conducts a review of proposed product names,
including an evaluation of potential for confusion with other product names. If the FDA objects to any of our proposed proprietary product names, we may
be required to expend significant additional resources in an effort to identify a suitable substitute name that would qualify under applicable trademark laws,
not infringe the existing rights of third parties and be acceptable to the FDA.
We may not be able to protect our intellectual property rights throughout the world.
Filing, prosecuting and defending patents on product candidates in all countries throughout the world would be prohibitively expensive, and our
intellectual property rights in some countries outside the United States can be less extensive than those in the United States. In addition, the laws of some
foreign countries do not protect intellectual property rights to the same extent as federal and state laws in the United States. Consequently, we may not be
able to prevent third parties from practicing our inventions in all countries outside the United States, or from selling or importing products made using our
inventions in and into the United States or other jurisdictions. Competitors may use our technologies in jurisdictions where we have not obtained patent
protection to develop their own products and further, may export otherwise infringing products to territories where we have patent protection, but
enforcement is not as strong as that in the United States. These products may compete with our products and our patents or other intellectual property rights
may not be effective or sufficient to prevent them from competing.
Many companies have encountered significant problems in protecting and defending intellectual property rights in foreign jurisdictions. The legal
systems of certain countries, particularly certain developing countries, do not favor the enforcement of patents, trade secrets and other intellectual property
protection, particularly those relating to biotechnology products, which could make it difficult for us to stop the infringement of our patents or marketing of
competing products in violation of our proprietary rights generally. Proceedings to enforce our patent rights in foreign jurisdictions could result in
substantial costs and divert our efforts and attention from other aspects of our business, could put our patents at risk of being invalidated or interpreted
narrowly and our patent applications at risk of not issuing and could provoke third parties to assert claims against us. We may not prevail in any lawsuits
that we initiate, and the damages or other remedies awarded, if any, may not be commercially meaningful. Accordingly, our efforts to enforce our
intellectual property rights around the world may be inadequate to obtain a significant commercial advantage from the intellectual property that we develop
or license.
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Risks Related to Employee Matters and Managing Growth
We have no sales, marketing or distribution experience and we will have to invest significant resources to develop those capabilities or enter into
acceptable third-party sales and marketing arrangements.
We have no sales, marketing or distribution experience. To develop sales, distribution and marketing capabilities, we will have to invest significant
amounts of financial and management resources, some of which will need to be committed prior to any confirmation that Oncoprex or any of our other
potential product candidates will be approved by the FDA. For product candidates for which we decide to perform sales, marketing and distribution
functions ourselves or through third parties, we could face a number of additional risks, including that we or our third-party sales collaborators may not be
able to build and maintain an effective marketing or sales force, and we may experience difficulty in managing the growth of our organization. If we use
third parties to market and sell our products, we may have limited or no control over their sales, marketing and distribution activities on which our future
revenues may depend.
We may not be able to manage our business effectively if we are unable to attract and retain key personnel and consultants.
As of March 20, 2020, we had eight full-time employees. As we advance our current and potential product candidates through preclinical studies
and clinical trials, we will need to increase our clinical trial management, product development, manufacturing, regulatory, and administrative headcount to
manage these programs. In addition, to meet our obligations as a public company, we may need to increase our general and administrative capabilities. We
may not be able to attract or retain qualified personnel and consultants due to the intense competition for qualified personnel and consultants among
biotechnology, pharmaceutical and other businesses. If we are not able to attract and retain necessary personnel and consultants to accomplish our business
objectives, we may experience constraints that will significantly impede the achievement of our development objectives, our ability to raise additional
capital and our ability to implement our business strategy.
We are highly dependent on the development, regulatory, commercialization and business development expertise of our management team, key
employees and consultants. Any of our executive officers or key employees or consultants may terminate their employment or engagement with us at any
time. If we lose one or more of our executive officers or key employees or consultants, our ability to implement our business strategy successfully could be
seriously harmed. Replacing executive officers, key employees and consultants may be difficult and may take an extended period of time because of the
limited number of individuals in our industry with the breadth of skills and experience required to develop, gain regulatory approval of and commercialize
products successfully. Competition to hire and retain employees and consultants from this limited pool is intense, and we may be unable to hire, train, retain
or motivate these additional key personnel and consultants. Our failure to retain key personnel or consultants could materially harm our business.
In addition, we have scientific and clinical advisors and consultants who assist us in formulating our research, development and clinical strategies.
These advisors are not our employees and may have commitments to, or consulting or advisory contracts with, other entities that may limit their availability
to us and typically they will not enter into non-compete agreements with us. If a conflict of interest arises between their work for us and their work for
another entity, we may lose their services. In addition, our advisors may have arrangements with other companies to assist those companies in developing
products or technologies that may compete with ours.
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We may use our financial and human resources to pursue a particular research program or product candidate and fail to capitalize on programs or
product candidates that may be more profitable or for which there is a greater likelihood of success.
Because we have limited resources, we may forego or delay pursuit of opportunities with certain programs or product candidates or for indications
that later prove to have greater commercial potential. Our resource allocation decisions may cause us to fail to capitalize on viable commercial products or
profitable market opportunities. Our spending on current and future research and development programs for product candidates may not yield any
commercially viable products. If we do not accurately evaluate the commercial potential or target market for a particular product candidate, we may
relinquish valuable rights to that product candidate through strategic collaboration, licensing or other royalty arrangements in cases in which it would have
been more advantageous for us to retain sole development and commercialization rights to such product candidate, or we may allocate internal resources to
a product candidate in a therapeutic area in which it would have been more advantageous to enter into a partnering arrangement.
If we engage in future acquisitions or strategic partnerships, this may increase our capital requirements, dilute our stockholders, cause us to incur debt
or assume contingent liabilities, and subject us to other risks.
We may evaluate and enter into various acquisitions and strategic partnerships, including licensing or acquiring additional products, intellectual
property rights, technologies, or businesses. Any potential acquisition or strategic partnership may entail numerous risks, including:
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increased operating expenses and cash requirements;
the assumption of additional indebtedness or contingent liabilities;
the issuance of our equity securities;
assimilation of operations, intellectual property and products of an acquired company, including difficulties associated with integrating new
personnel;
difficulties in achieving anticipated cost savings, synergies, business opportunities, and growth prospects from any business combination;
the diversion of our management’s attention from our existing product programs and initiatives in pursuing such a strategic merger or
acquisition;
retention of key employees, the loss of key personnel, and uncertainties in our ability to maintain key business relationships;
risks and uncertainties associated with the other party to such a transaction, including the prospects of that party and their existing products
or product candidates and marketing approvals; and
our inability to generate revenue from acquired technology and/or products sufficient to meet our objectives in undertaking the acquisition
or even to offset the associated acquisition and maintenance costs.
In addition, if we undertake acquisitions, we may issue dilutive securities, assume or incur debt obligations, incur large one-time expenses and
acquire intangible assets that could result in significant future amortization expense. Moreover, we may not be able to locate suitable acquisition
opportunities and this inability could impair our ability to grow or obtain access to technology or products that may be important to the development of our
business.
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Risks Related to our Securities
The market price of our common stock may be highly volatile, and you may lose all or part of your investment.
The market price of our common stock is likely to be volatile. Our stock price could be subject to wide fluctuations in response to a variety of
factors, including the following:
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inability to obtain additional funding;
adverse results or delays in preclinical or clinical trials;
reports of adverse events in other gene therapy products or clinical trials of such products;
any delay in filing an IND or BLA for any of our current and potential product candidates and any adverse development or perceived
adverse development with respect to the FDA’s review of that IND or BLA;
failure to develop successfully and commercialize our current and potential product candidates;
failure to maintain our existing strategic collaborations or enter into new collaborations;
failure by us or our licensors and strategic collaboration partners to prosecute, maintain or enforce our intellectual property rights;
changes in laws or regulations applicable to our products and product candidates;
inability to obtain adequate product supply for our current and potential product candidates or inability to do so at acceptable prices;
adverse regulatory decisions;
introduction of new products, services or technologies by our competitors;
failure to meet or exceed financial projections we may provide to the public;
failure to meet or exceed the financial projections of the investment community;
the perception of the pharmaceutical industry by the public, legislatures, regulators and the investment community;
announcements of significant acquisitions, strategic partnerships, joint ventures or capital commitments by us, our strategic collaboration
partners or our competitors;
disputes or other developments relating to proprietary rights, including patents, litigation matters and our ability to obtain patent protection
for our technologies;
additions or departures of key scientific or management personnel;
significant lawsuits, including patent or stockholder litigation;
changes in the market valuations of similar companies;
sales of our common stock by us or our stockholders in the future; and
trading volume of our common stock.
In addition, companies trading in the stock market in general, and in The Nasdaq Capital Market in particular, have experienced extreme price and
volume fluctuations that have often been unrelated or disproportionate to the operating performance of these companies. Broad market and industry factors
may negatively affect the market price of our common stock, regardless of our actual operating performance.
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We are currently listed on The Nasdaq Capital Market. If we are unable to maintain listing of our securities on Nasdaq or any stock exchange, our
stock price could be adversely affected and the liquidity of our stock and our ability to obtain financing could be impaired and it may be more difficult
for our stockholders to sell their securities.
Our common stock is currently listed on The Nasdaq Capital Market. In order to continue to have our securities listed on The Nasdaq Capital
Market, we must maintain and comply with certain standards including, but not limited to, standards relating to corporate governance, stockholders’ equity
and market value of listed securities. If we are unable to comply with the continued listing requirements of The Nasdaq Capital Market, our securities may
be delisted from The Nasdaq Capital Market. If our securities are delisted from The Nasdaq Capital Market, we could face significant adverse
consequences including, but not limited to:
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a limited availability of market quotations for our securities;
a limited amount of news and analyst coverage for our company; and
a decreased ability to issue additional securities or obtain additional financing in the future.
Unstable market and economic conditions may have serious adverse consequences on our business, financial condition and stock price.
Global credit and financial markets have experienced volatility and disruptions in past years, including severely diminished liquidity and credit
availability, declines in consumer confidence, declines in economic growth, increases in unemployment rates, concerns about medical epidemics, and
uncertainty about economic stability. We cannot assure you that further deterioration in credit and financial markets and confidence in economic conditions
will not occur. Our general business strategy may be adversely affected by any such economic downturn, volatile business environment or continued
unpredictable and unstable market conditions. If the current equity and credit markets deteriorate, or do not improve, it may make any necessary debt or
equity financing more difficult, more costly and more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could
have a material adverse effect on our growth strategy, financial performance and stock price and could require us to delay or abandon clinical development
plans. In addition, there is a risk that one or more of our current service providers, manufacturers and other partners may not survive difficult economic
times, which could directly affect our ability to attain our operating goals on schedule and on budget.
We may be at risk of securities class action litigation.
We may be at risk of securities class action litigation. In the past, biotechnology and pharmaceutical companies have experienced significant stock
price volatility, particularly when associated with binary events such as clinical trials and product approvals. If we face such litigation, it could result in
substantial costs and a diversion of management’s attention and resources, which could harm our business and results in a decline in the market price of our
common stock.
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The 2017 comprehensive tax reform could adversely affect our business and financial condition.
The Tax Cuts and Jobs Act of 2017 (the “Tax Cut Act”) among other things, contains significant changes to corporate taxation, including
reduction of the corporate tax rate from a top marginal rate of 35% to a single rate of 21%, limitation of the tax deduction for interest expense to 30% of
adjusted taxable income (except for certain small businesses), limitation of the deduction for net operating losses carried forward from taxable years
beginning after December 31, 2017 to 80% of current year taxable income and elimination of net operating loss carrybacks, one time taxation of offshore
earnings at reduced rates regardless of whether they are repatriated, elimination of U.S. tax on foreign earnings (subject to certain important exceptions),
providing immediate deductions for certain new investments instead of deductions for depreciation expense over time, and modifying or repealing many
business deductions and credits (including reduction of tax credits under the Orphan Drug Act). Notwithstanding the reduction in the corporate income tax
rate, the overall impact of the Tax Act is uncertain and our business and financial condition could be adversely affected. In addition, it is uncertain if, and to
what extent, various states will conform to the Tax Act. We urge our stockholders to consult with their legal and tax advisors with respect to any such
legislation and the potential tax consequences of investing in our securities.
We have no intention of declaring dividends in the foreseeable future.
We have never declared or paid cash dividends on our capital stock, and we do not currently anticipate declaring any dividends in the foreseeable
future. We anticipate that we will retain all future earnings for the development, operation, and expansion of our business. Any future determination to
declare dividends will be made at the discretion of our board of directors and will depend on, among other factors, our financial condition, operating
results, capital requirements, contractual restrictions, general business conditions and other factors that our board of directors may deem relevant. Investors
in our common stock should not expect to receive dividend income on their investment, and investors will be dependent on the appreciation of our common
stock, if any, to earn a return on their investment.
We are an emerging growth company, and we cannot be certain if the reduced reporting requirements applicable to emerging growth companies will
make our common stock less attractive to investors.
We are an emerging growth company, as defined in the JOBS Act. For as long as we continue to be an emerging growth company, we may take
advantage of exemptions from various reporting requirements that are applicable to other public companies that are not emerging growth companies,
including not being required to comply with the auditor attestation requirements of Section 404 of the Sarbanes-Oxley Act, reduced disclosure obligations
regarding executive compensation in our periodic reports and proxy statements and exemptions from the requirements of holding nonbinding advisory
votes on executive compensation and stockholder approval of any golden parachute payments not previously approved. We will remain an “emerging
growth company” until the earliest of (i) the last day of the fiscal year in which we have total annual gross revenues of $1.07 billion or more; (ii) the last
day of our fiscal year following the fifth anniversary of the date of our initial public offering; (iii) the date on which we have issued more than $1 billion in
nonconvertible debt during the previous three years; or (iv) the date on which we are deemed to be a large accelerated filer under the rules of the SEC.
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Even after we no longer qualify as an emerging growth company, we may still qualify as a “smaller reporting company” which would allow us to
take advantage of many of the same exemptions from disclosure requirements including not being required to comply with the auditor attestation
requirements of Section 404 of the Sarbanes-Oxley Act and reduced disclosure obligations regarding executive compensation in our periodic reports and
proxy statements. We cannot predict if investors will find our common stock less attractive because we may rely on these exemptions. If some investors
find our common stock less attractive as a result, there may be a less active trading market for our common stock and our stock price may be more volatile.
Under the JOBS Act, emerging growth companies can also delay adopting new or revised accounting standards until such time as those standards
apply to private companies; however, we have irrevocably elected not to avail ourselves of this exemption from new or revised accounting standards and,
therefore, will be subject to the same new or revised accounting standards as other public companies that are not emerging growth companies. As a result,
changes in rules of U.S. generally accepted accounting principles or their interpretation, the adoption of new guidance or the application of existing
guidance to changes in our business could significantly affect our financial position and results of operations.
Financial reporting obligations of being a public company in the United States are expensive and time-consuming, and our management will be
required to devote substantial time to compliance matters.
As a publicly traded company we incur significant legal, accounting and other expenses. The obligations of being a public company in the United
States require significant expenditures and places significant demands on our management and other personnel, including costs resulting from public
company reporting obligations under the Securities Exchange Act of 1934, as amended (Exchange Act) and the rules and regulations regarding corporate
governance practices, including those under the Sarbanes-Oxley Act of 2002 (Sarbanes-Oxley Act), the Dodd-Frank Wall Street Reform and Consumer
Protection Act, and the listing requirements of The Nasdaq Capital Market. These rules require the establishment and maintenance of effective disclosure
and financial controls and procedures, internal control over financial reporting and changes in corporate governance practices, among many other complex
rules that are often difficult to implement, monitor and maintain compliance with. Moreover, despite recent reforms made possible by the JOBS Act, the
reporting requirements, rules, and regulations will make some activities more time-consuming and costly, particularly after we are no longer an “emerging
growth company.” In addition, we expect these rules and regulations to make it more difficult and more expensive for us to obtain director and officer
liability insurance. Our management and other personnel will need to devote a substantial amount of time to ensure that we comply with all of these
requirements and to keep pace with new regulations, otherwise we may fall out of compliance and risk becoming subject to litigation or being delisted,
among other potential consequences.
If we fail to comply with the rules under Sarbanes-Oxley related to internal controls and procedures in the future, or, if we discover material
weaknesses and other deficiencies in our internal controls over financial reporting, our stock price could decline significantly and raising capital could
be more difficult.
Section 404 of Sarbanes-Oxley requires annual management assessments of the effectiveness of our internal controls over financial reporting. If
we fail to comply with the rules under Sarbanes-Oxley related to disclosure controls and procedures in the future, or, if we discover material weaknesses
and other deficiencies in our internal controls over financial reporting, our stock price could decline significantly and raising capital could be more difficult.
If material weaknesses or significant deficiencies are discovered or if we otherwise fail to achieve and maintain the adequacy of our internal controls, we
may not be able to ensure that we can conclude on an ongoing basis that we have effective internal controls over financial reporting in accordance with
Section 404 of Sarbanes-Oxley. Moreover, effective internal controls are necessary for us to produce reliable financial reports and are important to helping
prevent financial fraud. If we cannot provide reliable financial reports or prevent fraud, our business and operating results could be harmed, investors could
lose confidence in our reported financial information, and the trading price of our common stock could drop significantly.
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Our ability to use our net operating loss carryforwards and certain other tax attributes may be limited.
Under Sections 382 and 383 of the Internal Revenue Code of 1986, as amended, or the Code, if a corporation undergoes an “ownership change,”
generally defined as a cumulative change in its equity ownership by “5-percent shareholders” of greater than 50 percentage points (by value) over a three-
year period, the corporation’s ability to use its pre-change net operating loss carryforwards, or NOLs, and certain other pre-change tax attributes (such as
research tax credits) to offset its post-change taxable income and taxes, as applicable, may be limited. We have completed multiple rounds of financing
since our inception which may have resulted in an ownership change or could result in an ownership change in the future. We have not completed a Section
382 and 383 analysis regarding any limitations on our NOLs and research and development credit carryforwards and such limitations could be significant.
We may also experience ownership changes in the future as a result of subsequent shifts in our stock ownership. As a result, our ability to use our NOLs
and research and development credit carryforwards to offset our U.S. federal taxable income and taxes, as applicable, may be subject to limitations, which
could potentially result in increased future tax liability to us. In addition, at the state level, similar rules may apply and there may be periods during which
the use of NOLs is suspended or otherwise limited, which could accelerate or permanently increase state taxes owed.
Sales of a substantial number of shares of our common stock in the public market could cause our stock price to fall.
If our existing stockholders sell, or indicate an intention to sell, substantial amounts of our common stock in the public market, the market price of
our common stock could decline. We are unable to predict the effect that sales may have on the market price of our common stock If any shares of our
common stock are sold, or if it is perceived that they will be sold, in the public market, the market price of our common stock could decline.
Future sales and issuances of our securities could result in additional dilution of the percentage ownership of our shareholders and could cause our
share price to fall.
We expect that significant additional capital will be needed in the future to continue our planned operations, including research and development,
increased marketing, hiring new personnel, commercializing our products, and continuing activities as an operating public company. To the extent we raise
additional capital by issuing equity securities, our shareholders may experience substantial dilution. We may sell common stock, convertible securities or
other equity securities in one or more transactions at prices and in a manner we determine from time to time. If we sell common stock, convertible
securities or other equity securities in more than one transaction, investors may be materially diluted by subsequent sales. Such sales may also result in
material dilution to our existing shareholders, and new investors could gain rights superior to our existing shareholders.
If securities or industry analysts do not publish research or reports about us, or if they adversely change their recommendations regarding our common
stock, then our stock price and trading volume could decline.
The trading market for our common stock will be influenced by the research and reports that industry or securities analysts publish about us, our
industry and our market. If no analyst elects to cover us and publish research or reports about us, the market for our common stock could be severely
limited and our stock price could be adversely affected. In addition, if one or more analysts ceases coverage of us or fails to regularly publish reports on us,
we could lose visibility in the financial markets, which in turn could cause our stock price or trading volume to decline. If one or more analysts who elect to
cover us issue negative reports or adversely change their recommendations regarding our common stock, our stock price could decline.
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The concentration of our common stock ownership by our current management may limit your ability to influence corporate matters.
As of March 20, 2020, our directors and executive officers beneficially owned approximately 17.1% of our outstanding common stock.
Accordingly, our directors and executive officers will have the ability to exert significant influence over all corporate activities, including the election or
removal of directors and the outcome of tender offers, mergers, proxy contests or other purchases of common stock that could give our stockholders the
opportunity to realize a premium over the then-prevailing market price for their shares of common stock. This concentrated control will limit the ability of
other stockholders to influence corporate matters. In addition, such concentrated control could discourage others from initiating changes of control. In such
cases, the perception of our prospects in the market may be adversely affected and the market price of our common stock may decline.
Certain provisions in our organizational documents could enable our board of directors to prevent or delay a change of control.
We are authorized to issue up to 10,000,000 shares of preferred stock, none of which are outstanding as of March 20, 2020. This preferred stock
may be issued in one or more series, the terms of which may be determined at the time of issuance by our board of directors without further action by
stockholders. The terms of any series of preferred stock may include voting rights (including the right to vote as a series on particular matters), preferences
as to dividend, liquidation, conversion and redemption rights and sinking fund provisions. The issuance of any preferred stock could materially adversely
affect the rights of the holders of our common stock, and therefore, reduce the value of our common stock. The ability of our board of directors to issue
preferred stock also could have the effect of discouraging unsolicited acquisition proposals, thus adversely affecting the market price of our common stock.
In addition, our organizational documents contain provisions that may have the effect of discouraging, delaying or preventing a change of control
of, or unsolicited acquisition proposals, that a stockholder might consider favorable. These include provisions:
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requiring at least 66-2/3% of the voting power of all of our then-outstanding shares of capital stock entitled to vote generally in the election of
directors, voting together as a single class, to amend the Amended and Restated Bylaws;
providing that the authorized number of directors may be changed only by resolution of the board of directors;
providing that the directors may only be removed with cause and the affirmative vote of the holders of at least 66-2/3% of the voting power of all
of our then outstanding shares of capital stock entitled to vote generally at the election of directors;
providing that all vacancies, including newly created directorships, may, except as otherwise required by law, be filled by the affirmative vote of a
majority of directors then in office, even if less than a quorum;
dividing our board of directors into three classes;
requiring that any action to be taken by our stockholders must be effected at a duly called annual or special meeting of stockholders and not be
taken by written consent;
providing that stockholders seeking to present proposals before a meeting of stockholders or to nominate candidates for election as directors at a
meeting of stockholders must provide notice in writing in a timely manner and also specify requirements as to the form and content of a
stockholder’s notice;
that do not provide for cumulative voting rights (therefore allowing the holders of a majority of the shares of common stock entitled to vote in
any election of directors to elect all of the directors standing for election, if they should so choose); and
providing that special meetings of our stockholders may be called only by the Chairman of the board, our Chief Executive Officer or by the board
of directors pursuant to a resolution adopted by a majority of the total number of authorized directors.
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In addition, Delaware law makes it difficult for stockholders that recently have acquired a large interest in a corporation to cause the merger or
acquisition of the corporation against the directors’ wishes. Under Section 203 of the Delaware General Corporation Law, a Delaware corporation may not
engage in any merger or other business combination with an interested stockholder for a period of three years following the date that the stockholder
became an interested stockholder except in limited circumstances, including by approval of the corporation’s board of directors.
Market and economic conditions may negatively impact our business, financial condition and share price.
Concerns over inflation, energy costs, geopolitical issues, the U.S. mortgage market and a declining real estate market, unstable global credit
markets and financial conditions, and volatile oil prices have led to periods of significant economic instability, diminished liquidity and credit availability,
declines in consumer confidence and discretionary spending, diminished expectations for the global economy and expectations of slower global economic
growth going forward, increased unemployment rates, and increased credit defaults in recent years. Our general business strategy may be adversely
affected by any such economic downturns, volatile business environments and continued unstable or unpredictable economic and market conditions. If
these conditions continue to deteriorate or do not improve, it may make any necessary debt or equity financing more difficult to complete, more costly, and
more dilutive. Failure to secure any necessary financing in a timely manner and on favorable terms could have a material adverse effect on our growth
strategy, financial performance, and share price and could require us to delay or abandon development or commercialization plans.
Our Amended and Restated Certificate of Incorporation and Amended and Restated Bylaws contains an exclusive forum provision with respect to
certain actions which may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable and discourage lawsuits against us or
our current or former directors or officers and/or stockholders in such capacity.
Our Amended and Restated Bylaws provides that, unless the Company consents in writing to the selection of an alternative forum, the following
actions must be brought solely and exclusively in the Court of Chancery of the State of Delaware (i) any derivative action or proceeding brought on behalf
of the Company; (ii) any action asserting a claim of breach of a fiduciary duty owed by any director, officer or other employee of the Company to the
Company or the Company’s stockholders; (iii) any action asserting a claim against the Company or any director or officer or other employee of the
Company arising pursuant to any provision of the DGCL, the Company’s certificate of incorporation or the Company’s bylaws; or (iv) any action asserting
a claim against the Company or any director or officer or other employee of the Company governed by the internal affairs doctrine. We believe that the
exclusive forum provision may not apply to suits brought to enforce any liability or duty created by the Securities Act or the Exchange Act or any other
claim for which the federal courts have exclusive jurisdiction. We believe that to the extent that any such claims may be based upon federal law claims,
Section 27 of the Exchange Act creates exclusive federal jurisdiction over all suits brought to enforce any duty or liability created by the Exchange Act or
the rules and regulations thereunder. Furthermore, we believe that Section 22 of the Securities Act creates concurrent jurisdiction for federal and state
courts over all suits brought to enforce any duty or liability created by the Securities Act or the rules and regulations thereunder. This choice of forum
provision may limit a stockholder’s ability to bring a claim in a judicial forum that it finds favorable for disputes with the Company or its directors, officers
or other employees, which may discourage such lawsuits against the Company and its directors, officers or other employees. Alternatively, if a court were
to find the choice of forum provision contained in our Amended and Restated Certificate of Incorporation or Amended and Restated Bylaws to be
inapplicable or unenforceable in an action, the Company may incur additional costs associated with resolving such action in other jurisdictions, which
could have a material adverse effect on the Company’s business, results of operations, and financial condition.
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Item 1B. Unresolved Staff Comments.
None.
Item 2. Properties.
Our corporate and executive offices are located in leased facilities in Austin, Texas and Cambridge, Massachusetts. The Austin lease expires on
April 30, 2020. We are currently negotiating a renewal of the lease. The Cambridge lease is month-to-month. We believe our current facilities and those
that we believe are available to us are sufficient to meet our current needs and that suitable space will be available as and when needed. We do not own any
real property.
Item 3. Legal Proceedings.
From time to time, we may become involved in various lawsuits and legal proceedings, which arise in the ordinary course of business. Litigation
is subject to inherent uncertainties, and an adverse result in these or other matters may arise from time to time that may harm our business. We are currently
not aware of any such legal proceedings or claims that will have, individually or in the aggregate, a material adverse effect on our business, financial
condition or operating results.
Item 4. Mine Safety Disclosures.
Not applicable.
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Item 5. Market for Registrant’s Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities.
Market Information
PART II
Our common stock began trading on The Nasdaq Capital Market under the symbol “GNPX” on March 29, 2018. Prior to that date, there was no
public trading market for our common stock.
Holders of Record
As of March 20, 2020, there were approximately 195 stockholders of record of our common stock. The actual number of stockholders is greater
than this number of record holders and includes stockholders who are beneficial owners but whose shares are held in street name by brokers and other
nominees. This number of holders of record also does not include stockholders whose shares may be held in trust or by other entities.
Dividend Policy
We have never declared or paid cash dividends on our capital stock. We currently intend to retain all available funds and any future earnings for
use in the operation of our business and do not anticipate paying any dividends on our common stock in the foreseeable future. Any future determination to
declare dividends will be made at the discretion of our board of directors and will depend on, among other factors, our financial condition, operating
results, capital requirements, contractual restrictions, general business conditions and other factors that our board of directors may deem relevant.
Recent Sales of Unregistered Securities
None.
Item 6. Selected Financial Data.
As a smaller reporting company, we are not required to provide the information required by this item.
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Item 7. Management’s Discussion and Analysis of Financial Condition and Results of Operations.
This Management’s Discussion and Analysis of Financial Condition and Results of Operations (“MD&A”) contains certain forward-looking
statements. Historical results may not indicate future performance. Our forward-looking statements reflect our current views about future events, are based
on assumptions and are subject to known and unknown risks and uncertainties that could cause actual results to differ materially from those contemplated
by these statements. Factors that may cause differences between actual results and those contemplated by forward- looking statements include, but are not
limited to, those discussed in “Risk Factors.” We undertake no obligation to publicly update or revise any forward-looking statements, including any
changes that might result from any facts, events, or circumstances after the date hereof that may bear upon forward-looking statements. Furthermore, we
cannot guarantee future results, events, levels of activity, performance, or achievements.
Overview
Genprex™ is a clinical stage gene therapy company developing potentially life-changing treatments for cancer and diabetes. Our cancer therapies
are based upon our novel proprietary technology platform, including our lead drug candidate, Oncoprex™ immunogene therapy, or Oncoprex, for non-
small cell lung cancer (NSCLC). Oncoprex consists of a tumor suppressor gene inserted into a patient’s cells that has immunomodulatory effects and is
thereby considered an “immunogene therapy”. The gene is one of a series of genes whose therapeutic use is covered by an exclusive worldwide license
from The University of Texas MD Anderson Cancer Center. We also are developing a pre-clinical gene therapy that is covered by an exclusive worldwide
license from the Rangos Research Center at UPMC Children’s Hospital of Pittsburgh that has the potential to cure type 1 and type 2 diabetes. This
potential treatment works by reprogramming beta cells in the pancreas to restore their function, allowing them to replenish insulin levels.
Oncology Platform Technologies
Our oncology platform technologies are designed to administer cancer fighting genes by encapsulating them into nanoscale hollow spheres called
nanovesicles, which are then administered intravenously and taken up by tumor cells where they express proteins that are missing or found in low
quantities. Oncoprex has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer
cells, re-establishes pathways for apoptosis, or programmed cell death, in cancer cells, and modulates the immune response against cancer cells. Oncoprex
has also been shown to block mechanisms that create drug resistance.
With Oncoprex, we are initially targeting NSCLC. According to the World Health Organization, lung cancer is the leading cause of cancer deaths
worldwide, causing more deaths than breast, colon, kidney, liver, prostate or skin cancers, and lung cancer is one of the most common types of cancer. Each
year, there are more than two million new lung cancer cases and 1.7 million deaths from lung cancer worldwide.
In January, 2020, we received a United States FDA Fast Track Designation for use of Oncoprex™ in combination with EGFR inhibitor
osimertinib (AstraZeneca’s Tagrisso®) for the treatment of NSCLC patients with EFGR mutations that progressed after treatment with osimertinib alone.
According to the FLAURA study sponsored by AstraZeneca, the median length of time that patients are treated with osimertinib before their tumors
progress is 18 months. Osimertinib is now considered a new standard of care for NSCLC patients with an EGFR mutation. Given this and receipt of FDA’s
Fast Track Designation for use of Oncoprex combined with osimertinib in patients whose tumors progress on osimertinib, we are prioritizing this drug
combination and patient population and plan to initiate a Phase I/II clinical trial of Oncoprex combined with osimertinib in late 2020 or early 2021.
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Diabetes Gene Therapy
Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which leads over time to serious
damage to the heart, blood vessels, eyes, kidneys and nerves. The most common is type 2 diabetes, usually in adults, which occurs when the body becomes
resistant to insulin or doesn't make enough insulin. In the past three decades the prevalence of type 2 diabetes has risen dramatically. Type 1 diabetes, once
known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin by itself. According to
the World Health Organization, about 422 million people worldwide have diabetes and 1.6 million deaths are directly attributed to diabetes each year. Both
the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades.
Our diabetes gene therapy was developed by lead researcher Dr. George Gittes, at the Rangos Research Center at UPMC Children’s Hospital of
Pittsburgh. It works by reprogramming beta cells in the pancreas to restore their function, thereby replenishing levels of insulin. The infusion process uses
an endoscope and an adeno-associated virus (AAV) vector to deliver Pdx1 and MafA genes to the pancreas. The proteins these genes express have been
shown to transform alpha cells in the pancreas into functional beta-like cells, which can produce insulin but are distinct enough from beta cells to evade the
body’s immune system.
The diabetes gene therapy has been tested in vivo in mice and nonhuman primates. In studies of diabetic mice, the gene therapy approach restored
normal blood glucose levels for an extended period of time, typically around four months. According to Dr. Gittes, the duration of restored blood glucose
levels in mice could translate to decades in humans. If successful, this gene therapy could eliminate the need for insulin replacement therapy for diabetic
patients.
JOBS Act and Recent Accounting Pronouncements
The JOBS Act, enacted in 2012, provides that an “emerging growth company” may take advantage of the extended transition period provided in
Section 7(a)(2)(B) of the Securities Act of 1933, as amended, for complying with new or revised accounting standards. In other words, an “emerging
growth company” can delay the adoption of certain accounting standards until those standards would otherwise apply to private companies. We have
irrevocably elected not to avail ourselves of this extended transition period and, as a result, we will adopt new or revised accounting standards on the
relevant dates on which adoption of such standards is required for other public companies.
We have implemented all new accounting pronouncements that are in effect and may affect our financial statements and we do not believe that
there are any other new accounting pronouncements that have been issued that would have a material impact on our financial position or results of
operations.
Critical Accounting Policies and Significant Judgments and Estimates
Our financial statements have been prepared in accordance with generally accepted accounting principles in the United States (GAAP). The
preparation of these financial statements requires us to make estimates and assumptions that affect the reported amounts of assets and liabilities and the
disclosure of contingent assets and liabilities at the date of the financial statements, as well as the reported expenses incurred during the reporting periods.
Our estimates are based on our historical experience and on various other factors that we believe are reasonable under the circumstances, the results of
which form the basis for making judgments about the carrying value of assets and liabilities that are not readily apparent from other sources. Actual results
may differ from these estimates under different assumptions or conditions.
94
We believe that the following accounting policies are the most critical to aid in fully understanding and evaluating our reported financial results,
and they require our most difficult, subjective or complex judgments, resulting from the need to make estimates about the effect of matters that are
inherently uncertain.
Research and Development Costs
We record accrued expenses for costs invoiced from research and development activities conducted, on our behalf, by third-party service
providers, which include the conduct of preclinical studies and clinical trials and use of contract research and manufacturing activities. We record the costs
of research and development activities based upon the amount of services provided, and we include these costs in accrued liabilities in the balance sheets
and within research and development expense in the statement of operations. These costs are a significant component of our research and development
expenses. Purchased materials to be used in future research are capitalized and included in research and development supplies.
We estimate the amount of work completed through discussions with internal personnel and external service providers as to the progress or stage
of completion of the services and the agreed-upon fee to be paid for such services. We make significant judgments and estimates in determining the accrued
balance in each reporting period. As actual costs become known, we adjust our accrued estimates. Although we do not expect our estimates to be materially
different from amounts actually incurred, our understanding of the status and timing of services performed, the number of patients enrolled and the rate of
patient enrollment may vary from our estimates and could result in us reporting amounts that are too high or too low in any particular period. Our accrued
expenses are dependent, in part, upon the receipt of timely and accurate reporting from CROs and other third-party service providers. To date, there have
been no material differences from our accrued expenses to actual expenses.
Income Taxes
Deferred tax assets or liabilities are recorded for temporary differences between financial statement and tax basis of assets and liabilities, using
enacted rates in effect for the year in which the differences are expected to reverse. A valuation allowance is recorded if it is more likely than not that a
deferred tax asset will not be realized. We have provided a full valuation allowance on our deferred tax assets, which primarily consist of cumulative net
operating losses from April 1, 2009 (inception) to December 31, 2019. Due to our history of operating losses since inception and losses expected to be
incurred in the foreseeable future, a full valuation allowance was considered necessary.
Impairment of Long-Lived Assets
Management reviews long-lived assets for impairment whenever events or changes in circumstances indicate that the carrying amount may not be
realizable or at a minimum annually during the fourth quarter of the year. If an evaluation is required, the estimated future undiscounted cash flows
associated with the asset are compared to the asset’s carrying value to determine if an impairment of such asset is necessary. The effect of any impairment
would be to expense the difference between the fair value of such asset and its carrying value.
95
Components of our Results of Operations and Financial Condition
Operating expenses
We classify our operating expenses into three categories: research and development, general and administrative, and depreciation.
Research and development. Research and development expenses consist primarily of:
•
•
•
•
costs incurred to conduct research, such as the discovery and development of our current and potential product candidates;
costs related to production and storage of clinical supplies, including fees paid to contract manufacturers, manufacturing consultants, and
cold-storage facilities;
fees paid to clinical consultants, clinical trial sites and vendors, including CROs in conjunction with implementing and monitoring our
clinical trials and acquiring and evaluating clinical trial data, including all related fees, such as patient screening fees, laboratory work, and
statistical compilation and analysis; and
costs related to compliance with drug development regulatory requirements.
We recognize all research and development costs as they are incurred. Clinical trial costs, contract manufacturing and other development costs
incurred by third parties are expensed as the contracted work is performed.
We expect our research and development expenses to increase in the future as we advance our current and potential product candidates into and
through clinical trials, as we expand our clinical programs to a greater number of sites, as we pursue regulatory approval of our current and potential
product candidates in the United States and Europe, and as we expand our research programs to include new therapies and new therapy combinations. The
process of conducting the necessary clinical research to obtain regulatory approval is costly and time-consuming. The actual probability of success for our
current and potential product candidates may be affected by a variety of factors including the quality of our current and potential product candidates, early
clinical data, investment in our clinical program, competition, manufacturing capability and commercial viability. We may never succeed in achieving
regulatory approval for any of our current and potential product candidates. As a result of the uncertainties discussed above, we are unable to determine the
duration and completion costs of our research and development projects or when and to what extent we will generate revenue from the commercialization
and sale of our current and potential product candidates.
General and administrative. General and administrative expense consists of personnel related costs, which include salaries, as well as the costs of
professional services, such as accounting and legal, travel, facilities, information technology and other administrative expenses. We expect our general and
administrative expense to increase in future periods due to the anticipated growth of our business and related infrastructure as well as accounting,
insurance, investor relations, and other costs associated with being a public company.
Depreciation. Depreciation expense consists of depreciation from our fixed assets consisting of our property, equipment, and furniture. We
depreciate our assets over their estimated useful life. We estimate furniture and computer and office equipment to have a 5-year life.
96
Results of Operations
Comparison of the Years Ended December 31, 2019 and 2018
The following summarizes our results of operations for the years ended December 31, 2019 and 2018.
Research and Development Expense. Research and development expense was $1,967,007 for the year ended December 31, 2019 as compared to
$971,427 for the year ended December 31, 2018. This increase of $995,580, or 102%, was due to our acceleration of preclinical research and
manufacturing process development in 2019 in preparation for the advancement of clinical programs.
We expect research and development expense to increase in future periods as we expand our clinical programs to a greater number of sites and our
research programs to include new therapy combinations.
General and Administrative Expense. General and administrative expense for the year ended December 31, 2019 was $8,702,596 as compared
to $11,386,229 for the year ended December 31, 2018. The decrease of $2,683,633, or 24%, in general and administrative expense is related primarily to a
one-time larger than normal equity-based compensation amount issued in 2018 to recruit and retain executive leadership, board members, and technical
experts to our team. Excluding this expense, a decrease of $778,235, or 13%, for the year ended December 31, 2019 versus December 31, 2018 was
primarily due to greater expenses incurred in 2018 related to our initial public offering and private placement.
Interest Income. Interest income was $27,905 and $29,184 for the years ended December 31, 2019 and 2018, respectively. This decrease of
$1,279, or 4%, was due to changes in rates and balances of our money market instruments in 2019 as we had greater utilization of cash for growing
operations and research programs ended December 31, 2019 as opposed to the prior year.
Interest Expense. Interest expense was $0 and $37,982 for the years ended December 31, 2019 and 2018, respectively. This decrease of $37,982
was due to decrease in utilization of debt in the year ended December 31, 2019.
Depreciation Expense. Depreciation expense was $13,070 and $5,885 for the years ended December 31, 2019 and 2018, respectively.
The increase of $7,185, or 122%, in depreciation is due to additional equipment purchased and utilized by new employees immediately following the initial
public offering and realized in the year ended in December 31, 2019.
97
Liquidity and Capital Resources
From our inception through December 31, 2019, we have never generated revenue from product sales and have incurred net losses in each year
since inception. As of December 31, 2019, we had an accumulated deficit of $40,479,459. Prior to our initial public offering, we funded our operations
primarily through the sale and issuance of preferred stock. In connection with our initial public offering, we converted all preferred stock to common stock
and forward-split the common stock on a 6.6841954-to-1 basis.
As of December 31, 2019, we had $2,002,492 in cash.
On January 21, 2020, January 27, 2020, and February 19, 2020, we sold in aggregate 13,581,000 shares of our common stock for net proceeds of
approximately $23.4 million after commissions and expenses.
We believe the cash at December 31, 2019 on a pro forma as adjusted basis from sales of our securities in 2020 is sufficient to meet our cash,
operational and liquidity requirements for at least 24 months. We are actively pursuing opportunities to extend capital resources to advance long-
term corporate and research and development objectives.
We do not expect to generate revenue from product sales unless and until we successfully complete development of, obtain regulatory approval for
and begin to commercialize one or more of our current and potential product candidates, which we expect will take a number of years and which is subject
to significant uncertainty. Accordingly, we anticipate that we will need to raise additional capital to fund our future operations. Until such time as we can
generate substantial revenue from product sales, if ever, we expect to finance our operating activities through a combination of equity offerings and debt
financings and we may seek to raise additional capital through strategic collaborations. However, we may be unable to raise additional funds or enter into
such arrangements when needed on favorable terms, or at all, which would have a negative impact on our financial condition and could force us to delay,
limit, reduce or terminate our development programs or commercialization efforts or grant to others rights to develop or market product candidates that we
would otherwise prefer to develop and market ourselves. Failure to receive additional funding could cause us to cease operations, in part or in full.
Furthermore, even if we believe we have sufficient funds for our current or future operating plans, we may seek additional capital due to favorable market
conditions or strategic considerations.
The following table sets forth the primary sources and uses of cash for the years ended December 31, 2019 and 2018:
Net cash used in operating activities
Net cash used in investing activities
Net cash provided by financing activities
Net (decrease) increase in cash
98
$
Years Ended December 31,
2019
(6,918,721) $
(946,899)
1,267,194
(6,598,426)
2018
(6,846,534)
(103,317)
15,389,518
8,439,667
Cash used in operating activities
Net cash used in operating activities was $6,918,721 and $6,846,534 for the years ended December 31, 2019 and 2018, respectively. The
increase of $72,187, or 1%, in net cash used in operating activities was primarily due to increased general and administrative and research and development
expenses in 2019 to support increased operations to support acceleration of our clinical programs.
Cash used in investing activities
Net cash used in investing activities was $946,899 and $103,317 for the years ended December 31, 2019 and 2018, respectively. The increase in
net cash used in investing activities of $843,582, or 816%, was primarily due to the purchase and manufacturing of research and development supplies
during the year ended December 31, 2019 for use, over time, for clinical and preclinical research programs.
Cash provided by financing activities
Net cash provided by financing activities was $1,267,194 and $15,389,518 for the years ended December 31, 2019 and 2018, respectively.
The decrease of $14,122,324, or 92%, in net cash provided by financing activities was due to our initial public offering and private placement in 2018 and
less reliance on funding in the year ended December 31, 2019.
Item 7A. Quantitative and Qualitative Disclosures About Market Risk.
As a smaller reporting company, we are not required to provide the information required by this item.
Item 8. Financial Statements and Supplementary Data.
The financial statements and supplementary data required by this item are included after Part IV of this Annual Report on Form 10-K beginning
on page F-1.
Item 9. Changes in and Disagreements With Accountants on Accounting and Financial Disclosure.
None.
Item 9A. Controls and Procedures.
Evaluation of Disclosure Controls and Procedures
As required by Rules 13a-15(b) and 15d-15(b) of the Exchange Act, our management with the participation of our Chief Executive Officer and our
Chief Financial Officer, evaluated the effectiveness of our disclosure controls and procedures as of December 31, 2019. The term “disclosure controls and
procedures” as defined in Rules 13a-15(e) and 15d-15(e) under the Exchange Act, means controls and other procedures of a company that are designed to
ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange Act is recorded, processed,
summarized and reported, within the time periods specified in the SEC’s rules and forms. Disclosure controls and procedures include, without limitation,
controls and procedures designed to ensure that information required to be disclosed by a company in the reports that it files or submits under the Exchange
Act is accumulated and communicated to a company’s management, including its principal executive and principal financial officer, as appropriate to allow
timely decisions regarding required disclosure. Management recognizes that any controls and procedures, no matter how well designed and operated, can
provide only reasonable assurance of achieving their objectives, and management necessarily applies its judgment in evaluating the cost-benefit
relationship of possible controls and procedures. Based on the evaluation of our disclosure controls and procedures as of December 31, 2019, our Chief
Executive Officer and our Chief Financial Officer concluded that, as of such date, our disclosure controls and procedures were not effective due to material
weakness in our internal control over financial reporting due to lack of segregation of duties.
99
Management’s Report on Internal Control over Financial Reporting
Our principal executive officer and our principal accounting and financial officer are responsible for establishing and maintaining adequate
internal control over financial reporting, as such term is defined in Exchange Act Rules 13a-15(f) and 15d-15f. Management conducted an assessment of
the effectiveness of our internal control over financial reporting as of December 31, 2019. In making this assessment, management used the criteria
described in Internal Control-Integrated Framework (2013) issued by the Committee of Sponsoring Organizations of the Treadway Commission (COSO).
Our management concluded that our internal controls over financial reporting were, and continue to be, ineffective as of December 31, 2019 due to a
material weakness in our internal controls due to the lack of segregation of duties.
It should be noted that any system of controls, however well designed and operated, can provide only reasonable and not absolute assurance that
the objectives of the system are met. In addition, the design of any control system is based in part upon certain assumptions about the likelihood of certain
events. Because of these and other inherent limitations of control systems, there can be no assurance that any design will succeed in achieving its stated
goals under all potential future conditions, regardless of how remote.
In light of the material weakness described below, we performed additional analysis and other post-closing procedures to ensure our financial
statements were prepared in accordance with generally accepted accounting principles. Accordingly, we believe that the financial statements included in
this report fairly present, in all material respects, our financial condition, results of operations and cash flows for the periods presented.
During the last quarter of fiscal 2019 and as our operational activities increased, management determined and continues to determine that it does
not have sufficient segregation of duties within its accounting functions, which is a basic internal control. Due to our size and nature, segregation of all
conflicting duties may not always be possible and may not be economically feasible. However, to the extent possible, the initiation of transactions, the
custody of assets and the recording of transactions should be performed by separate individuals. Management evaluated the impact of our failure to
maintain effective segregation of duties on our assessment of our internal control over financial reporting and has concluded that the control deficiency
represents a material weakness. Management intends to further increase its accounting staff and enhance its system of financial accounting and reporting,
as soon as economically feasible and sustainable, to remediate this material weakness.
Changes in Internal Control over Financial Reporting
There were no changes in our internal control over financial reporting that occurred during the year ended December 31, 2019 that have materially
affected, or are reasonably likely to materially affect, our internal control over financial reporting.
Inherent Limitations of Disclosure Controls and Internal Control over Financial Reporting
Because of their inherent limitations, our disclosure controls and procedures and our internal control over financial reporting may not prevent
material errors or fraud. A control system, no matter how well conceived and operated, can provide only reasonable, not absolute, assurance that the
objectives of the control system are met. The effectiveness of our disclosure controls and procedures and our internal control over financial reporting is
subject to risks, including that the controls may become inadequate because of changes in conditions or that the degree of compliance with our policies or
procedures may deteriorate.
Item 9B. Other Information.
None.
100
Item 10. Directors, Executive Officers and Corporate Governance.
PART III
The information required by this Item 10 is incorporated herein by reference to the information that will be contained in our definitive proxy
statement (the “Proxy Statement”) for the 2020 annual meeting of stockholders (the “Annual Meeting”), which is expected to be filed not later than
120 days after the end of our fiscal year ended December 31, 2019.
Item 11. Executive Compensation.
The information required by this Item 11 is incorporated herein by reference to the information that will be contained in our Proxy Statement for
the Annual Meeting.
Item 12. Security Ownership of Certain Beneficial Owners and Management and Related Stockholder Matters.
The information required by this Item 12 is incorporated herein by reference to the information that will be contained in our Proxy Statement for
the Annual Meeting.
Item 13. Certain Relationships and Related Transactions, and Director Independence.
The information required by this Item 13 is incorporated herein by reference to the information that will be contained in our Proxy Statement for
the Annual Meeting.
Item 14. Principal Accounting Fees and Services.
The information required by this Item 14 is incorporated herein by reference to the information that will be contained in our Proxy Statement for
the Annual Meeting.
Item 15. Exhibits, Financial Statement Schedules.
(a)(1) Financial statements.
PART IV
The financial statements and supplementary data required by this item begin on page F-1.
(a)(2) Financial Statement Schedules.
All schedules are omitted because the required information is inapplicable or the information is presented in the financial statements and the
related notes.
(a)(3) Exhibits.
101
Exhibit
Number Description of Exhibit
EXHIBIT INDEX
3.1
3.2
4.1
4.2
4.3
4.4
4.5
4.6
4.7
4.8
4.9
Amended and Restated Certificate of Incorporation of the Registrant, incorporated by reference to Exhibit 3.1 of the Registrant’s Current
Report on Form 8-K filed on April 10, 2018.
Amended and Restated Bylaws of the Registrant, incorporated by reference to Exhibit 3.2 of the Registrant’s Current Report on Form 8-K
filed on April 10, 2018.
Form of Common Stock Certificate of the Registrant, incorporated by reference to Exhibit 4.1 of the Registrant’s Registration Statement on
Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Warrant Agreement, dated December 17, 2015, issued to DABS Advanced Biotech Solutions, LLC, incorporated by reference to Exhibit 4.4
of the Registrant’s Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Warrant Agreement, dated December 17, 2015, issued to DABS Advanced Biotech Solutions, LLC, incorporated by reference to Exhibit 4.5
of the Registrant's Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Warrant Agreement, dated November 3, 2016, issued to Viet Ly, incorporated by reference to Exhibit 4.6 of the Registrant’s Registration
Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Form of Underwriter’s Warrant Agreement, incorporated by reference to Exhibit 4.7 of the Registrant’s Registration Statement on Form S-1
(File No. 333-219386), as amended, originally filed on July 21, 2017.
Form of Common Stock Purchase Warrant, incorporated by reference to Exhibit 4.1 of the Registrant’s Current Report on Form 8-K filed on
May 10, 2018.
Warrant Agreement, dated July 27, 2018, issued to Cancer Revolution, LLC, incorporated by reference to Exhibit 4.1 of the Registrant’s
Current Report on Form 8-K filed on August 6, 2018.
Warrant Agreement, dated July 27, 2018, issued to Inception Capital Management, LLC, incorporated by reference to Exhibit 4.2 of the
Registrant’s Current Report on Form 8-K filed on August 6, 2018.
Warrant Agreement, dated July 27, 2018, issued to Cancer Biotech, LLC, incorporated by reference to Exhibit 4.3 of the Registrant’s Current
Report on Form 8-K filed on August 6, 2018.
4.10
Form of Warrant, incorporated by reference to Exhibit 10.2 of the Registrant’s Current Report on Form 8-K filed on November 22, 2019.
4.12*
Description of Registrant's Securities.
10.1+
10.2+
10.3+
10.4+
10.5+
Form of Indemnity Agreement by and between the Registrant and its directors and officers, incorporated by reference to Exhibit 10.1 of the
Registrant's Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Registrant’s 2009 Equity Incentive Plan and Forms of Grant Notices and Agreements thereunder, incorporated by reference to Exhibit 10.2 of
the Registrant's Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Genprex, Inc. 2018 Equity Incentive Plan and Forms of Stock Option Grant Notice, Option Agreement and Notice of Exercise thereunder,
incorporated by reference to Exhibit 10.3 of the Registrant’s Annual Report on Form 10-K filed April 17, 2018.
Genprex, Inc. 2018 Employee Stock Purchase Plan, incorporated by reference to Exhibit 10.4 of the Registrant’s Annual Report on Form 10-
K filed April 17, 2018.
Genprex, Inc. Non-Employee Director Compensation Policy, incorporated by reference to Exhibit 10.1 of the Registrant's Current Report on
Form 8-K filed on November 8, 2018.
102
Exhibit
Number Description of Exhibit
10.6
10.7
10.8
10.9
10.10
10.11
10.12
10.13
10.14
10.15+
10.16+
10.17+
10.18
10.19
Patent and Technology License Agreement dated effective July 20, 1994, by and between the Board of Regents of the University of Texas
System, The University of Texas M.D. Anderson Cancer Center and Intron Therapeutics, Inc., incorporated by reference to Exhibit 10.6 of
the Registrant's Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Amendment No. 3 to Patent and Technology License Agreement dated October 4, 2001, incorporated by reference to Exhibit 10.7 of the
Registrant's Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Technology Sublicense Agreement effective March 7, 2007, by and between Introgen Therapeutics, Inc., and Introgen Research Institute,
Inc., incorporated by reference to Exhibit 10.8 of the Registrant's Registration Statement on Form S-1 (File No. 333-219386), as amended,
originally filed on July 21, 2017.
Assignment and Collaboration Agreement effective April 13, 2009, by and between Gensolve, Inc. and the Registrant, incorporated by
reference to Exhibit 10.9 of the Registrant's Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July
21, 2017.
Technology License Agreement dated as of February 26, 2010, by and between Introgen Research Institute, Inc. and P53, Inc., incorporated
by reference to Exhibit 10.10 of the Registrant’s Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on
July 21, 2017.
Technology Sublicense Agreement effective June 1, 2011, by and between the Registrant and Introgen Research Institute, Inc., incorporated
by reference to Exhibit 10.12 of the Registrant’s Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on
July 21, 2017.
Amended Collaboration and Assignment Agreement effective July 1, 2011, by and between Introgen Research Institute, Inc. and the
Registrant, incorporated by reference to Exhibit 10.13 of the Registrant’s Registration Statement on Form S-1 (File No. 333-219386), as
amended, originally filed on July 21, 2017.
Clinical Study Agreement dated February 10, 2014, by and between The University of Texas M.D. Anderson Cancer Center and the
Registrant, incorporated by reference to Exhibit 10.14 of the Registrant’s Registration Statement on Form S-1 (File No. 333-219386), as
amended, originally filed on July 21, 2017.
Amendment No. 1 to Clinical Study Agreement dated June 25, 2015, incorporated by reference to Exhibit 10.15 of the Registrant’s
Registration Statement on Form S-1 (File No. 333-219386), as amended, originally filed on July 21, 2017.
Amended and Restated Executive Employment Agreement, dated May 23, 2018, by and between the Registrant and Julien L. Pham, M.D.,
M.P.H., incorporated by reference to Exhibit 10.1 of the Registrant’s Current Report on Form 8-K filed on May 30, 2018.
Executive Employment Agreement dated April 13, 2018, by and between the Registrant and Rodney Varner, incorporated by reference to
Exhibit 10.16 of the Registrant’s Annual Report on Form 10-K filed on April 17, 2018.
Executive Employment Agreement dated April 13, 2018, by and between the Registrant and Ryan Confer, incorporated by reference to
Exhibit 10.17 of the Registrant’s Annual Report on Form 10-K filed on April 17. 2018.
Securities Purchase Agreement dated as of May 6, 2018, by and between the Registrant and the persons named on the signature pages
thereto, incorporated by reference to Exhibit 10.1 of the Registrant’s Current Report on Form 8-K filed on May 10, 2018.
Form of Registration Rights Agreement, incorporated by reference to Exhibit 10.1 of the Registrant’s Current Report on Form 8-K filed on
May 10, 2018.
10.20+
Consulting Agreement, dated August 13, 2018, by and between the Registrant and Viet Ly, incorporated by reference to Exhibit 10.1 of the
Registrant’s Quarterly Report on Form 10-Q filed on August 14, 2018.
10.21
Form of Securities Purchase Agreement dated November 20, 2019, incorporated by reference to Exhibit 10.1 of the Registrant’s Current
Report on Form 8-K filed on November 22, 2019.
103
Exhibit
Number Description of Exhibit
10.22
10.23
10.24
Form of Securities Purchase Agreement dated January 16, 2020, incorporated by reference to Exhibit 10.1 of the Registrant’s Current Report
on Form 8-K filed on January 17, 2020.
Form of Securities Purchase Agreement dated January 23, 2020, incorporated by reference to Exhibit 10.1 of the Registrant’s Current Report
on Form 8-K filed on January 24, 2020.
Exclusive License Agreement dated as of February 11, 2020, by and between the Registrant and the University of Pittsburgh – Of the
Commonwealth System of Higher Education, incorporated by reference to Exhibit 10.1 of the Registrant’s Current Report on Form 8-K filed
on February 18, 2020.
10.25
Form of Securities Purchase Agreement dated February 19, 2020, incorporated by reference to Exhibit 10.1 of the Registrant’s Current
Report on Form 8-K filed on February 20, 2020.
10.26+
Executive Employment Agreement dated March 12, 2020, by and between the Registrant and Catherine Vaczy, incorporated by reference to
Exhibit 10.1 of the Registrant’s Current Report on Form 8-K filed on March 23, 2020.
10.27+
Executive Employment Agreement dated March 12, 2020, by and between the Registrant and Michael Redman, incorporated by reference to
Exhibit 10.2 of the Registrant’s Current Report on Form 8-K filed on March 23, 2020.
31.1*
Certification of Chief Executive Officer Pursuant to Rules 13a-14(a) of the Securities Exchange Act, as Adopted Pursuant to Section 302 of
the Sarbanes-Oxley Act of 2002.
31.2*
Certification of Chief Financial Officer Pursuant to Rules 13a-14(a) of the Securities Exchange Act, as Adopted Pursuant to Section 302 of
the Sarbanes-Oxley Act of 2002.
32.1*
Certification of Chief Executive Officer and Chief Financial Officer Pursuant to 18 U.S.C. Section 1350, as Adopted Pursuant to Section 906
of the Sarbanes-Oxley Act of 2002.
101.INS* XBRL Instance Document.
101.SCH* XBRL Taxonomy Extension Schema Document.
101.CAL* XBRL Taxonomy Extension Calculation Linkbase Document.
101.DEF* XBRL Taxonomy Extension Definition Linkbase Document.
101.LAB* XBRL Taxonomy Extension Label Linkbase Document.
101.PRE* XBRL Taxonomy Extension Presentation Document.
*
+
Filed herewith.
Indicates management contract or compensatory plan.
Item 16. Form 10–K Summary.
None.
104
Pursuant to the requirements of Section 13 or 15(d) of the Securities Exchange Act of 1934, the registrant has duly caused this annual report on
Form 10-K to be signed on its behalf by the undersigned, thereunto duly authorized.
SIGNATURES
Date: March 30, 2020
GENPREX, INC.
By: /s/ J. Rodney Varner
J. Rodney Varner
Chief Executive Officer
(Principal Executive Officer)
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, this report has been signed below by the following persons on
behalf of the registrant in the capacities and on the dates indicated.
POWER OF ATTORNEY
Signature
/s/ J. Rodney Varner
J. Rodney Varner
/s/ Ryan M. Confer
Ryan M. Confer
/s/ David E. Friedman
David E. Friedman
/s/ Robert W. Pearson
Robert W. Pearson
/s/ Brent Longnecker
Brent Longnecker
/s/ Jose Antonio Moreno Toscano
Jose Antonio Moreno Toscano
/s/ Will R. Wilson, Jr.
Will R. Wilson, Jr.
Title
Chief Executive Officer and
Member of the Board of Directors
(Principal Executive Officer)
Chief Financial Officer
(Principal Financial and Accounting Officer)
Date
March 30, 2020
March 30, 2020
Member of the Board of Directors
March 30, 2020
Member of the Board of Directors
March 30, 2020
Member of the Board of Directors
March 30, 2020
Member of the Board of Directors
March 30, 2020
Member of the Board of Directors
March 30, 2020
105
INDEX TO FINANCIAL STATEMENTS
Report of Independent Registered Public Accounting Firm
Balance Sheets
Statements of Operations
Statements of Changes in Stockholders’ Equity
Statements of Cash Flows
Notes to Financial Statements
F-1
F-2
F-3
F-4
F-5
F-6
F-7
Report of Independent Registered Public Accounting Firm
To the Board of Directors and
Stockholders of Genprex, Inc.
Austin, Texas
Opinion on the Financial Statements
We have audited the accompanying balance sheets of Genprex, Inc. (the “Company”) at December 31, 2019 and 2018, and the related statements of
operations, changes in stockholders’ equity, and cash flows for each of the years in the two-year period ended December 31, 2019, and the related notes
(collectively referred to as the financial statements). In our opinion, the financial statements present fairly, in all material respects, the financial position of
the Company as of December 31, 2019 and 2018, and the results of its operations and its cash flows for each of the years in the two-year period ended
December 31, 2019, in conformity with accounting principles generally accepted in the United States of America.
Basis for Opinion
These financial statements are the responsibility of the Company’s management. Our responsibility is to express an opinion on the Company’s financial
statements based on our audits. We are a public accounting firm registered with the Public Company Accounting Oversight Board (United States)
(PCAOB) and are required to be independent with respect to the Company in accordance with the U.S. federal securities laws and the applicable rules and
regulations of the Securities and Exchange Commission and the PCAOB.
We conducted our audits in accordance with the standards of the PCAOB. Those standards require that we plan and perform the audit to obtain reasonable
assurance about whether the financial statements are free of material misstatement, whether due to error or fraud. The Company is not required to have, nor
were we engaged to perform, an audit of its internal control over financial reporting. As part of our audits, we are required to obtain an understanding of
internal control over financial reporting, but not for the purpose of expressing an opinion on the effectiveness of the Company’s internal control over
financial reporting. Accordingly, we express no such opinion.
Our audits included performing procedures to assess the risks of material misstatement of the financial statements, whether due to error or fraud, and
performing procedures that respond to those risks. Such procedures included examining, on a test basis, evidence regarding the amounts and disclosures in
the financial statements. Our audits also included evaluating the accounting principles used and significant estimates made by management, as well as
evaluating the overall presentation of the financial statements. We believe that our audits provide a reasonable basis for our opinion.
/s/ Daszkal Bolton LLP
We have served as the Company’s auditor since 2014.
Boca Raton, FL
March 30, 2020
F-2
Genprex, Inc.
Balance Sheets
Assets
Current assets:
Cash
Accounts receivable
Prepaid expenses and other
Supplies
Total current assets
Property and equipment, net
Other assets:
Security deposits
Intellectual property, net
Total other assets
Total assets
Liabilities and Stockholders' Equity
Current liabilities:
Accounts payable and accrued expenses
Other current liabilities
Total current liabilities
Investment unit
Commitments and contingencies
Stockholders' equity:
Common stock $0.001 par value: 200,000,000 shares authorized; 19,263,841 and 15,239,148 shares issued and
outstanding, respectively
Additional paid-in capital
Accumulated deficit
Total stockholders' equity
Total liabilities and stockholders' equity
See accompanying notes to the financial statements
F-3
$
$
$
2019
2018
2,002,492 $
655
171,716
801,780
2,976,643
44,654
21,732
491,200
512,932
3,534,229 $
8,600,918
9,297
236,851
—
8,847,066
24,354
18,085
379,451
397,536
9,268,956
436,258 $
74,426
510,684
—
295,069
92,752
387,821
—
19,264
43,483,740
(40,479,459)
3,023,545
3,534,229 $
15,240
38,690,586
(29,824,691)
8,881,135
9,268,956
$
Genprex, Inc.
Statements of Operations
Revenues
Cost and expenses:
Depreciation
Research and development
General and administrative
Total costs and expenses
Operating loss
Interest income
Interest expense
Net loss
Net loss per share — basic and diluted
Weighted average number of common shares — basic and diluted
See accompanying notes to the financial statements
F-4
Year Ended
December 31,
2019
2018
$
— $
—
5,885
13,070
971,427
1,967,007
11,386,229
8,702,596
12,363,541
10,682,673
(12,363,541)
(10,682,673)
29,184
27,905
(37,982)
—
$ (10,654,768) $ (12,372,339)
(0.66) $
(0.90)
$
13,771,020
16,026,980
Balance at December 31, 2017
Issuance of stock for cash
Issuance of stock for services
Share based compensation
Net loss
Balance at December 31, 2018
Issuance of stock for cash
Issuance of stock for services
Share based compensation
Net loss
Balance at December 31, 2019
Genprex, Inc.
Statements of Changes in Stockholders’ Equity
Common Stock
Shares
11,721,584 $
3,282,940
234,624
—
—
15,239,148 $
3,517,986
506,707
—
—
19,263,841 $
Amount
11,721 $
3,284
235
—
—
15,240 $
3,518
506
—
—
19,264 $
Accumulated
Deficit
Additional
Paid-In
Capital
17,869,205 $ (17,452,352) $
—
15,386,234
—
553,068
—
4,882,079
(12,372,339)
—
38,690,586 $ (29,824,691) $
—
1,263,676
—
469,082
—
3,060,396
(10,654,768)
—
43,483,740 $ (40,479,459) $
Total
428,574
15,389,518
553,303
4,882,079
(12,372,339)
8,881,135
1,267,194
469,588
3,060,396
(10,654,768)
3,023,545
See accompanying notes to the financial statements
F-5
Genprex, Inc.
Statements of Cash Flows
Cash flows from operating activities:
Net loss
Adjustments to reconcile net loss to net cash used in operating activities:
Depreciation
Share based compensation
Changes in operating assets and liabilities:
Accounts receivable
Prepaid expenses and other
Deposits
Deferred offering costs
Accounts payable and accrued expenses
Other current liabilities
Net cash used in operating activities
Cash flows from investing activities:
Additions to property and equipment
Additions to intellectual property
Additions to research and development supplies
Net cash used in investing activities
Cash flows from financing activities:
Proceeds from issuances of common stock
Net cash provided by financing activities
Net (decrease) increase in cash
Cash, beginning of year
Cash, end of year
See accompanying notes to the financial statements
F-6
2019
2018
$ (10,654,768) $ (12,372,339)
13,070
3,529,984
5,885
5,435,382
8,642
65,135
(3,647)
—
141,189
(18,326)
(6,918,721)
(33,370)
(111,749)
(801,780)
(946,899)
(453)
(213,372)
(18,085)
759,591
(443,143)
—
(6,846,534)
(22,435)
(80,882)
—
(103,317)
1,267,194
1,267,194
(6,598,426)
8,600,918
2,002,492 $
15,389,518
15,389,518
8,439,667
161,251
8,600,918
$
Genprex, Inc.
Notes to Financial Statements
Note 1 – Description of Business and Basis of Presentation
Genprex™ is a clinical stage gene therapy company developing potentially life-changing treatments for cancer and diabetes. Our cancer therapies
are based upon our novel proprietary technology platform, including our lead drug candidate, Oncoprex™ immunogene therapy, or Oncoprex, for non-
small cell lung cancer (NSCLC). Oncoprex consists of a tumor suppressor gene inserted into a patient’s cells that has immunomodulatory effects and is
thereby considered an “immunogene therapy”. The gene is one of a series of genes whose therapeutic use is covered by an exclusive worldwide license
from The University of Texas MD Anderson Cancer Center. We also are developing a pre-clinical gene therapy that is covered by an exclusive worldwide
license from the Rangos Research Center at UPMC Children’s Hospital of Pittsburgh that has the potential to cure type 1 and type 2 diabetes. This
potential treatment works by reprogramming beta cells in the pancreas to restore their function, allowing them to replenish insulin levels.
Oncology Platform Technologies
Our oncology platform technologies are designed to administer cancer fighting genes by encapsulating them into nanoscale hollow spheres called
nanovesicles, which are then administered intravenously and taken up by tumor cells where they express proteins that are missing or found in low
quantities. Oncoprex has a multimodal mechanism of action whereby it interrupts cell signaling pathways that cause replication and proliferation of cancer
cells, re-establishes pathways for apoptosis, or programmed cell death, in cancer cells, and modulates the immune response against cancer cells. Oncoprex
has also been shown to block mechanisms that create drug resistance.
With Oncoprex, we are initially targeting NSCLC. According to the World Health Organization, lung cancer is the leading cause of cancer deaths
worldwide, causing more deaths than breast, colon, kidney, liver, prostate or skin cancers, and lung cancer is one of the most common types of cancer. Each
year, there are more than two million new lung cancer cases and 1.7 million deaths from lung cancer worldwide.
In January, 2020, we received a United States FDA Fast Track Designation for use of Oncoprex™ in combination with EGFR inhibitor
osimertinib (AstraZeneca’s Tagrisso®) for the treatment of NSCLC patients with EFGR mutations whose tumors progressed after treatment with
osimertinib alone. According to the FLAURA study sponsored by AstraZeneca, the median length of time that patients are treated with osimertinib before
their tumors progress is 18 months. Osimertinib is now considered a new standard of care for NSCLC patients with an EGFR mutation. Given this and
receipt of FDA’s Fast Track Designation for use of Oncoprex combined with osimertinib in patients whose tumors progress on osimertinib, we
are prioritizing this drug combination and patient population and plan to initiate a Phase I/II clinical trial of Oncoprex combined with osimertinib in late
2020 or early 2021.
F-7
Diabetes Gene Therapy
Diabetes is a chronic, metabolic disease characterized by elevated levels of blood glucose (or blood sugar), which leads over time to serious
damage to the heart, blood vessels, eyes, kidneys and nerves. The most common is type 2 diabetes, usually in adults, which occurs when the body becomes
resistant to insulin or doesn't make enough insulin. In the past three decades the prevalence of type 2 diabetes has risen dramatically. Type 1 diabetes, once
known as juvenile diabetes or insulin-dependent diabetes, is a chronic condition in which the pancreas produces little or no insulin by itself. According to
the World Health Organization, about 422 million people worldwide have diabetes and 1.6 million deaths are directly attributed to diabetes each year. Both
the number of cases and the prevalence of diabetes have been steadily increasing over the past few decades.
Our diabetes gene therapy was developed by lead researcher Dr. George Gittes, at the Rangos Research Center at UPMC Children’s Hospital of
Pittsburgh. It works by reprogramming beta cells in the pancreas to restore their function, thereby replenishing levels of insulin. The infusion process uses
an endoscope and an adeno-associated virus (AAV) vector to deliver Pdx1 and MafA genes to the pancreas. The proteins these genes express have been
shown to transform alpha cells in the pancreas into functional beta-like cells, which can produce insulin but are distinct enough from beta cells to evade the
body’s immune system.
The diabetes gene therapy has been tested in vivo in mice and nonhuman primates. In studies of diabetic mice, the gene therapy approach restored
normal blood glucose levels for an extended period of time, typically around four months. According to Dr. Gittes, the duration of restored blood glucose
levels in mice could translate to decades in humans. If successful, this gene therapy could eliminate the need for insulin replacement therapy for diabetic
patients.
Capital Requirements, Liquidity and Going Concern Considerations
Our financial statements are prepared using the generally accepted accounting principles applicable to a going concern, which contemplates the realization
of assets and liquidation of liabilities in the normal course of business. However, as shown in the accompanying financial statements, we have sustained
substantial losses from operations since inception and have no current source of revenue. In addition, we have used, rather than provided, cash in our
operations. We expect to continue to incur significant expenditures to further clinical trials for the commercial development of our patents.
Management recognizes that we must obtain additional resources to successfully commercialize our intellectual property. To date, we have received
funding in the form of equity and debt, and we plan to seek additional funding in the future. However, no assurances can be given that we will be successful
in raising additional capital. If we are not able to timely and successfully raise additional capital, the timing of our clinical trials, financial condition and
results of operations will continue to be materially affected. These financial statements do not include any adjustments relating to the recoverability and
classification of recorded asset amounts and classification of liabilities.
F-8
Note 2 – Summary of Significant Accounting Policies
The Company’s financial statements have been prepared in accordance with U.S. generally accepted accounting principles (“GAAP”). Accordingly, they
do not include all the information and footnotes required by generally accepted accounting principles for complete financial statements. In our opinion the
financial statements include all adjustments (consisting of normal recurring accruals) necessary to make the financial statements not misleading. The results
of operations for any interim periods are not necessarily indicative of results to be expected for the full year. A summary of our significant accounting
policies consistently applied in the preparation of the accompanying financial statements follows.
Capital Stock
In connection with the Company’s completed IPO in April 2018, all of the Company’s Preferred Stock and Non-Voting Common Stock were converted into
shares of the Company’s Common Stock. The Company’s Common Stock was then forward-split at a ratio of 6.6841954-to-1. Furthermore, prior to the
closing of the IPO, the Company’s Certificate of Incorporation was amended and restated to provide the Company with the authority to issue up to
210,000,000 shares of stock consisting of 200,000,000 shares of Common Stock at a par value of $0.001 per share and 10,000,000 shares of Preferred
Stock at a par value of $0.001 per share.
Use of Estimates
The preparation of our financial statements in conformity with GAAP requires us to make estimates and assumptions that affect the reported amounts of
assets and liabilities and disclosure of contingent assets and liabilities at the date of the financial statements and the reported amounts of expenses during
the reporting period. Actual results could differ from those estimates.
Cash
We consider all highly liquid short-term investments with an initial maturity of three months or less to be cash equivalents. Any amounts of cash in
financial institutions which exceed FDIC insured limits expose us to cash concentration risk. We have no cash equivalents, and had $1,761,278 and
$8,465,768 in excess of FDIC insured limits of $250,000 at December 31, 2019 and December 31, 2018 respectively.
F-9
Fair Value of Financial Instruments
The carrying amounts reported in the balance sheet for cash, accounts receivable, accounts payable and accrued expenses approximate fair value because of
the immediate or short-term maturity of these financial instruments.
ASC 820, Fair Value Measurements and Disclosures, defines fair value, provides a consistent framework for measuring fair value under GAAP and
expands fair value financial statement disclosure requirements. ASC 820’s valuation techniques are based on observable and unobservable inputs.
Observable inputs reflect readily obtainable data from independent sources, while unobservable inputs reflect our market assumptions. ASC 820 classifies
these inputs into the following hierarchy:
Level 1:
Quoted prices for identical instruments in active markets.
Level 2:
Quoted prices for similar instruments in active markets; quoted prices for identical or similar instruments in markets that are not
active; and model-derived valuations whose inputs are observable or whose significant value drivers are observable.
Level 3:
Instruments with primarily unobservable value drivers.
Property and Equipment
Furniture and equipment are stated at cost. Depreciation is calculated using the straight-line method over the estimated useful lives of the assets, which
range from three to five years. Routine maintenance and repairs are charged to expense as incurred and major renovations or improvements are capitalized.
Research and Development Materials Costs
Research and development expenditures are comprised of costs incurred to conduct research and development activities. These include payments to
collaborative research partners, including wages and associated employee benefits, facilities and overhead costs. These expenditures relate to preclinical,
Phase I, and Phase II clinical trials and are expensed as incurred. Purchased materials to be used in future research are capitalized and included in research
and development supplies. Research and development supplies purchased and capitalized for future use was $801,780 and $0 at December 31, 2019 and
December 31, 2018, respectively.
F-10
Awards
In 2010, we were awarded $4.5 million from the State of Texas Emerging Technology Fund ("TETF"). The award was received in two tranches of $2.25
million during 2010 and 2011. The award proceeds were used for the development and future commercialization of our nanomolecular therapy product for
the treatment of cancer. In consideration for the award, we provided the TETF with an "Investment Unit", consisting of (i) a Promissory Note ("Note") and
(ii) a right to purchase our equity shares ("Warrant"). The funds received for this award were assigned to the Investment Unit, and classified separately
from equity as "mezzanine" in the balance sheet.
In 2010, we also were awarded approximately $244,500 from the U.S. Treasury Department for our QTDP Program Nanoparticle Therapy for Lung
Cancer. The award was received during 2011 for our historical activities, and required no prospective expenditures. We accounted for these funds received
as revenue at that time.
Intellectual Property
Intellectual property consists of external legal and related costs associated with patents and other proprietary technology acquired, licensed by, or
maintained by us that we believe contribute to a probable economic benefit toward such patents and activities. These legal costs incurred in connection with
the patent applications and patent maintenance are capitalized. Intellectual property is stated at cost, to be amortized on a straight-line basis over the
estimated useful lives of the assets.
Accounting for Stock-Based Compensation
We use the fair value-based method of accounting for stock-based compensation for options granted to employees, independent consultants and
contractors. We measure options granted at fair value determined as of the grant date, and recognize the expense over the periods in which the related
services are rendered based on the terms and conditions of the award. Generally, where the award only has a service condition, the requisite service period
is the same as the vesting period.
Financial Instruments
We have elected the Fair Value Option to account for the Investment Unit at fair value as a combined hybrid financial instrument containing a Warrant and
a Note (see Investment Unit Note). Prior to its exercise, the Warrant component was not classified within equity, as the exercise price of the warrants was
affected by the market price of our stock in a future qualifying financing transaction and was not considered to be indexed to our own stock. The Note is
not classified within liabilities, as our management can determine the timing of the repayment obligation, if any. As a result, the Warrant and Note that
comprised the Investment Unit were aggregated and classified within the mezzanine section of the balance sheet.
Due to the contingent terms of the financial instruments, changes in the fair value of the Investment Unit were calculated and realized in earnings. There
were no changes in the fair value of the Investment Unit at December 31, 2019. In August 2019, the remaining articles of the Investment Unit were
terminated.
F-11
Long-Lived Assets
We review long-lived assets and certain identifiable intangibles held and used for possible impairment whenever events or changes in circumstances
indicate that the carrying amount of an asset may not be recoverable. In evaluating the fair value and future benefits of its intangible assets, management
performs an analysis of the anticipated undiscounted future net cash flow of the individual assets over the remaining amortization period. We recognize an
impairment loss if the carrying value of the asset exceeds the expected future cash flows. During the years ended December 31, 2019 and December 31,
2018, there were no deemed impairments of our long-lived assets.
Recent Accounting Developments
Accounting pronouncements issued but not effective until after December 31, 2019 are not expected to have a significant effect on our financial condition,
results of operations, or cash flows.
Note 3 – Intellectual Property
We have exclusive license agreements on thirty-four (34) issued patents for technologies developed by researchers at the National Cancer Institute, the
University of Texas MD Anderson Cancer Center ("MDACC"), the University of Texas Southwestern Medical Center, and the University of
Pittsburgh. These patents comprise various therapeutic, diagnostic, technical and processing claims. These license rights will be amortized on a straight-line
basis over the estimated period of useful lives of the underlying patents or the license agreements.
Note 4 – Investment Unit
The Texas Emerging Technology Fund (“TETF”) was created as an incentive for economic development to the Texas economy by providing financial
support that leverages private investment for the creation of high-quality technology jobs in Texas. The award received required us to comply with certain
performance conditions to ensure the monies the Company received were used for development activities in the state of Texas, and that we maintained our
corporate nexus in Texas. Further, in connection with the award, the Company issued an Investment Unit to the TETF. On September 25, 2017 and again on
August 16, 2019, the Company entered into Termination Agreements with the Texas Treasury Safekeeping Trust Company ("TTSTC"), the entity managing
and controlling TETF interests, that terminated Article II and the all remaining Articles of the Investment Unit, respectively, so that the entirety of the
Investment Unit was effectively terminated. As further described below, the Investment Unit consisted of a Promissory Note and a Right to Purchase.
Promissory Note
The Promissory Note was an obligation to repay the $4.5 million principal amount, with interest accrued at 8% per annum, but only if an event of default
occurred prior to August 13, 2020. If no event of default occurred prior to August 13, 2020, the Promissory Note and all related interest would be
cancelled.
Consistent with the stated objectives of the TETF, an event of default that would trigger the repayment obligation under the Promissory Note was a failure
to maintain our principal place of business or our principal executive offices headquartered in the State of Texas (referred to as the “Residency
Requirement”) until August 13, 2020.
F-12
Warrant
The Warrant was an obligation to issue (a Right to purchase by the TETF) shares of the same class of stock to be issued in a “First Qualifying Financing
Transaction,” at 80% of the per share transaction value (effectively a 20% discount). Alternatively, the TETF could exercise its right to purchase at any
time prior to the occurrence of a First Qualifying Financial Transaction for $0.001 per share.
The Warrant included a provision that required changes in the strike price, driven by the pricing of the “First Qualifying Financing Transaction.” As a
result, the Warrant embedded in the Investment Unit was accounted for as a derivative financial instrument and classified outside of equity under ASC 815-
40-15 as the settlement adjustment from the future transaction did not permit for the strike price to be considered fixed.
On March 12, 2014, the TETF exercised its Right to Purchase for $0.001 per share, and we issued to the TETF an aggregate of 184,797 shares of our Series
B preferred stock. These shares were subsequently forward-split and converted to 1,235,219 shares of Common Stock in connection with our IPO.
Accounting for the Investment Unit
We accounted for the Investment Unit as a hybrid financial instrument under FASB Statement 155, and measured the Investment Unit at the amount of
proceeds received from the TETF award. The First Qualifying Financial Transaction occurred during December 2013, resulting in an adjustment to the fair
value of the Investment Unit in the amount of approximately $2.5 million. The TETF exercised the Warrant for $0.001 per share. We received notice of
purchase from the TETF during March 2014, and issued 184,797 shares of Series B Preferred Stock, which has since been converted to 1,235,219 shares of
Common Stock upon completion of the Company’s IPO. Upon exercise by the TETF of the Warrant, the remaining component within the Investment Unit
was the Promissory Note. The Investment Unit was valued at zero, because our obligation to repay the Promissory Note arose from an event of default (a
failure to maintain the Texas Residency Requirement), which was an event which rested entirely within our control.
Note 5 – Equity
Initial Public Offering
On April 3, 2018, the Company completed its IPO, whereby the Company sold an aggregate of 1,280,000 shares of its common stock, at $5.00 per share,
resulting in estimated net proceeds of $5,025,000 after underwriting discounts, commissions and estimated offering expenses of $895,000. Additionally, the
underwriters have been issued warrants to purchase common stock equal to 3% of the securities sold in the IPO, or 38,400 shares of Common Stock.
Private Investment
On May 9, 2018, the Company completed a private placement, whereby the Company sold to investors an aggregate of 828,500 shares of its common stock
at $12.07 per share and warrants to purchase up to 621,376 shares of the Company’s common stock with an initial exercise price equal to $15.62 per share.
The per share price and warrant exercise price were subject to automatic adjustment, if applicable, based on the volume weighted average daily prices on
the three days after the registration statement registering the resale of the shares of common stock sold to the investors and the shares of the common stock
issuable upon exercise of the warrant was declared effective and the Company's shareholders approved the transaction. In no event would the purchase
price or warrant exercise price be less than $4.25 per share. The Company received net proceeds of $9,250,000 after commissions and expenses.
On August 1, 2018, following the effectiveness of our Registration Statement on Form S-1 (File No. 333-225090) and pursuant to the terms of the Purchase
Agreement and Warrants, we issued to the original investors of the private placement an aggregate of 1,174,440 additional shares of our common stock and
the Warrants became exercisable for a total of 2,283,740 shares of our common stock with an exercise price equal to $4.25 per share.
F-13
Registered Direct Offering
On November 22, 2019, the Company completed a registered direct offering (“RDO”), whereby the Company sold to investors an aggregate of 3,167,986
shares of the Company’s common stock at $0.40 per share and warrants to purchase up to 3,167,986 shares of the Company’s common stock at an exercise
price of $0.46 per share. The warrants are first exercisable on May 22, 2020. The Company received net proceeds of approximately $1,093,000 after
commissions and expenses. Additionally, the underwriters have been issued warrants to purchase common stock equal to 7% of the aggregate number of
shares of Common Stock issued and issuable pursuant to the RDO (including shares underlying any warrants and options), or 443,518 shares of Common
Stock at an exercise price of 125% of the RDO price per share, or $0.58 per share.
In connection with the closing of the Company’s RDO, the Company further adjusted the warrants to purchase up to 2,283,740 shares of the Company's
common stock, that had been issued as part of the May 9, 2018 Private Placement and adjusted in August 2018 to (i) reduce the exercise price for each
share from $4.25 per share to $0.46 per share, (ii) extended the exercisable date of these warrants to May 22, 2020, and (iii) extended the termination date
of the warrants by six months and one day.
Stock Issuances
During the year ended December 31, 2019, we issued (i) 3,167,986 shares of Common Stock from the Company’s RDO for cash of $1,267,194, (ii)
506,707 shares of Common Stock for service provided to us, valued at $469,588, and (iii) we issued 350,000 shares of Common Stock held in abeyance for
an investor in the Private Placement.
During the year ended December 31, 2018, we issued (i) 200,009 shares of Common Stock, taking into account the forward-split ratio from the Company’s
IPO, for service provided to us, valued at $553,303, and we issued (ii) 3,282,940 shares of Common Stock in the Company’s IPO and Private Placement for
cash of $16,400,000.
Preferred Stock
In connection with the Company’s IPO, all Preferred Stock included in Series A through Series G, totaling 1,394,953 shares at December 31, 2018, were
converted into 9,324,177 shares of Common Stock in association with the forward-split (See Capital Stock Note). Upon the completion of the IPO, the
Company is authorized to issue 10,000,000 shares of Preferred Stock at a par value of $0.001 per share, none of which are outstanding as of December 31,
2019.
Common Stock
Upon the completion of the IPO, all of the Company’s non-voting Common Stock automatically converted into Voting Common Stock on a one-to-one
basis. Immediately following the completion of the IPO, the Company is authorized to issue 200,000,000 shares of Common Stock at a par value of $0.001
per share, all of which is Voting Common Stock. There were 19,263,841 shares of Common Stock outstanding at December 31, 2019.
F-14
Common Stock Purchase Warrants
Common Stock purchase warrant activity for the years ended December 31, 2019 and 2018 respectively are as follows:
Outstanding at January 1, 2018
Issued
Cancelled or expired
Exercised
Outstanding at December 31, 2018
Issued
Cancelled or expired
Exercised
Outstanding at December 31, 2019
Number of
Warrants
Weighted
Avg. Exercise
Price
748,060 $
3,166,492
(15,385)
(34,615)
3,864,552 $
3,611,504
—
—
7,476,056 $
5.17
1.74
—
—
2.36
0.47
—
—
1.45
In the year ending December 31, 2019, we (i) issued warrants to purchase 3,167,986 shares of our Common Stock at $0.46 per share to the investors in the
Company’s RDO, (ii) issued warrants to purchase 443,518 shares of our Common Stock at $0.58 per share to the underwriter of the Company’s RDO, and
(iii) reduced the purchase price of the warrants, issued to investors in the Company’s Private Placement in May 2018, to purchase 2,283,740 shares of the
Company’s common stock from $4.25 per share to $0.46 per share.
In the year ended December 31, 2018, we granted (i) warrants to purchase 38,400 shares of our Common Stock at $6.25 per share to the underwriter of the
Company’s IPO and (ii) warrants to purchase 2,283,740 shares of our Common Stock at $4.25 per share to the investors in the Company’s private
placement. We also granted warrants to purchase up to 844,352 shares of Common Stock in consideration of services valued at $2,203,506 including (i)
warrants to purchase up to 425,000 shares of Common Stock to Cancer Revolution, LLC, (ii) warrants to purchase up to 225,000 shares of Common Stock
to Cancer Biotech, LLC, (iii) warrants to purchase up to 144,352 shares of Common Stock to Inception Capital Management, LLC, and (iv) warrants to
purchase up to 50,000 shares of Common Stock to World Wide Holdings, LLC at $5.00 per share.
On January 29, 2018, the Company entered into an agreement with a consultant whereby the Company agreed to grant warrants to purchase 6,000 shares of
our Common Stock at $5.00 per share in consideration of services valued at $30,000 provided to the company. As of December 31, 2019, the Company has
not issued these warrant shares.
On September 20, 2018, World Wide Holdings, LLC exercised its warrant to purchase 50,000 shares of our Common Stock via a cashless exercise option.
As a result, the Company issued 34,615 shares of Common Stock to World Wide Holdings in exchange for the cashless exercise of the warrant and the
remaining 15,385 shares of Common Stock were cancelled.
F-15
2018 Equity Incentive Plan
The Company’s board of directors and stockholders have approved and adopted the Company’s 2018 Equity Incentive Plan (“2018 Plan”), which became
effective on the completion of the IPO on April 3, 2018. The 2018 Plan provides for the grant of incentive stock options (“ISOs”), nonstatutory stock
options, stock appreciation rights, restricted stock awards, restricted stock unit awards, performance-based stock awards, other forms of equity
compensation and performance cash awards. ISOs may be granted only to employees. All other awards may be granted to employees, including officers,
and to the Company’s non-employee directors and consultants, and affiliates.
A total of 4,160,000 shares of Common Stock are available under the 2018 Plan, which includes 554,963 shares of Common Stock reserved for issuance
under our 2009 Equity Incentive Plan that were added to the 2018 Plan. No further grants will be made under the 2009 Plan and any shares subject to
outstanding stock options under the 2009 Plan that would otherwise be returned to the 2009 Plan will instead be added to the shares initially reserved under
the 2018 Plan.
In addition, the number of shares of Common Stock reserved for issuance under the 2018 Plan will automatically increase on January 1 of each year,
beginning on January 1, 2019 by 5% of the total number of shares of the Company’s Common Stock outstanding on December 31 of the preceding
calendar year, or a lesser number of shares determined by the administrator of the 2018 Plan. On January 1, 2019 and 2020, the number of shares of
common stock reserved for issuance under the 2018 Plan was increased by an aggregate of 761,957 and 963,192 shares, respectively.
2018 Employee Stock Purchase Plan
The Company’s board of directors and stockholders have approved and adopted the Company’s 2018 Employee Stock Purchase Plan (“ESPP”), which
became effective on the completion of the IPO on April 3, 2018. The ESPP authorizes the issuance of 208,500 shares of the Company’s common stock
pursuant to purchase rights granted to our eligible employees. The number of shares of common stock reserved for issuance will automatically increase on
January 1 of each calendar year, from January 1, 2019 by the lesser of 2% of the total number of shares of our common stock outstanding on December 31
of the preceding calendar year or a number determined by the administrator of the ESPP. The administrator of the ESPP, which is our Board of Directors,
determined not to increase the number of shares for issuance under the ESPP on January 1, 2019 or January 1, 2020 due to the ESPP not currently being
utilized.
Stock Options
As of December 31, 2019, the Company has outstanding stock options to purchase 5,982,923 shares of Common Stock that have been granted to various
employees, vendors and independent contractors. These options can vest immediately or over periods ranging from twelve (12) to forty-eight (48) months,
are exercisable for a period of ten years, and enable the holders to purchase shares of our Common Stock at exercise prices ranging from $0.001 - $9.80.
The per-share fair values of these options range from $0.001 to $7.93, based on Black-Scholes-Merton pricing models with the following assumptions:
Expected term:
Risk-free rate:
Volatility:
Dividend yield:
10 years
1.51% – 2.63%
75.98% – 79.89%
0%
F-16
In the year ending December 31, 2019, Company granted stock options to employees and consultants to purchase 1,744,300 shares of Common Stock with
exercise prices ranging from $0.30 to $1.62 per share and cancelled options to purchase 297,058 shares of Common Stock due to the inactivity of service
providers.
In the year ended December 31, 2018, the Company granted stock options to employees and consultants to purchase 2,034,525 shares of Common Stock
with exercise prices ranging from $2.15 to $9.80 per share and cancelled options to purchase 127,593 shares of Common Stock due to the inactivity of the
service providers.
The weighted average remaining contractual term for the outstanding options at December 31, 2019 and 2018 is 7.45 and 7.74 years, respectively.
Stock option activity for the years ended December 31, 2019 and 2018, respectively, is as follows:
Outstanding at January 1, 2018
Options granted
Options exercised
Options expired
Outstanding at December 31, 2018
Options granted
Options exercised
Options expired
Outstanding at December 31, 2019
Share-Based Compensation
Number of
Shares
2,628,749 $
2,034,525
—
(127,593)
4,535,681 $
1,744,300
—
(297,058)
5,982,923 $
Weighted
Avg. Exercise
Price
1.31
6.21
—
—
3.31
1.48
—
—
2.66
As of December 31, 2019, the Company’s total compensation cost related to nonvested time-based stock option awards granted to employees and board
members and not yet recognized was approximately $4.5 million. The Company expects to record this stock-based compensation expense over the next two
years, in the amount of $4.3 million with respect to stock option awards using a graded vesting method and $0.2 million with respect to stock option awards
using a cliff vesting method. As of December 31, 2019, the weighted average term over which these expenses are expected to be recognized are 1.86 years
and 0.47 years, for stock options granted using a graded vesting method and a cliff vesting method respectively.
As of December 31, 2019, the Company’s total compensation cost related to nonvested performance-based stock option awards granted to an employee and
not yet recognized was approximately $1.3 million. The entirety of this award may be recognized and recorded, upon the achievement of certain
milestones, within 1.35 years from December 31, 2019.
In the year ended December 31, 2019, the Company's total share-based compensation was approximately $3.5 million with approximately $3.0 million
representing the vesting of options issued to service providers, employees, and board members.
F-17
Note 6 - Related Party Transactions
Domecq Sebastian, LLC
Domecq-Sebastian LLC (“Domecq”) is an entity affiliated with David Nance, a former director and officer who is now deceased. During December 2017,
we entered into a promissory note with Domecq for a total amount of $200,000 that carried a 15% interest rate and is due and payable on or before March
31, 2018. The note carried a 18% default interest on amounts paid after the maturity date. This note was subsequently repaid in full in April 2018.
Introgen Research Institute
Introgen Research Institute (“IRI”) is a Texas-based technology company, currently affiliated with Rodney Varner, our CEO. In April 2009, prior to Mr.
Varner becoming an officer and director of our Company in August 2012, we entered into an Assignment and Collaboration Agreement with IRI, providing
us with the exclusive right to commercialize a portfolio of intellectual property. This agreement was amended in 2011 to include additional sublicensing of
additional intellectual property made available to IRI from the University of Texas MD Anderson Cancer Center.
Rodney Varner
Rodney Varner is the Company’s Chief Executive Officer. On March 28, 2018, we entered into a promissory note with Rodney Varner, Trustee, for a total
amount of $45,000 that carried a 0% interest rate and is due and payable on or the earlier of (i) five days after funding of the Company’s initial public
offering, or (ii) April 30, 2018, the maturity date. If paid after the maturity date, the note carried a 10% interest rate. This note was paid in full prior to the
maturity date in April 2018.
Viet Ly
Viet Ly manages several investment funds that have provided the Company with investment funds since 2013. On March 9, 2018, we entered into a
promissory note with Viet Ly for a total amount of $25,000 that carried a 0% interest rate and is due and payable on or before June 9, 2018, the maturity
date. If paid after the maturity date, the note carried a 10% interest rate. This note was paid in full prior to the maturity date in April 2018.
The Company entered into a consulting agreement with Viet Ly on April 19, 2018. The Company agreed to pay Mr. Ly at an initial rate of $175,000 per
year, with compensation variable from time-to-time as determined by the Company, for strategic consulting services.
F-18
Note 7 - Commitments and Contingencies
Leases
On April 16, 2018, the Company executed a service agreement with CIC Innovation Communities, LLC, to establish and lease offices at the Cambridge
Innovation Center in Cambridge, Massachusetts. The Company does not have a long-term agreement in place to occupy this location, but rather occupies
on a month-to-month basis.
On April 16, 2018, the Company also executed a space utilization agreement with the Board of Regents of the University of Texas System to establish and
lease offices at the Dell Medical School in Austin, Texas. The Company pays $2,050 per month to occupy this location and the lease is effective until April
30, 2020.
Commitments
MD Anderson
We have entered into a clinical study agreement with the University of Texas MD Anderson Cancer Center in Houston, Texas, to administer a Phase I/II
clinical trial, combining FUS1-nanoparticles and Erlotinib in Stage IV lung cancer patients. The trial was expected to run through the end of 2018 with a
projected total cost of approximately $2 million. Payments are due and payable when invoiced throughout the clinical trial period. The agreement may be
terminated at any time.
In July 2018, the Company entered into a two-year sponsored research agreement with MD Anderson Cancer Center to sponsor preclinical studies focused
on the combination of TUSC2 with an immunotherapy with a projected total cost of approximately $2 million. Payments are due and payable when
invoiced throughout the clinical trial period. The agreement may be terminated at any time.
In 2009, we agreed to assume certain contractual and other obligations of IRI in consideration for the sublicense rights, expertise, and assistance associated
with the assignment of certain technologies and intellectual property. We also agreed to pay royalties of one percent (1%) on sales of resulting Licensed
Products, for a period of 21 years following the termination of the last of the MD Anderson License Agreement and Sublicense Agreement, to IRI and we
assumed patent prosecution costs and an annual minimum royalty of $20,000 payable to the National Institutes of Health.
National Institutes of Health
Our $191,393 payment obligation to the National Institutes of Health (“NIH”) represented a current obligation, of which $15,393 of 2016 patent
prosecution costs were paid in the fourth quarter of 2016 and $176,000 was included in Accounts Payable at December 31, 2016 (consisting of accrued
annual royalties of $140,000 and patent costs of $36,000). During the first quarter of 2017, we modified the terms of our accrued royalty obligation to NIH.
Under the modified agreement, NIH agreed to extinguish $120,000 of the accrued royalties payable to them in consideration for payment by us of (i)
accrued patent costs of $36,000, (ii) a royalty payment of $20,000, and (iii) a contingent payment of $240,000, increasing at $20,000 per year starting in
2018, to be paid upon our receipt of FDA approval. The payments for the patent costs of $36,000 and royalties of $20,000 were paid during the second
quarter of 2017.
As a result of our modified agreement with the NIH, we have recognized the exchange of the $120,000 fixed obligation for the $240,000 contingent
obligation as a $120,000 reduction to intellectual property expense (classified within General and Administrative Expense) during the first quarter of 2017.
The $240,000 contingent obligation which increases annually by $20,000 and is $280,000 as of December 31, 2019 will be recognized when we obtain
regulatory approval (the event that triggers the payment obligation).
F-19
Contingencies
From time to time we may become subject to threatened and/or asserted claims arising in the ordinary course of our business. Management is not aware of
any matters, either individually or in the aggregate, that are reasonably likely to have a material impact on our Company’s financial condition, results of
operations or liquidity.
During October 2017, we received an informal demand from a former financial advisor, claiming that it is entitled to a warrant to purchase shares of
common stock equal to three (3) percent of our outstanding shares at December 1, 2015. We believe this asserted claim lacks merit, and we intend to
defend the claim vigorously.
Note 8 – Income Taxes
The provision for income taxes differs from the amount computed by applying the statutory federal income tax rate to income before provision for income
taxes. The sources and tax effects of the differences are as follows:
Income tax provision at the federal statutory rate
Effect of operating losses
21%
(21)%
0%
At December 31, 2019, the Company has a net operating loss carryforward of approximately $16.5 million for Federal and state purposes. This loss will be
available to offset future taxable income. If not used, this carryforward will begin to expire in 2029. The deferred tax asset relating to the operating loss
carryforward has been fully reserved at December 31, 2019 and December 31, 2018. The principal differences between the operating loss for income tax
purposes and reporting purposes are shares issued for services and share-based compensation and a temporary difference in depreciation expense.
Note 9 – Subsequent Events
Reserves of 2018 Equity Incentive Plan and 2018 Employee Stock Purchase Plan
On January 1, 2020, the total shares of common stock reserved under the 2018 Equity Incentive Plan increased 963,192 shares. On March 18, 2020, the
Company's Board of Directors determined that no additional shares would be reserved during the 2020 fiscal year for the 2018 Employee Stock Purchase
Plan given that no shares have yet been issued under the plan.
Regulatory Designation
On January 14, 2020, the Company received U.S. FDA Fast Track Designation for its Oncoprex immunogene therepay in combination with the EGFR
tyrosine kinase inhibitor osimertinib.
F-20
Registered Direct Offerings
On January 21, 2020, the Company completed a registered direct offering, in which the Company sold to an accredited investor 961,000 shares of the
Company’s common stock at $0.24 per share. The Company received net proceeds of approximately $200,000 after commissions and expenses.
On January 23, 2020, the Company completed a registered direct offering, in which the Company sold to investors an aggregate of 7,620,000 shares of the
Company’s common stock at $1.05 per share. The Company received net proceeds of approximately $7.2 million after commissions and expenses.
On February 19, 2020, the Company amended its Registration Statement on Form S-3 to increase the maximum offering size by approximately $3,000,000.
On February 21, 2020, the Company completed a registered direct offering under the amended S-3 Registration Statement, in which the Company sold to
investors an aggregate of 5,000,000 shares of the Company’s common stock at $3.50 per share. The Company received net proceeds of approximately $16
million after commissions and expenses.
Option Grants
On January 25, 2020, the Company’s Board of Directors approved the grant of stock options to purchase a total of 40,000 shares of Common Stock to key
service providers.
On March 12, 2020, in connection with appointments of new officers, the Company granted stock options to newly appointed officers to purchase an
aggregate of 1,090,000 shares of Common Stock.
On March 18, 2020, in connection with appointments of new directors, the Company granted stock options to newly appointed directors to purchase an
aggregate of 35,325 shares of Common Stock.
License Agreement
On February 11, 2020, the Company entered into an exclusive license agreement with the University of Pittsburgh for patented gene therapy technologies
used in the treatment of Type 1 and Type 2 diabetes.
Director & Officer Appointments
On March 12, 2020, the Company appointed Catherine M. Vaczy, as Executive Vice President and Chief Strategy Officer, and Michael T. Redman, as
Executive Vice President and Chief Operating Officer.
On March 18, 2020, the Company's Board of Directors appointed three independent directors. Brent Longnecker was appointed to the Board as a Class I
director. Jose Antonio Moreno Toscano was appointed to the Board as a Class III director. Will R. Wilson Jr. was appointed to the Board as a Class
II director.
F-21
DESCRIPTION OF THE COMPANY'S SECURITIES REGISTERED
UNDER SECTION 12 OF THE SECURITIES EXCHANGE ACT OF 1934, AS AMENDED
The following description summarizes the most important terms of our common stock. Because it is only a summary, it does not contain all the
information that may be important to you. For a complete description of the matters set forth in this “Description of Common Stock,” you should refer to
our amended and restated certificate of incorporation (the “Restated Certificate”), and amended and restated bylaws (the “Restated Bylaws”), which are
included as exhibits to our Annual Report on Form 10-K, and to the applicable provisions of Delaware law. Our authorized capital stock consists of
200,000,000 shares of common stock, par value $0.001 per share, and 10,000,000 shares of undesignated preferred stock, par value $0.001 per share. Our
board of directors is authorized, without stockholder approval except as required by the listing standards of The Nasdaq Stock Market LLC, to issue
additional shares of our capital stock. In addition, our board of directors may, without further action by our stockholders, designate the rights, preferences,
privileges, and restrictions of our preferred stock in one or more series.
Exhibit 4.12
Common Stock
Voting
Our common stock is entitled to one vote for each share held of record on all matters submitted to a vote of the stockholders, including the
election of directors, and does not have cumulative voting rights. Accordingly, the holders of a majority of the shares of our common stock entitled to vote
in any election of directors can elect all of the directors standing for election.
Dividends
Subject to preferences that may be applicable to any then-outstanding preferred stock, the holders of common stock are entitled to receive
dividends, if any, as may be declared from time to time by our board of directors out of legally available funds.
Liquidation
In the event of our liquidation, dissolution or winding-up, holders of our common stock will be entitled to share ratably in the net assets legally
available for distribution to stockholders after the payment of all of our debts and other liabilities, subject to the satisfaction of any liquidation preference
granted to the holders of any outstanding shares of preferred stock.
Rights and Preferences
Holders of our common stock have no preemptive, conversion or subscription rights, and there are no redemption or sinking fund provisions
applicable to our common stock. The rights, preferences and privileges of the holders of our common stock are subject to, and may be adversely affected
by, the rights of the holders of shares of any series of our preferred stock that we may designate and issue in the future.
Fully Paid and Nonassessable
All of our outstanding shares of common stock are, and the shares of common stock to be issued in this offering will be, fully paid and
nonassessable.
Anti-Takeover Effects of Provisions of Our Amended and Restated Certificate of Incorporation, Our Amended and Restated Bylaws and
Delaware Law
Delaware Anti-Takeover Law
We are subject to Section 203 of the Delaware General Corporation Law, or Section 203. Section 203 generally prohibits a public Delaware
corporation from engaging in a “business combination” with an “interested stockholder” for a period of three years following the time that such stockholder
became an interested stockholder, unless:
●
●
●
prior to such time the board of directors of the corporation approved either the business combination or the transaction which resulted in the
stockholder becoming an interested stockholder;
upon consummation of the transaction which resulted in the stockholder becoming an interested stockholder, the interested stockholder
owned at least 85% of the voting stock of the corporation outstanding at the time the transaction commenced, excluding for purposes of
determining the voting stock outstanding (but not the outstanding voting stock owned by the interested stockholder) those shares owned (1)
by persons who are directors and also officers and (2) employee stock plans in which employee participants do not have the right to
determine confidentially whether shares held subject to the plan will be tendered in a tender or exchange offer; or
at or subsequent to such time, the business combination is approved by the board of directors and authorized at an annual or special meeting
of stockholders, and not by written consent, by the affirmative vote of at least 66-2/3% of the outstanding voting stock which is not owned
by the interested stockholder.
Section 203 defines a business combination to include:
●
●
●
●
●
any merger or consolidation involving the corporation and the interested stockholder;
any sale, transfer, pledge or other disposition involving the interested stockholder of 10% or more of the assets of the corporation;
subject to exceptions, any transaction that results in the issuance or transfer by the corporation of any stock of the corporation to the
interested stockholder;
subject to exceptions, any transaction involving the corporation that has the effect of increasing the proportionate share of the stock of any
class or series of the corporation beneficially owned by the interested stockholder; and
the receipt by the interested stockholder of the benefit of any loans, advances, guarantees, pledges or other financial benefits provided by or
through the corporation.
In general, Section 203 defines an interested stockholder as any entity or person beneficially owning 15% or more of the outstanding voting stock
of the corporation and any entity or person affiliated with or controlling or controlled by the entity or person.
Amended and Restated Certificate of Incorporation and Amended and Restated Bylaws
Provisions of our amended and restated certificate of incorporation and amended and restated bylaws may delay or discourage transactions
involving an actual or potential change in our control or change in our management, including transactions in which stockholders might otherwise receive a
premium for their shares or transactions that our stockholders might otherwise deem to be in their best interests. Therefore, these provisions could
adversely affect the price of our common stock. Among other things, our amended and restated certificate of incorporation and amended and restated
bylaws:
●
●
●
●
●
●
●
●
●
●
permit our board of directors to issue up to 10,000,000 shares of preferred stock, with any rights, preferences and privileges as they may
designate (including the right to approve an acquisition or other change in our control);
provide that the authorized number of directors may be changed only by resolution of the board of directors;
provide that the board of directors or any individual director may only be removed with cause and the affirmative vote of the holders of at
least 66-2/3% of the voting power of all of our then outstanding common stock;
provide that all vacancies, including newly created directorships, may, except as otherwise required by law, be filled by the affirmative vote
of a majority of directors then in office, even if less than a quorum;
divide our board of directors into three classes;
require that any action to be taken by our stockholders must be effected at a duly called annual or special meeting of stockholders and not
be taken by written consent;
provide that stockholders seeking to present proposals before a meeting of stockholders or to nominate candidates for election as directors
at a meeting of stockholders must provide notice in writing in a timely manner and also specify requirements as to the form and content of a
stockholder’s notice;
do not provide for cumulative voting rights (therefore allowing the holders of a majority of the shares of common stock entitled to vote in
any election of directors to elect all of the directors standing for election, if they should so choose);
provide that special meetings of our stockholders may be called only by the chairman of the board, our Chief Executive Officer or by the
board of directors pursuant to a resolution adopted by a majority of the total number of authorized directors; and
provide that the Court of Chancery of the State of Delaware will be the sole and exclusive forum for (i) any derivative action or proceeding
brought on our behalf, (ii) any action asserting a claim of breach of a fiduciary duty owed by any of our directors or officers to us or our
stockholders, (iii) any action asserting a claim against us arising pursuant to any provision of the Delaware General Corporation Law or our
certificate of incorporation or bylaws, or (iv) any action asserting a claim against us governed by the internal affairs doctrine. This
exclusive forum provision would not apply to actions brought to enforce any liability or duty created by the Securities Act or the Exchange
Act or any other claim over which the federal courts have exclusive jurisdiction. To the extent that any such claims may be based upon
federal law claims, Section 27 of the Exchange Act creates exclusive federal jurisdiction over all suits brought to enforce any duty or
liability created by the Exchange Act or the rules and regulations thereunder, and Section 22 of the Securities Act creates concurrent
jurisdiction for federal and state courts over all suits brought to enforce any duty or liability created by the Securities Act or the rules and
regulations thereunder. Although our amended and restated certificate of incorporation contains the choice of forum provision described
above, it is possible that a court could rule that such a provision is inapplicable for a particular claim or action or that such provision is
unenforceable.
The amendment of any of these provisions, with the exception of the ability of our board of directors to issue shares of preferred stock and
designate any rights, preferences and privileges thereto, would require approval by the holders of at least 66-2/3% of our then-outstanding common stock.
Nasdaq Capital Market Listing
Our common stock is listed on the Nasdaq Capital Market under the symbol “GNPX”.
Transfer Agent and Registrar
The transfer agent and registrar for our common stock is V Stock Transfer, LLC. The transfer agent and registrar’s address is 18 Lafayette Place,
Woodmere, New York 11598.
CERTIFICATION PURSUANT TO
RULES 13a-14(a) AND 15d-14(a) UNDER THE SECURITIES EXCHANGE ACT OF 1934,
AS ADOPTED PURSUANT TO SECTION 302 OF THE SARBANES-OXLEY ACT OF 2002
Exhibit 31.1
I, J. Rodney Varner, certify that:
1.
2.
3.
4.
I have reviewed this annual report on Form 10-K of Genprex, Inc., a Delaware corporation (the “registrant”);
Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make
the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered
by this report;
Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects
the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;
The registrant's other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in
Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and
15d-15(f)) for the registrant and have:
(a)
(b)
(c)
(d)
Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our
supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us
by others within those entities, particularly during the period in which this report is being prepared;
Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under
our supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial
statements for external purposes in accordance with generally accepted accounting principles;
Evaluated the effectiveness of the registrant's disclosure controls and procedures and presented in this report our conclusions about the
effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and
Disclosed in this report any change in the registrant's internal control over financial reporting that occurred during the registrant's most
recent fiscal quarter (the registrant's fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably
likely to materially affect, the registrant's internal control over financial reporting; and
5.
The registrant's other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting,
to the registrant's auditors and the audit committee of the registrant's board of directors (or persons performing the equivalent functions):
(a)
(b)
All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are
reasonably likely to adversely affect the registrant's ability to record, process, summarize and report financial information; and
Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant's
internal control over financial reporting.
Date: March 30, 2020
By: /s/ J. Rodney Varner
J. Rodney Varner
Chief Executive Officer
(Principal Executive Officer)
CERTIFICATION PURSUANT TO
RULES 13a-14(a) AND 15d-14(a) UNDER THE SECURITIES EXCHANGE ACT OF 1934,
AS ADOPTED PURSUANT TO SECTION 302 OF THE SARBANES-OXLEY ACT OF 2002
Exhibit 31.2
I, Ryan M. Confer, certify that:
1.
2.
3.
4.
I have reviewed this annual report on Form 10-K of Genprex, Inc., a Delaware corporation (the “registrant”);
Based on my knowledge, this report does not contain any untrue statement of a material fact or omit to state a material fact necessary to make
the statements made, in light of the circumstances under which such statements were made, not misleading with respect to the period covered
by this report;
Based on my knowledge, the financial statements, and other financial information included in this report, fairly present in all material respects
the financial condition, results of operations and cash flows of the registrant as of, and for, the periods presented in this report;
The registrant's other certifying officer and I are responsible for establishing and maintaining disclosure controls and procedures (as defined in
Exchange Act Rules 13a-15(e) and 15d-15(e)) and internal control over financial reporting (as defined in Exchange Act Rules 13a-15(f) and
15d-15(f)) for the registrant and have:
(a)
(b)
(c)
(d)
Designed such disclosure controls and procedures, or caused such disclosure controls and procedures to be designed under our
supervision, to ensure that material information relating to the registrant, including its consolidated subsidiaries, is made known to us
by others within those entities, particularly during the period in which this report is being prepared;
Designed such internal control over financial reporting, or caused such internal control over financial reporting to be designed under
our supervision, to provide reasonable assurance regarding the reliability of financial reporting and the preparation of financial
statements for external purposes in accordance with generally accepted accounting principles;
Evaluated the effectiveness of the registrant's disclosure controls and procedures and presented in this report our conclusions about the
effectiveness of the disclosure controls and procedures, as of the end of the period covered by this report based on such evaluation; and
Disclosed in this report any change in the registrant's internal control over financial reporting that occurred during the registrant's most
recent fiscal quarter (the registrant's fourth fiscal quarter in the case of an annual report) that has materially affected, or is reasonably
likely to materially affect, the registrant's internal control over financial reporting; and
5.
The registrant's other certifying officer and I have disclosed, based on our most recent evaluation of internal control over financial reporting,
to the registrant's auditors and the audit committee of the registrant's board of directors (or persons performing the equivalent functions):
(a)
(b)
All significant deficiencies and material weaknesses in the design or operation of internal control over financial reporting which are
reasonably likely to adversely affect the registrant's ability to record, process, summarize and report financial information; and
Any fraud, whether or not material, that involves management or other employees who have a significant role in the registrant's
internal control over financial reporting.
Date: March 30, 2020
By: /s/ Ryan M. Confer
Ryan M. Confer
Chief Financial Officer
(Principal Financial Officer)
CERTIFICATION PURSUANT TO
18 U.S.C. SECTION 1350, AS ADOPTED PURSUANT TO
SECTION 906 OF THE SARBANES-OXLEY ACT OF 2002
Exhibit 32.1
In connection with the Annual Report on Form 10-K of Genprex, Inc. (the “Company”) for the period ended December 31, 2019 as filed with the
Securities and Exchange Commission on the date hereof (the “Report”), each of the undersigned, J. Rodney Varner, Chief Executive Officer of the
Company, and Ryan M. Confer, Chief Financial Officer of the Company, hereby certifies, pursuant to Rule 13a-14(b) of the Securities Exchange Act of
1934, as amended and 18 U.S.C. § 1350, as adopted pursuant to § 906 of the Sarbanes-Oxley Act of 2002, that to his knowledge:
(1) The Report fully complies with the requirements of section 13(a) or 15(d) of the Securities Exchange Act of 1934; and
(2) The information contained in the Report fairly presents, in all material respects, the financial condition and results of operations of the
Company.
Date: March 30, 2020
By: /s/ J. Rodney Varner
J. Rodney Varner
Chief Executive Officer
(Principal Executive Officer)
By: /s/ Ryan M. Confer
Ryan M. Confer
Chief Financial Officer
(Principal Financial Officer)
This certification accompanies the Report, is not deemed filed with the Securities and Exchange Commission and is not to be incorporated by reference into
any filing of the Company under the Securities Act of 1933, as amended, or the Securities Exchange Act of 1934, as amended (whether made before or
after the date of the Report), irrespective of any general incorporation language contained in such filing.