10-K
1
form10-k.htm
UNITED
STATES
SECURITIES
AND EXCHANGE COMMISSION
Washington,
D.C. 20549
Form
10-K
(Mark
One)
For
the fiscal year ended December 31, 2020
For
the Transition Period from to
Commission
File Number: 001-39555
GREENWICH
LIFESCIENCES, INC.
(Exact
name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
(Registrant’s telephone number, including area code)
Securities registered pursuant to Section 12(b) of the Act:
Title of each class Name of each exchange on which registered
Common Stock, $0.001 par value The NASDAQ Capital Market
Securities registered pursuant to Section 12(g) of the Act: None
Indicate
by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes [ ]
No [X]
Indicate
by check if the registrant is not required to file reports pursuant to Section 13 or Section 15(d) of the Act. Yes [ ]
No [X]
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 [X] No [ ]
Indicate
by check mark whether the registrant has submitted electronically and posted on its corporate Web site, if any, every Interactive
Data File required to be submitted and posted 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 and post such files). Yes [X] No [ ]
Indicate
by check mark if disclosure of delinquent filers pursuant to Item 405 of Regulation S-K (§229.405 of this chapter) is not
contained herein, and will not be contained, to the best of registrant’s knowledge, in definitive proxy or information statements
incorporated by reference in Part III of this Form 10-K or any amendment to this Form 10-K. [X]
Indicate
by check mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, or a smaller
reporting 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.
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for
complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. [ ]
Indicate
by check mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness
of its internal control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the
registered public accounting firm that prepared or issued its audit report. [ ]
Indicate
by check mark whether the registrant is a shell company (as defined in Rule 12b-2 of the Act). Yes [ ] No [X]
The
Registrant was not a public company as of the last business day of its most recently completed second fiscal quarter and, therefore,
cannot calculate the aggregate market value of its voting and non-voting common equity held by non-affiliates as of such date.
As
of March 15, 2021, 12,846,897 shares of the registrant’s common stock, $0.001 par value per share, were issued
and outstanding.
TABLE
OF CONTENTS
Page
PART I
Item 1 Business 6
Item 1A Risk Factors 26
Item 1B Unresolved Staff Comments 51
Item 2 Properties 51
Item 3 Legal Proceedings 51
Item 4 Mine Safety Disclosures 51
PART II
Item 6 Selected Financial Data 52
Item 7A Quantitative and Qualitative Disclosures About Market Risk 56
Item 8 Financial Statements and Supplementary Data 56
Item 9A Controls and Procedures 56
Item 9B Other Information 56
PART III
Item 10 Directors, Executive Officers, and Corporate Governance 57
Item 11 Executive Compensation 61
Item 14 Principal Accountant Fees and Services 66
PART IV
SIGNATURES 68
Table of Contents
Forward-Looking
Statements
This
Annual Report on Form 10-K contains forward-looking statements which are made pursuant to the safe harbor provisions of Section
27A of the Securities Act of 1933, as amended (the “Securities Act”), and Section 21E of the Securities Exchange Act
of 1934, as amended (the “Exchange Act”). These statements may be identified by such forward-looking terminology as
“may,” “should,” “expects,” “intends,” “plans,” “anticipates,”
“believes,” “estimates,” “predicts,” “potential,” “continue” or the
negative of these terms or other comparable terminology. Our forward-looking statements are based on a series of expectations,
assumptions, estimates and projections about our company, are not guarantees of future results or performance and involve substantial
risks and uncertainty. We may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements.
Actual results or events could differ materially from the plans, intentions and expectations disclosed in these forward-looking
statements. Our business and our forward-looking statements involve substantial known and unknown risks and uncertainties, including
the risks and uncertainties inherent in our statements regarding:
● our projected financial position and estimated cash burn rate;
● our estimates regarding expenses, future revenues and capital requirements;
● our ability to continue as a going concern;
● our need to raise substantial additional capital to fund our operations;
● the success, cost and timing of our clinical trials;
● our dependence on third parties in the conduct of our clinical trial;
● the results of market research conducted by us or others;
● our reliance on third-party suppliers and manufacturers;
● the success of competing therapies and products that are or become available;
All
of our forward-looking statements are as of the date of this Annual Report on Form 10-K only. In each case, actual results may
differ materially from such forward-looking information. We can give no assurance that such expectations or forward-looking statements
will prove to be correct. An occurrence of, or any material adverse change in, one or more of the risk factors or risks and uncertainties
referred to in this Annual Report on Form 10-K or included in our other public disclosures or our other periodic reports or other
documents or filings filed with or furnished to the U.S. Securities and Exchange Commission (the “SEC”) could materially
and adversely affect our business, prospects, financial condition and results of operations. Except as required by law, we do
not undertake or plan to update or revise any such forward-looking statements to reflect actual results, changes in plans, assumptions,
estimates or projections or other circumstances affecting such forward-looking statements occurring after the date of this Annual
Report on Form 10-K, even if such results, changes or circumstances make it clear that any forward-looking information will not
be realized. Any public statements or disclosures by us following this Annual Report on Form 10-K that modify or impact any of
the forward-looking statements contained in this Annual Report on Form 10-K will be deemed to modify or supersede such statements
in this Annual Report on Form 10-K.
This
Annual Report on Form 10-K may include market data and certain industry data and forecasts, which we may obtain from internal
company surveys, market research, consultant surveys, publicly available information, reports of governmental agencies and industry
publications, articles and surveys. Industry surveys, publications, consultant surveys and forecasts generally state that the
information contained therein has been obtained from sources believed to be reliable, but the accuracy and completeness of such
information is not guaranteed. While we believe that such studies and publications are reliable, we have not independently verified
market and industry data from third-party sources.
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Risk
Factor Summary
Our
business is subject to significant risks and uncertainties that make an investment in us speculative and risky. Below we summarize
what we believe are the principal risk factors but these risks are not the only ones we face, and you should carefully review
and consider the full discussion of our risk factors in the section titled “Risk Factors”, together with the other
information in this Annual Report on Form 10-K. If any of the following risks actually occurs (or if any of those listed elsewhere
in this Annual Report on Form 10-K occur), our business, reputation, financial condition, results of operations, revenue, and
future prospects could be seriously harmed. Additional risks and uncertainties that we are unaware of, or that we currently believe
are not material, may also become important factors that adversely affect our business.
Risks
Relating to Our Financial Position and Capital Needs
We
have incurred substantial losses since our inception and anticipate that we will continue to incur substantial and increasing
losses for the foreseeable future.
We
need significant additional financing to fund our operations and complete the development and, if approved, the commercialization
of our product candidate. If we are unable to raise capital when needed, we could be forced to delay, reduce or eliminate our
product development programs or commercialization efforts.
Raising
additional capital may cause dilution to our existing stockholders, restrict our operations or require us to relinquish rights
to our product candidate on unfavorable terms to us.
We
currently have no source of revenues. We may never generate revenues or achieve profitability.
Risks
Related to the Development and Regulatory Approval of Our Product Candidate
Clinical-stage
biopharmaceutical companies with product candidates in clinical development face a wide range of challenging activities which
may entail substantial risk.
We
may find it difficult to enroll patients in our clinical trials given the limited number of patients who have the diseases for
which our product candidate is being studied which could delay or prevent the start of clinical trials for our product candidate.
The
results of preclinical studies or earlier clinical trials are not necessarily predictive of future results. Our existing product
candidate in clinical trials, and any other product candidates that may advance into clinical trials, may not have favorable results
in later clinical trials or receive regulatory approval.
Clinical
drug development involves a lengthy and expensive process with an uncertain outcome.
Our
current and future product candidates, the methods used to deliver them or their dosage levels may cause undesirable side effects
or have other properties that could delay or prevent their regulatory approval, limit the commercial profile of an approved label
or result in significant negative consequences following any regulatory approval.
Our
product development program may not uncover all possible adverse events that patients who take our product candidate may experience.
The number of subjects exposed to our product candidate and the average exposure time in the clinical development program may
be inadequate to detect rare adverse events or chance findings that may only be detected once the product is administered to more
patients and for greater periods of time.
Our
future success is dependent on the regulatory approval of our product candidate.
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Our
current product candidate and future product candidates could fail to receive regulatory approval from the FDA.
Even
if our current candidate receive regulatory approval, it may still face future development and regulatory difficulties.
Risks
Related to Our Manufacturing
We
have limited to no manufacturing, sales, marketing or distribution capability and must rely upon third parties for such.
We
are subject to a multitude of manufacturing risks, any of which could substantially increase our costs and limit supply of our
product candidate.
In
the clinical trials using GP2, GM-CSF is also administered and its availability is dependent upon a third-party manufacturer,
which may or may not reliably provide GM-CSF, thus jeopardizing the completion of the trials.
Risks
Related to Our Dependence on Third Parties and Our License Agreements
We
rely on third parties to conduct our preclinical studies and clinical trials. If these third parties do not successfully carry
out their contractual duties or meet expected deadlines, or if we lose any of our CROs or other key third-party vendors, we may
not be able to obtain regulatory approval for or commercialize our current or future product candidates on a timely basis, if
at all.
We
are dependent on technologies we license, and if we lose the right to license such technologies or we fail to license new technologies
in the future, our ability to develop new products would be harmed, and if we fail to meet our obligations under our license agreements,
we may lose the ability to develop our product candidate.
Risks
Related to Our Intellectual Property
We
rely on an exclusive license granted to us by HJF with respect to GP2, and if HJF does not adequately defend such license, our
business may be harmed.
Risks
Related to Commercialization of Our Current Product Candidate and Future Product Candidates
Our
commercial success depends upon attaining significant market acceptance of our current product candidate and future product candidates,
if approved, among physicians, patients, healthcare payors and cancer treatment centers.
Even
if we are able to commercialize our current product candidate or any future product candidates, the products may not receive coverage
and adequate reimbursement from third-party payors in the U.S. and in other countries in which we seek to commercialize our products,
which could harm our business.
Risks
Related to Healthcare Compliance Regulations
Our
relationships with customers and third-party payors will be subject to applicable anti-kickback, fraud and abuse and other healthcare
laws and regulations, which could expose us to criminal sanctions, civil penalties, contractual damages, reputational harm and
diminished profits and future earnings. If we or they are unable to comply with these provisions, we may become subject to civil
and criminal investigations and proceedings that could have a material adverse effect on our business, financial condition and
prospects.
Risks
Related to our Business Operations
We
face substantial competition, which may result in others discovering, developing or commercializing products before or more successfully
than we do.
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Our
business may be adversely affected by the ongoing coronavirus pandemic
Risks
Related to Owning our Common Stock
The
price of our common stock may fluctuate substantially.
Because
certain of our stockholders control a significant number of shares of our common stock, they may have effective control over actions
requiring stockholder approval.
Future
sales and issuances of our common stock could result in additional dilution of the percentage ownership of our stockholders and
could cause our share price to fall.
If
we fail to maintain an effective system of internal control over financial reporting in the future, we may not be able to accurately
report our financial condition, results of operations or cash flows.
PART
I
ITEM
1. BUSINESS
BUSINESS
Overview
We
are a biopharmaceutical company that is developing GP2, an immunotherapy designed to prevent the recurrence of breast cancer following
surgery. GP2 is a 9 amino acid transmembrane peptide of the HER2/neu protein, a cell surface receptor protein that is expressed
in a variety of common cancers, including expression in 75% of breast cancers at low (1+), intermediate (2+), and high (3+ or
over-expressor) levels. In a completed Phase IIb clinical trial led by MD Anderson Cancer Center, no recurrences were observed
in the HER2/neu 3+ adjuvant setting after median 5 years of follow-up, if the patient received the 6 primary intradermal
injections over the first 6 months. We are planning to commence a Phase III clinical trial in 2021.
Our
Product Candidate
GP2
is a HER2/neu transmembrane peptide that elicits a targeted immune response against HER2/neu-expressing cancers.
Below is an image of a cell surface showing therapeutically relevant cell surface proteins in cancer. Breast cancers and other
solid tumors with elevated expression of HER2/neu protein are highly aggressive with an increased disease recurrence and
a worse prognosis.
GM-CSF
Immunoadjuvant
Recombinant
human granulocyte macrophage colony-stimulating factor or GM-CSF (sargramostim, Leukine®) has been shown to enhance monocyte
as well as neutrophil cytotoxicity against melanoma tumor cells and to enhance activity-dependent cellular cytotoxicity of monocytes
and neutrophils against targets coated with the anti-ganglioside antibodies. GP2 will be delivered in combination with GM-CSF
to induce GP2 peptide specific immunity. GP2 treatment is administered via an intradermal injection by mixing GP2 peptide and
GM-CSF at the time of administration.
GM-CSF
is available in both liquid and lyophilized forms exclusively from one manufacturer, and we will continue to be dependent on such
manufacturer for our supply of GM-CSF in combination with GP2 in our ongoing GP2 trials and upon potential commercialization of
GP2. Although GM-CSF is currently approved for sale in the U.S. by the FDA and is available in other countries on a name patient
basis through a specialized company that focuses on making products approved in the U.S. available globally, GM-CSF may be registered
for sale in other countries by such manufacturer in the future.
Cancer
Immunotherapy
Cancer
immunotherapies seek to stimulate an individual’s own immune system to selectively attack cancer cells while not affecting
normal cells or delivering certain immune system components in order to inhibit the spread of cancer. Cancer immunotherapy drugs
are a new method of cancer treatment which are in addition to more established treatment options such as surgery, chemotherapy,
targeted therapy, and radiation therapy. Therefore, cancer immunotherapy is an important and rapidly emerging field, which has
led to new clinical research studies and garnered the attention of biotechnology and pharmaceutical companies, regulatory agencies,
payors and hospital systems, cancer patients and their families, and the general public at large.
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Cancer
immunotherapy harnesses the body’s natural immune system response to fight and/or prevent tumor growth. An essential characteristic
of the immune system, which is a network of tissues, cells, and signaling molecules that work to protect the body, is its ability
to differentiate foreign threats, including cancerous growths, from normal cells. Despite the fact that tumor cells originate
from normal cells, tumor cells can be recognized as foreign threats because of their ability to elicit the production of tumor
antigens. These antigens may be released in the interstitial tissues, and eventually in the bloodstream or may remain on the surface
of cognate cancer cells. The HER2/neu protein is one of the most widely expressed tumor antigens in multiple malignances.
Several
cell types play an important role in the development and maintenance of immune responses against cancer. The most important cell
types with regard to immune response are antigen-presenting cells (“APCs”) and lymphocytes. APCs include various subtypes,
such as dendritic cells, monocytes and macrophages. Once a patient is exposed to a tumor antigen (either by the presence of cancer
itself or through active immunization through a vaccine type immunotherapeutic), the tumor antigen gets recognized by the APC
and becomes “processed” through digestion into smaller fragments within the APC. Subsequently, the APC “communicates”
with a specific type of lymphocyte called a T-cell. Inactive T-cells search for tumor antigens by transiently binding to antigens
presented by major histocompatibility complexes (“MHCs”) on the APCs. There is great variability in the expression
of different subtypes of MHCs in the human population. The MHC system expresses human leukocyte antigens (“HLAs”)
and these HLA subtypes determine the vigor and duration of any given T-cell response to a cancer among different patients.
As
shown below, following GP2 immunotherapy, CD8+ cytotoxic T lymphocytes recognize and destroy HER2/neu-expressing cancer
cells. GP2 is administered in combination with an FDA-approved immunoadjuvant GM-CSF, which stimulates the proliferation of antigen
presenting cells. Preclinical studies have shown that T cells sensitized against the GP2 peptide demonstrate significant recognition
of HER2/neu-expressing tumors. Both ovarian and breast cancer-specific CTLs recognize GP2, which is widely expressed in
HER2/neu-expressing tumors and is capable of inducing tumor-specific CTL populations in vitro.
Breast
Cancer Treatment Approach — Adjuvant & Neoadjuvant Treatments
As
shown below, in the adjuvant setting, a HER2/neu 3+ patient typically receives Herceptin in the first year following breast
cancer surgery, with the hope that their breast cancer will not recur, and with the odds of recurrence slowly decreasing over
the first 5 years following surgery. Herceptin has been shown to reduce recurrence rates by approximately 50%, from 25% to 12%,
in the adjuvant setting. In the neoadjuvant setting, a HER2/neu 3+ patient receives treatment before surgery and based
on the results of a biopsy at surgery, will receive Herceptin or Kadcyla, a more potent form of Herceptin, following surgery.
Kadcyla has been shown to reduce recurrence rates by 50%, from 22% to 11%, in the neoadjuvant setting. Accordingly, we believe
that GP2 may be effective in safely addressing the 50% of recurring patients who do not respond to either Herceptin or Kadcyla.
GP2
is administered in combination with the immunoadjuvant GM-CSF in years 2-4, following the first year of treatment with Herceptin,
in a series of 11 intradermal injections comprising 6 primary injections over 6 months (1 injection per month) followed by 5 booster
injections every 6 months thereafter. Furthermore, we believe that recently approved drugs such as Perjeta and Nerlynx do not
fully address this unmet need, even in their most efficacious subpopulations, and that in the initial GP2 indication, approximately
17,000 new patients may be eligible for GP2 treatment per year, which could save approximately 1,500 to 2,000 lives per year.
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As
only injection site reactions were observed (which speaks to the immunogenicity of GP2) and no SAEs were reported in the GP2 Phase
IIb clinical trial, GP2 may be positioned as the final treatment for patients post-surgery. Furthermore, we believe that clinicians
and patients are seeking a de-escalation and a return to normal life free of toxic treatments, especially if the chance of recurrence
is reduced substantially. Lastly, we believe that GP2 may be the treatment that will synergistically overlap with or follow Herceptin,
Kadcyla, or Enhertu (fam-trastuzumab deruxtecan-nxki, DS-8201) or any of the other Herceptin derivatives or antibody drug conjugates
being developed.
We
believe that U.S. academic centers will be moving higher risk, node positive patients into neoadjuvant treatment and will use
Kadcyla if residual disease is observed at the time of surgery; however community centers and international markets may not move
as quickly or at all, due to the high dual therapy costs and the lack of approval or reimbursement of Kadcyla in markets outside
of the U.S. and Europe. GP2 will be pursued in both the adjuvant and neoadjuvant settings in HER2/neu 3+ patients in our
planned Phase III trial.
GP2
Clinical Data & Planned Phase III Trial
In
the Phase IIb and three Phase I clinical trials where 138 patients received GP2 immunotherapy, there were no SAEs reported in
any of the trials, including for GP2 and GM-CSF combination treatments or any other GP2 combination treatments.
Clinical Trial Description Status
GP2 Phase IIb Clinical Trial Trial Completed
● 89 patients treated with GP2 + GM-CSF, 91 placebo patients treated with GM-CSF
GP2 Phase I Clinical Trial — Combination with AE37 Trial Completed
● 14 patients treated with GP2 + AE37 + GM-CSF
GP2 Phase I Clinical Trial — Combination with Trastuzumab Trial Completed
● 17 patients treated with GP2 + GM-CSF + trastuzumab
First GP2 Phase I Clinical Trial Trial Completed
● Phase Ib Trial of HER2/neu Peptide (GP2) Vaccine in Breast Cancer Patients
● 18 patients treated with GP2 + GM-CSF
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Phase
I Clinical Trials
First
GP2 Phase I Clinical Trial
As
shown in the table above, the first GP2 Phase I clinical trial was conducted at Walter Reed Army Medical Center. The study was
conducted in patients over the age of 18 years with a diagnosis of HER2/neu 1-3+, node negative breast cancer who had undergone
primary surgical and medical therapies and who were without evidence of disease at the time of enrollment into the study. Patients
were HLA typed and HLA-A02 patients were skin tested for recall antigens. HLA-A02 patients found to be immunologically intact
received the vaccine. There were no grade 3-5 toxicities among the 18 patients receiving a total of 108 doses of GP2 + GM-CSF.
Among all patients, the maximum local toxicity occurring during the entire series was grade 1 in 38.9% and grade 2 in 61.1% of
the patients. The maximum systemic toxicity during the series was grade 0 in 5.6%, grade 1 in 61.1%, and grade 2 in 33.3% of the
patients. The most common local reactions included erythema and induration (100% of patients), pruritis (25%), and inflammation
(23%). The most common systemic reactions were grade 1 fatigue (40%) and grade 1 arthralgia/myalgia (15%). There were no recurrences
and no deaths reported in study subjects. Additional data analysis included topics such as pre-existing immunity, dosing, and
epitope spreading.
GP2
Phase I Clinical Trial — Combination with Trastuzumab
Preclinical
research has previously demonstrated that a synergy may exist between trastuzumab and GP2 peptide-stimulated CTLs ex vivo. Pretreatment
of breast cancer cells with trastuzumab followed by incubation with GP2 peptide-induced CTLs resulted in enhanced cytotoxicity
in 3 tumor cell lines compared to treatment with trastuzumab or GP2-specific CTLs alone. These results suggest that concurrent
GP2 vaccination during trastuzumab therapy may be a possible combination immunotherapy.
As
shown in the table above, a Phase I trial evaluating the combination therapy of GP2 + GM-CSF administered simultaneously with
trastuzumab was conducted. The combination therapy was found to be well tolerated when given concurrently in 17 clinically disease-free,
HER2/neu over-expressing breast cancer patients.
GP2
Phase I Clinical Trial — Combination with AE37
As
shown in the table above, a Phase I trial evaluating the combination therapy of GP2 + GM-CSF administered simultaneously with
HER2/neu peptide AE37 in 14 clinically disease-free, HER2/neu breast cancer and ovarian cancer patients was conducted.
While 28 patients enrolled, 14 patients completed the 6 vaccination series. Initial results suggest that combining GP2 and AE37
peptides is well tolerated at all tested dosing levels. Additionally, we believe the combination is capable of stimulating strong
peptide-specific in vivo immune responses.
During
the primary vaccination series, an AE37/GP2+GM-CSF dual peptide vaccine resulted in robust T-cell proliferation. However, significant
immune responses became more variable at 6 and 12 months post vaccination suggesting the need for boosters in some individuals.
Phase
II Clinical Trial
GP2
Phase IIb Clinical Trial Overview
In
a prospective, randomized, single-blinded, placebo-controlled, multi-center (16 sites led by MD Anderson Cancer Center) Phase
IIb clinical trial of HLA-A02 breast cancer patients, the combination of GP2-GMCSF-Herceptin treatment resulted in no recurrences
in 46 HER2/neu 3+ over-expressor patients who were fully treated with GP2 versus 50 placebo patients who were treated with
GMCSF-Herceptin and who recurred at a rate similar to historical recurrence rates for patients treated with Herceptin. After median
5 years of follow-up, there were 0% cancer recurrences in the HER2/neu 3+ patients treated with GP2-GMCSF-Herceptin, if
the patient received the 6 primary intradermal injections over the first 6 months, versus an 11% cancer recurrence rate in the
placebo arm treated with GMCSF-Herceptin (p = 0.0338). Thus, sequentially combining Herceptin in year 1 and GP2-GMCSF in
years 2-4 may dramatically lower breast cancer recurrences in this patient population.
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The
design of the Phase IIb trial was as follows:
The
Phase IIb clinical trial closed in December 2018. The final median 5 year follow-up data from this Phase IIb clinical trial is
currently being collected and analyzed.
Of
the total 180 intent-to-treat patients enrolled, 168 patients completed the 6 primary intradermal injection series over the first
6 months. HER2/neu status was determined based on the expression levels of the HER2/neu protein in each patient
using standard of care HER2/neu diagnostic technology. The trial was prospectively designed to analyze these fully treated
patients by 2 distinct patient populations, namely HER2/neu 3+ (over expressors) and HER2/neu 1-2+ (low to intermediate
expressors):
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San
Antonio Breast Cancer Symposium Poster Presentation of Median 5 Year Top-Line Data
The
median 5 year top-line data described below was presented at the San Antonio Breast Cancer Symposium in a poster on December 9,
2020, entitled “Five year median follow-up data from a prospective, randomized, placebo-controlled, single-blinded, multicenter,
phase IIb study evaluating the reduction of recurrences using HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab
in HER2 positive women with operable breast cancer.”
The
final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial investigating
GP2+GM-CSF administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors
expressing any degree of HER2 (immuno-histochemistry [IHC] 1-3+) (NCT00524277) is now complete with 5 year follow-up. The
trial enrolled HLA-A02 patients randomized to receive GP2+GM-CSF versus GM-CSF alone. The trial’s primary objective was
to determine if treatment with GP2, a HER2-derived peptide, reduces recurrence rates.
Each
enrolled and consented subject was randomized and scheduled to receive a total of 6 GP2+GM-CSF (500 mcg GP2:125 mcg GM-CSF) or
placebo (125 mcg GM-CSF alone) intradermal injections every 3-4 weeks as part of the Primary Immunization Series (“PIS”)
for the first 6 months and 4 GP2+GM-CSF booster or placebo intradermal injections every 6 months thereafter. Boosters were introduced
during the trial, thus some patients did not receive all 4 boosters.
This
168 patient (Intent to Treat, “ITT”: n=180) basket trial across 16 clinical sites explored 96 HER2 3+ patients, who
received a standard course of trastuzumab after surgery and subsequently completed the full PIS or placebo, starting the PIS at
median 17.1 months after surgery, and 72 HER2 1-2+ patients, who did not receive trastuzumab after surgery and subsequently completed
the full PIS or placebo, starting the PIS at median 10.8 months after surgery. Subject disease characteristics are described in
Table 1.
Since
GP2 is synergistic with trastuzumab, and the HER2 1-2+ patients did not receive trastuzumab, it was prespecified to compare recurrence
rates ITT versus per protocol in these 2 distinct, independently reported populations, excluding those patients who did not complete
the PIS. Figure 1 depicts evidence that disease free survival (“DFS”) is more likely in HER2 3+ GP2-treated subjects
(p = 0.0338). Figure 2 provides DFS for the HER2 1-2+ group.
GP2
was shown to be well tolerated with no SAEs and elicited a potent immune response measured by local skin tests and immunological
assays, which suggest peak immunity is reached at 6 months upon completion of the PIS.
Table
1: Clinicopathologic Characteristics by Treatment Group for HER2 3+ and HER2 1-2+ Subjects Who Completed the PIS(1)
(1)
Continuous variables difference between treatment groups assessed by t-test. Categorical variables difference between treatment
group distribution assessed by chi-square test.
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As
shown above, after 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 46 HER2 3+ patients treated with GP2+GM-CSF,
if the patient completed the PIS, was 100% versus 89.4% (95% CI:76.2, 95.5%) in the 50 placebo patients treated with GM-CSF (p
= 0.0338). As shown in Table 1, the treated versus placebo HER2 3+ patients were well-matched, where approximately 53% were
stage T1, 41% were stages T2-T4, 55% were node positive, 58% were hormone receptor positive and received endocrine therapy, 77%
received adjuvant radiation, 77% received adjuvant chemotherapy, and 89% received trastuzumab.
As
shown above, after 5 years of follow-up, the Kaplan-Meier estimated 5-year DFS rate in the 35 HER2 1-2+ patients treated with
GP2+GM-CSF, if the patient completed the PIS, was 77.1% (95% CI:59.5, 87.9%) versus 77.6% (95% CI:60.1, 88.2%) in the 37 placebo
patients treated with GM-CSF (p = 0.9142).
Safety
& Immune Response Data of GP2 Phase II Trial – Median 3 Year Data
A
median 3 year interim analysis of the GP2 Phase II trial was published in 2016 and presented efficacy, safety, and immunological
data, and a median 4 year interim analysis of the GP2 Phase II trial was published in April 2020. The safety and immunological
data is shown below.
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In
both patient populations, GP2 was shown to be well tolerated, consisting of primarily injection site reactions which are caused
by GM-CSF and can be mitigated by reducing the GM-CSF dose (and then the GP2 dose, if necessary). No SAEs were reported in the
GP2 treated patients. Maximum local and systemic toxicities were primarily grade 1 and grade 2. Toxicities ranged from redness
at injection site to flu-like symptoms and can be largely attributed to GM-CSF, and not to GP2.
Toxicity:
The maximum local and systemic toxicity experienced by patients administered the GP2+GM-CSF vaccine were comparable to those experienced
by patients receiving GM-CSF alone. For patients receiving GP2 + GM-CSF, maximum local toxicities experienced during the primary
vaccination series were grade 1 (70%), grade 2 (28%), or grade 3 (1%). The most common toxicities included erythema, induration
and pruritis; the grade 3 toxicity was induration. Maximum systemic toxicities were grade 0 (13%), grade 1 (71%), grade 2 (15%),
or grade 3 (1%). The most common systemic toxicities included fatigue, headache, and myalgias. The grade 3 toxicity was a diffuse
maculopapular rash. The toxicities were comparable for patients receiving GM-CSF only, with maximum local toxicities being grade
1 (75%) or grade 2 (25%); and maximum systemic toxicities being grade 0 (21%), grade 1 (60%), grade 2 (15%), or grade 3 (3%).
The grade 3 systemic toxicities in this group included diffuse urticarial reactions, syncope and extremity pain.
GP2
immunotherapy elicited a potent immune response in HLA-A02 patients after they received the 6 primary intradermal injections over
the first 6 months. The immune response was measured by a local skin test and immunological assays. Further, booster injections
given every 6 months thereafter prolonged the immune response, thereby providing longer term protection.
● Boosters were administered every 6 months to sustain immunity.
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Planned
Phase III Trial
We
are planning to launch a Phase III clinical trial in 2021, using a similar treatment regime as the Phase IIb clinical trial. The
manufacturing plan and the Phase III trial protocol have been reviewed by the FDA, and final revisions to the Phase III trial
protocol are under way, which may include an interim analysis/adaptive trial design that will result in the finalization of the
size of the trial. The primary endpoint of the Phase III clinical trial will compare recurrence rate of GP2 + GM-CSF treated patients
versus placebo patients at various time points using standard of care follow-up. We believe that it may require up to 2 years
to fully enroll all patients for the trial, and that we may follow-up patients for up to a median 5 years following enrollment
in such trial; however the addition of an interim analysis may reduce the time required to report clinical data and to file a
BLA application. These design features of the Phase III clinical trial are currently being finalized by our clinical advisors.
An
overview of the Phase III clinical trial design is shown below.
We
have commenced GP2 manufacturing, and we are currently in the process of finalizing our engagement of CMOs and CROs for the Phase
III clinical trial.
Large
Initial & Expandable Breast Cancer Market
We
believe that the potential market for the proposed initial and follow-on indications is large. HER2/neu 3+ breast cancer
patients comprise approximately 25% of all breast cancer patients. Approximately 40% to 50% of the U.S. population contains the
HLA-A02 allele, while node positive and high risk node negative patients comprise approximately 50% of the market. Therefore,
we believe that the initial market for GP2 could be the combination of the three populations above which together comprises 6%
of breast cancer patients. We believe that follow-on indications could include additional HLA types (an additional 30% of the
U.S. population) and the low to intermediate expressors of HER2/neu 1-2+ patients (an additional 50% of all breast cancer
patients) which would expand the GP2 market from our estimated initial 6% to 30% of breast cancer patients who undergo surgery.
Thus the market for GP2, including follow-on indications, could be 2.4 times the current Herceptin adjuvant setting market, which
constitutes approximately 12.5% of breast cancer patients.
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We
believe that the potential market for GP2 could be estimated as follows, with the long term multi-billion dollar annual revenue
potential of GP2 based on 16,750 to 79,800 potential new patients treated per year and Herceptin’s 2018 annual per patient
price of $74,500:
Competition
Cancer
immunotherapy has become a significant growth area for the biopharmaceutical industry, attracting large pharmaceutical companies
as well as small niche players. Generally, our principal competitors in the cancer immunotherapy market comprise both types of
companies with currently approved products for various indications, such as manufacturers of approved bispecific antibodies, CAR-T
cells, and checkpoint inhibitors, as well as companies currently engaged in cancer immunotherapy clinical development. The large
and medium-size players who have successfully obtained approval for cancer immunotherapy products include Bristol-Myers Squib
Company, Merck & Co., Inc., Genentech, Inc. (a subsidiary of Roche Holding AG), AstraZeneca PLC, Celgene Corporation, Johnson
& Johnson, Amgen, Novartis, Juno Therapeutics, Inc. (a subsidiary of Celgene), Kite Pharma, Inc., a wholly-owned subsidiary
of Gilead Sciences, Inc. and Pfizer, Inc./EMD Serono, Inc. Most of these companies, either alone or together with their collaborative
partners, have substantially greater financial resources than we do.
Companies
developing novel products with similar indications to those we are pursuing are expected to influence our ability to penetrate
and maintain market share. For patients with early stage breast cancer, adjuvant therapy is often given to prevent recurrence
and increase the chance of long-term disease free survival. Adjuvant therapy for breast cancer can include chemotherapy, hormonal
therapy, radiation therapy, or combinations thereof. In addition, the HER2 targeted drug Herceptin (trastuzumab) alone or in combination
with Perjeta (pertuzumab), both manufactured and marketed by Roche/Genentech, may be given to patients with tumors with high expression
of HER2/neu.
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There
are a number of approved HER2/neu targeted therapies, some of which include the following: Genentech’s Herceptin,
Perjeta and Kadcyla (TDM-1, ado-trastuzumab emtansine); Puma’s Nerlynx; Daichi Sanko’s Enhertu (DS-8201, fam-trastuzumab
deruxtecan-nxki), and Seattle Genetics’ (Tukysa, tucatanib). In addition, the following biosimilars to trastuzumab have
been approved: Biocon/Mylan’s (Ogivri — trastuzumab-dkst; Celltrion/Teva’s (Herzuma — trastuzumab-pkrb);
Samsung/Biogen/Merck’s (Ontruzant — trastuzumab-dttb); Pfizer’s (Trazimera — trastuzumab-qyyp); and Allergan/Amgen’s
(Kanjinti; trastuzumab-anns). Furthermore, the following immune checkpoint inhibitors have also been approved or are under review
by the FDA to treat breast cancer patients: Merck’s Keytruda (pembrolizumab) and Genentech’s Tecentriq (atezolumab).
Moreover we believe that drug candidates from Sellas (formerly Galena), Marker (formerly TapImmune), Epithany, Antigen Express
(Generex subsidiary), and various companies pursuing neoantigen technologies are in clinical development and are being pursued
for different sub-populations or are behind GP2 in clinic development.
We
believe that GP2 will act synergistically with Herceptin, Perjeta, Nerlynx, and the newest entrants Kadcyla and Enhertu.
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Many
of our competitors, either alone or with their strategic partners, have substantially greater financial, technical and human resources
than we do, and more experience in obtaining FDA and other regulatory approvals of treatments and in commercializing those treatments.
Accordingly, our competitors may be more successful than us in obtaining approval for cancer immunotherapy products and achieving
widespread market acceptance. Our competitors’ treatments may be more effectively marketed and sold than any products we
may commercialize, thus causing limited market share before we can recover the expenses of developing and commercializing our
cancer immunotherapy product candidate.
Mergers
and acquisitions in the biotechnology and pharmaceutical industries may result in even more resources being concentrated among
a smaller number of our competitors. Smaller or early stage companies may also prove to be significant competitors, particularly
through collaborative arrangements with large and established companies. These activities may lead to consolidated efforts that
allow for more rapid development of cancer immunotherapy product candidates.
These
competitors also compete with us in the recruiting and retaining of qualified scientific and management personnel, the ability
to work with specific clinical contract organizations due to conflict of interest, and the conduct of trials in the ability to
recruit clinical trial sites and subjects for our clinical trials.
We
expect any products that we develop and commercialize to compete on the basis of, among other things, efficacy, safety, price,
and the availability of coverage and reimbursement from government and other third-party payors. Our commercial opportunity could
be reduced or eliminated if our competitors develop and commercialize products that are viewed as safer, more convenient, or less
expensive than any products that we may develop. Our competitors also may obtain FDA or other regulatory approval for their products
more rapidly than we may obtain approval for our current product candidate or any other future product candidate, which could
result in our competitors establishing a strong market position before we are able to enter the market.
Manufacturing
We
do not own or operate manufacturing facilities for the production of our product candidate nor do we have plans to develop our
own manufacturing operations in the foreseeable future. We currently depend on third-party contract manufacturers for all of our
required raw materials, active pharmaceutical ingredients (“APIs”), and finished product candidate for our clinical
trials. We do not have any current contractual arrangements for the manufacture of commercial supplies of our product candidate.
For
prior clinical trials, GP2 was formulated, filled, labeled, stored, tested, packaged, and distributed to clinical sites by the