UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C.
20549
FORM 10-K
(Mark One)
For the fiscal year ended December 31, 2024
or
For the transition period from _______________________ to ___________________
Commission File Number: 001-38207
Celcuity Inc.
(Exact name of registrant as specified in its charter)
(Address of principal executive offices) (Zip Code)
Registrant’s telephone number, including area
code: (763)392-0767
_________________________________________
Securities registered pursuant to Section 12(b)
of the Act:
Title of each class Trading Symbol(s) Name of each exchange on which registered
Common Stock, $0.001 par value per share CELC The Nasdaq Stock Market LLC
Securities registered pursuant to Section 12(g)
of the Act:
None
Indicate by check mark if the registrant is a well-known seasoned issuer,
as defined in Rule 405 of the Securities Act. ☐ Yes ☒ No
Indicate by check mark if the registrant is not required to file reports
pursuant to Section 13 or Section 15(d) of the Act. ☐ Yes ☒ No
Indicate by check mark whether the registrant (1) has filed all reports
required to be filed by Section 13 or 15(d) of the Securities Exchange Act of 1934 during the preceding 12 months (or for such shorter
period that the registrant was required to file such reports), and (2) has been subject to such filing requirements for the past 90 days.
☒ Yes☐ No
Indicate by check mark whether the registrant has submitted electronically
every Interactive Data File required to be submitted pursuant to Rule 405 of Regulation S-T (§232.405 of this chapter) during the
preceding 12 months (or for such shorter period that the registrant was required to submit such files). ☒
Yes☐ No
Indicate by check mark whether the registrant is a large accelerated filer,
an accelerated filer, a non-accelerated filer, a smaller reporting company, or 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 ☐ Accelerated filer ☐
Non-accelerated filer ☒ Smaller reporting company ☒
Emerging growth company ☐
If an emerging growth company, indicate by check mark if the registrant
has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant
to Section 13(a) of the Exchange Act ☐
Indicate by check mark whether the registrant has filed a report on and
attestation to its management’s assessment of the effectiveness of its internal control over financial reporting under Section 404(b)
of the Sarbanes-Oxley Act (15 U.S.C. 262(b)) by the registered public accounting firm that prepared or issued its audit report. ☐
If securities are registered pursuant to Section 12(b) of the Act, indicate
by check mark whether the financial statements of the registrant included in the filing reflect the correction of an error to previously
issued financial statements. ☐
Indicate by check mark whether any of those error corrections are restatements
that required a recovery analysis of incentive-based compensation received by any of the registrant’s executive officers during
the relevant recovery period pursuant to §240.10D-1(b). ☐
Indicate by check mark 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, based on $16.38, the closing price of the shares of common stock on June 28, 2024 (the last business
day of the registrant’s most recently completed second fiscal quarter) as reported by The Nasdaq Capital Market on such date, was
approximately $530,223,434.
As of March 24, 2025, there were 37,839,392shares
of the registrant’s common stock outstanding.
DOCUMENTS INCORPORATED IN PART BY REFERENCE
Portions of the registrant’s definitive proxy statement relating
to its 2025 Annual Meeting of Stockholders are incorporated by reference into Part III of this Annual Report on Form 10-K.
2024 Annual Report on Form 10-K
Table of Contents
Page
PART I
Item 1. Business 5
Item 1A. Risk Factors 21
Item 1B. Unresolved Staff Comments 37
Item 1C. Cybersecurity 37
Item 2. Properties 38
Item 3. Legal Proceedings 38
Item 4. Mine Safety Disclosures 38
PART II
Item 6. Reserved 40
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 47
Item 8. Financial Statements and Supplementary Data 48
Item 9A. Controls and Procedures 67
Item 9B. Other Information 67
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 67
PART III
Item 10. Directors, Executive Officers and Corporate Governance 68
Item 11. Executive Compensation 70
Item 14. Principal Accountant Fees and Services 70
PART IV
Item 15. Exhibits and Financial Statement Schedules 71
Signatures 72
SPECIAL NOTE REGARDING FORWARD-LOOKING STATEMENTS
The Private
Securities Litigation Reform Act of 1995 provides a “safe harbor” for forward-looking statements. This Annual
Report on Form 10-K (this “Annual Report”) contains forward-looking statements regarding us, our business prospects and our
results of operations that are subject to certain risks and uncertainties that could cause our actual business, prospects and results
of operations to differ materially from those that may be anticipated by such forward-looking statements. Factors that could cause
or contribute to such differences include, but are not limited to, those described in Part I, Item 1A, “Risk Factors” and
elsewhere in this Annual Report. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only
as of the date of this Annual Report. We expressly disclaim any intent or obligation to update or revise any forward-looking statements,
whether as a result of new information, future events or otherwise. Readers are urged to carefully review and consider the various
disclosures made by us in this Annual Report and in our other reports filed with the Securities and Exchange Commission (the “SEC”)
that advise interested parties of the risks and uncertainties that may affect our business.
All statements, other than statements of historical
facts, contained in this Annual Report, including statements regarding our plans, objectives and expectations for our business, operations
and financial performance and condition, are forward-looking statements. In some cases, you can identify forward-looking statements by
the following words: “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,”
“intend,” “may,” “might,” “target,” “ongoing,” “plan,” “potential,”
“predict,” “project,” “should,” “will,” “would,” or the negative of these terms or other
comparable terminology, although not all forward-looking statements contain these words. Forward-looking statements involve known and
unknown risks, uncertainties and other factors that may cause our results, performance or achievements to be materially different from
the information expressed or implied by the forward-looking statements in this Annual Report. Additionally, our forward-looking statements
do not reflect the potential impact of any future acquisitions, mergers, dispositions, joint ventures or investments that we may make.
Forward-looking statements may include, among other things, statements relating to:
● our revenue expectations;
● our expectations as to the use of proceeds from our financing activities;
● our plans with respect to potentially raising capital; and
These statements involve known and unknown risks, uncertainties and other
factors that may cause our results or our industry’s actual results, levels of activity, performance or achievements to be materially
different from the information expressed or implied by these forward-looking statements. Certain risks, uncertainties and other factors
include, but are not limited to, our limited operating history; our potential inability to develop, validate and commercialize gedatolisib
on a timely basis or at all; the uncertainties and costs associated with clinical studies and with developing and commercializing biopharmaceuticals;
the complexity and difficulty of demonstrating the safety and sufficient magnitude of benefit to support regulatory approval of gedatolisib
and other products we may develop; challenges we may face in developing and maintaining relationships with pharmaceutical company partners; the uncertainty and costs associated with clinical trials; the uncertainty
regarding market acceptance by physicians, patients, third-party payors and others in the medical community, and with the size of market
opportunities available to us; difficulties we may face in managing growth, such as hiring and retaining
a qualified sales force and attracting and retaining key personnel; changes in government regulations; tightening credit markets and limitations
on access to capital; stock market volatility or other factors that may affect our ability to access capital on favorable terms or at
all; and obtaining and maintaining intellectual property protection for our technology and time and expense associated with defending
third-party claims of intellectual property infringement, investigations or litigation threatened or initiated against us. See
“Risk Factors” in Part I, Item 1A of this Annual Report for additional risks, uncertainties and other factors applicable to
the Company.
SUMMARY OF RISK FACTORS
Below is a summary of the material factors that make an investment in our
common stock speculative or risky. This summary does not address all of the risks that we face. Additional discussion of the risks summarized
in this risk factor summary, and other risks that we face, can be found in the “Risk Factors” section of Part I, Item 1A of
this Annual Report and should be carefully considered, together with other information in this Annual Report and our other filings with
the Securities and Exchange Commission before making investment decisions regarding our common stock.
● We will be dependent on our ability to attract and retain key personnel;
● The price of our common stock may be volatile and fluctuate substantially.
PART I
ITEM 1. Business
Overview
Unless otherwise provided in this Annual Report,
references to the “Company,” “we,” “us,” and “our” and similar references refer to Celcuity
Inc., a Delaware corporation. We own various unregistered trademarks and service marks, including our corporate logo. Solely for convenience,
the trademarks, trade names and service marks in this Annual Report, including those owned by third parties, may be referred to without
the ®,TM or SM symbols, but such references should not be construed as any indicator that the
owner of such trademarks, trade names and service marks will not assert, to the fullest extent under applicable law, their rights thereto.
We do not intend the use or display of other companies’ trademarks, trade names and service marks to imply an endorsement or sponsorship
of us by any other companies.
We are a clinical-stage biotechnology company focused
on the development of targeted therapies for the treatment of multiple solid tumor indications. Our lead therapeutic candidate is gedatolisib,
a potent, well-tolerated, small molecule reversible inhibitor, administered intravenously, that selectively targets all Class I isoforms
of phosphatidylinositol-3-kinase (“PI3K”) and the two mechanistic targets of rapamycin (“mTOR”) sub-complexes,
mTORC1 and mTORC2. Gedatolisib’s mechanism of action and pharmacokinetic properties are differentiated from other currently approved
and investigational therapies that target PI3K or mTOR alone or together. We believe there is significant potential for gedatolisib to
address breast and prostate cancer tumors, and it has the potential to be used in other tumor types where the PI3K/protein kinase B (“AKT”)/mTOR
(“PAM”) pathway is either: i) driving tumorigenesis directly; ii) cooperating with other dysregulated signaling pathways;
or iii) a mechanism of resistance to other drug therapies.
Our initial clinical development programs for gedatolisib
are focusing on the treatment of patients with hormone receptor positive (“HR+”), human epidermal growth factor receptor 2
negative (“HER2-”), or HR+/HER2-, advanced or metastatic breast cancer (“ABC”), and patients with metastatic castration
resistant prostate cancer (“mCRPC”).
In January 2022, gedatolisib was granted Fast Track
designation for the treatment of patients with HR+/HER2- advanced breast cancer after progression on CDK4/6 therapy. Fast Track designation
is granted by the FDA for products that are intended for the treatment of serious or life-threatening diseases or conditions and which
demonstrate the potential to address an unmet medical need.
In July 2022, gedatolisib was granted Breakthrough
Therapy Designation for HR+/HER2- advanced breast cancer after progression on CDK4/6 therapy. Breakthrough Therapy designation is granted
by the FDA to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening
condition. The criteria for Breakthrough Therapy designation requires preliminary clinical evidence that demonstrates the drug may have
substantial improvement on one or more clinically significant endpoints over available therapy.
In December 2022, we dosed the first patient in our
Phase 3, open-label, randomized two-part clinical trial, VIKTORIA-1. This trial is evaluating the efficacy and safety of gedatolisib in
combination with fulvestrant with and without palbociclib in adults with HR+, HER2- advanced breast cancer who have received prior treatment
with a CDK4/6 inhibitor in combination with an aromatase inhibitor. Two studies based on PIK3CA mutation status are included in the trial.
According to confirmed PIK3CA mutation status, patients will be manually assigned to a cohort evaluating patients who have PIK3CA wild
type (“WT”) tumors or to a cohort evaluating patients who have PIK3CA mutant (“MT”) tumors. The two cohorts are
randomized separately. The cohort evaluating PIK3CA WT patients completed enrollment during the fourth quarter of 2024 while the cohort
evaluating patients with PIK3CA MT (as defined below) continues to enroll patients.
In February 2024, we dosed our first patient in our
Phase 1b/2 clinical trial, CELC-G-201, evaluating gedatolisib in combination with darolutamide in patients with mCRPC. Initial preliminary
data for the Phase 1 portion of the trial is expected to be available by the end of the second quarter of 2025.
During the third quarter of
2024, we commenced site selection and activation activities to support a Phase 3, open-label, randomized clinical trial, VIKTORIA-2.
This trial is expected to dose its first patient in Q2 2025. This trial will evaluate the efficacy and safety of gedatolisib plus a
CDK4/6 inhibitor and fulvestrant as first-line treatment for patients with HR+/HER2- endocrine treatment resistant advanced breast
cancer. For the CDK4/6 inhibitor, investigators may choose either ribociclib or palbociclib. Approximately 200 clinical sites in
North America, Europe, Latin America, and Asia-Pacific, including many sites included in the VIKTORIA-1 clinical
trial, will participate in the study.
The PI3K/AKT/mTOR (PAM) Pathway
Dysregulation of the PAM signaling pathway is observed
in many types of cancer, including breast and prostate cancer. The important role the PAM pathway plays in cancer has led to significant
investment in the development of many different PI3K and mTOR inhibitors for solid tumors.
Activities associated with PI3K involve complex essential
cell regulatory mechanisms, including feedforward and feedback signaling loops. Overactivation of the pathway is frequently present in
human malignancies and plays a key role in cancer progression. Four catalytic isoforms of Class I PI3K preferentially mediate signal transduction
and tumor cell survival based on the type of malignancy and the genetic or epigenetic alterations an individual patient harbors. Due to
the multiple subcellular locations, activities, and importance of the different PI3K complexes in regulating many types of cancer cell
proliferation, control of PI3K activity is an important target in cancer therapy.
mTOR is a critical effector in cell-signaling pathways
commonly dysregulated in human cancers. The mTOR signaling pathway integrates both intracellular and extracellular signals and serves
as a central regulator of cell metabolism, growth, proliferation, and survival. mTOR is a serine/threonine protein kinase, a downstream
effector of PI3K, and regulated by hormones, growth factors, and nutrients, that are contained in two functionally distinct protein assemblies
– mTORC1 and mTORC2. In cancer, dysfunctional signaling leads to various constitutive activities of the mTOR complexes, making mTOR
a good therapeutic target.
Developing efficacious and well-tolerated therapies
that target this pathway has been challenging. This reflects the inherent adaptability and complexity of the PAM pathway, where numerous
feedforward and feedback loops, crosstalk with other pathways, and compensatory pathways enable resistance to PAM pathway inhibition.
Another major hurdle for the development of PAM pathway inhibitors has been the inability to achieve optimal drug-target blockade in tumors
while avoiding undue toxicities in patients.
Gedatolisib
By targeting multiple nodes of the PAM pathway, gedatolisib
can overcome adaptive resistance mechanisms that inhibitors targeting single PI3K/AKT/mTOR nodes do not address. As a result, we believe
gedatolisib offers distinct advantages over currently approved and investigational therapies that target PI3K or mTOR alone or together.
Gedatolisib is a pan-class I isoform PI3K inhibitor with low
nanomolar potency for the p110α, p110β, p110γ, and p110δ isoforms. Because gedatolisib inhibits all four PI3K isoforms
and both the mTORC1 and mTORC2 complexes, it prevents the confounding effect of isoform interaction that may occur with isoform specific
PI3K inhibitors and the confounding interaction between PI3K isoforms, AKT, and mTOR. By contrast, node-specific inhibitors cross-activate
uninhibited sub-units due to numerous feedforward and feedback loops between the PI3K isoforms, AKT, and mTOR complexes, which in turn
induces compensatory resistance that reduces the efficacy of isoform specific PI3K, AKT, or mTORC1 inhibitors.
To compare the functional effect of inhibiting single versus
multiple PAM pathway nodes, we evaluated gedatolisib, and node-selective inhibitors for PI3Kα (alpelisib), AKT (capivasertib) and
mTORC1 (everolimus) in a panel of breast cancer cell lines using a live cell proliferation rate dose response analysis. The results of
this analysis are presented in the table below.
Breast Cancer Cell Line Proliferation
Rate Dose Response Analysis
Average values for 14 PIK3CA MT and 14
PIK3CA WT breast cancer cell lines
Note: Growth rate (“GR”) was assessed using 28
cell lines by measuring live cells reducing potential with Real Time-Glo MT luciferase assay before and after 72-hour drug treatment.
GR50 (concentration required to inhibit growth rate by 50%) is a measure of potency. Max cell growth inhibition (GR at highest drug concentration
tested) is a measure of efficacy.
Source: Rossetti S. et.al., npj Breast Cancer, 2024
On average, gedatolisib was 300-fold more potent than the single
node PAM inhibitors analyzed and only gedatolisib induced a significant cytotoxic effect. In addition, gedatolisib’s potency and
efficacy was comparable in cell lines with and without PIK3CA mutations, in contrast to the single node PAM inhibitors.
● Better tolerated by patients than oral PI3K and mTOR drugs.
Gedatolisib is administered intravenously (IV) on a four-week
cycle of three-weeks-on, one-week-off, in contrast to the orally administered pan-PI3K or dual PI3K/mTOR inhibitors that are no longer
being clinically developed. Oral pan-PI3K or PI3K/mTOR inhibitors have repeatably been found to induce significant side effects that were
not well tolerated by patients. This typically leads to a high proportion of patients requiring dose reductions or treatment discontinuation,
despite showing promising efficacy. By contrast, gedatolisib stabilizes at lower concentration levels in plasma compared to orally administered
PI3K inhibitors, resulting in less toxicity, while maintaining concentrations sufficient to inhibit PAM pathway signaling.
Isoform-specific PI3K or mTORC1 inhibitors administered orally
were developed to reduce toxicities in patients. While the range of toxicities associated with single-node PAM inhibitors is narrower
than oral pan-PI3K or PI3K/mTOR inhibitors, administering them orally on a continuous basis still leads to challenging toxicities. The
experience with the FDA approved oral PI3K-α inhibitor, alpelisib, and mTORC1 inhibitor, everolimus, illustrates the challenge.
In their Phase 3 pivotal trials, alpelisib and everolimus were found to induce hyperglycemia in 79% and 69% of patients evaluated, respectively.
In addition, 26% and 24% of patients discontinued alpelisib and everolimus, respectively, due to treatment related adverse events. By
contrast, in the 103-patient dose expansion portion of the Phase 1b clinical trial with gedatolisib, only 25% of patients experienced
hyperglycemia and less than 9% discontinued treatment.
Clinical Development
As of December 31, 2024, 492 patients with solid tumors
have received gedatolisib in eight completed clinical trials. Gedatolisib’s safety, tolerability and pharmacokinetic profile were
determined in a Phase 1 First-in-Human clinical trial. Of the 492 patients, 129 were treated with gedatolisib as a single agent in three
clinical trials. The remaining 363 patients received gedatolisib in combination with other anti-cancer agents in five clinical trials.
Additional patients received gedatolisib in combination with other anti-cancer agents in nine investigator sponsored clinical trials.
Breast Cancer Program
Breast cancer is the most prevalent cancer in women,
accounting for 30% of all female cancers and 13% of cancer-related deaths in the United States. The National Cancer Institute estimated
that approximately 310,720 new cases of breast cancer would be diagnosed in the United States in 2024, and approximately 42,250 breast
cancer patients would die of the disease.
Four different breast cancer subtypes are currently
identified using molecular tests that determine the level of HR and HER2 expression. The most common subtype of ABC is HR+/HER2-. Approximately
70% of all breast cancer tumors express the estrogen receptor (“ER”), which, upon activation, regulates the expression of
various genes involved in tumor proliferation. Despite progress in treatment strategies, metastatic HR+/HER2- breast cancer (“MBC”) remains
an incurable disease, with a median overall survival (OS) of three years and a five-year survival rate of 34%.
Three different classes of targeted therapies are
currently used to treat HR+/HER2- tumors: endocrine-based therapies, CDK4/6 inhibitors, and PAM inhibitors. Each of the CDK4/6 inhibitors
and PAM inhibitors are generally used to respond to the related mechanisms of resistance to endocrine therapy, namely, activation of the
CDK4/6 and PAM pathways.
Over 70% of breast cancers have direct or indirect
activation of the PAM pathway. The upregulation of the PAM pathway promotes hormone-dependent and independent ER transcriptional activity,
which contributes to endocrine resistance, leading to tumor cell growth, survival, motility, and metabolism. Clinical studies have demonstrated
that PAM inhibition can restore sensitivity to estrogen therapy (ET).
Additionally, the PAM pathway, like other mitogenic
pathways, can also promote the activities of cyclin D and CDK4/6 to drive proliferative cell cycling. The available evidence indicates
that resistance to CDK4/6 inhibition in patients with HR+/HER2- advanced breast cancer is a transient adaptive mechanism, most likely
involving the PAM pathway. This data indicates that CDK4/6 signaling may be restored in CDK4/6 resistant tumors when PAM inhibitors are
applied. Thus, continuing CDK4/6 inhibitor treatment in combination with a PAM inhibitor in patients who progressed on their prior CDK4/6
inhibitor, would both blockade the potentially reactivated CDK4/6 pathway and prevent adaptive activation of the PAM pathway. This suggests
the limited efficacy induced by current standard-of-care (SOC) therapies in patients who have progressed on a CDK4/6 therapy reflects
the mechanistic inadequacy of relying on partial PAM inhibition (e.g., alpelisib or everolimus) and no CDK4/6 inhibition to address this
complex disease mechanism.
We believe the complex connection between the PAM
and CDK4/6 pathways can potentially enable gedatolisib to adaptively reactivate CDK4/6 signaling that reportedly occurs in CDK4/6 resistant
tumors when the PAM pathway is comprehensively blockaded. By re-activating CDK4/6 signaling, we believe gedatolisib can restore the therapeutic
effect of CDK4/6 inhibition when it is combined with a CDK4/6 inhibitor. The contributory effect of a CDK4/6 inhibitor when combined with
gedatolisib would thus largely reflect the interaction between the two therapies that gedatolisib initiates.
Evidence of gedatolisib’s anti-tumor activity
in breast cancer cells was provided in a study evaluating the MCF7 xenograft model (ER+/HER2-/PIK3CA mutant), where the combination of
gedatolisib with palbociclib and fulvestrant caused 90% tumor regression with no tumor regrowth observed for more than 60 days after the
final dose.
Source: Layman SABCS 2021
Clinical Experience with Gedatolisib in Breast Cancer
The favorability of preliminary results from our most
recently completed clinical trial, a Phase 1b clinical trial which evaluated 138 patients with HR+/HER2- ABC, led us to focus on our initial
clinical development program on advanced breast cancer.
On January 13, 2022, gedatolisib was granted Fast
Track designation for the treatment of patients with HR+/HER2- advanced breast cancer after progression on CDK4/6 therapy. Fast Track
designation is granted by the FDA for products that are intended for the treatment of serious or life-threatening diseases or conditions
and which demonstrate the potential to address an unmet medical need. The designation offers the opportunity for frequent interactions
with the FDA to discuss the drug’s development plan and to ensure collection of appropriate data needed to support drug approval,
as well as eligibility for rolling submission of a New Drug Application.
On July 18, 2022, gedatolisib was granted Breakthrough
Therapy Designation for HR+/HER2- advanced breast cancer after progression on CDK4/6 therapy. Breakthrough Therapy designation is granted
by the FDA to expedite the development and regulatory review of an investigational medicine that is intended to treat a serious or life-threatening
condition. The criteria for Breakthrough Therapy designation require preliminary clinical evidence that demonstrates the drug may have
substantial improvement on one or more clinically significant endpoints over available therapies. The benefits of Breakthrough Therapy
Designation include more intensive guidance from the FDA on an efficient development program, access to a scientific liaison to help accelerate
review time, and potential eligibility for priority review if relevant criteria are met. Celcuity’s breakthrough application was
supported by data from a Phase 1b clinical trial that assessed the safety, tolerability and clinical activity of gedatolisib in combination
with palbociclib and fulvestrant in patients with HR+/HER2- advanced breast cancer whose disease progressed during treatment with a CDK4/6
therapy and an aromatase inhibitor.
Phase 1b HR+/HER2- ABC Clinical Trial Results
A Phase 1b dose-finding trial with an expansion portion
for safety and efficacy evaluated gedatolisib when added to either the standard doses of palbociclib plus letrozole or palbociclib plus
fulvestrant in patients with HR+/HER2- advanced breast cancer. PI3K mutation status was not used as an eligibility criterion. Patient
enrollment for the trial is complete.
A total of 138 patients with HR+/HER2- advanced breast
cancer were dosed in the clinical trial. Four patients from this study continue to receive study treatment, as of December 31, 2024, each
of whom have received study treatment for more than five years.
Source: Layman SABCS 2021
● Safety analysis:
● Best overall response data for each arm is presented in the table below:
Total Expansion Arms (N=103)
Arm A Arm B Arm C Arm D
Study Treatment P + L + G P + F + G P + F + G P + F + G
Gedatolisib schedule weekly weekly weekly 3 wks on/1 wk off
WT MT WT MT WT MT WT MT
(1) ORR represents PR, except in Arm A, which had 1 CR = Complete
response. Responses per RECIST 1.1; (2) Includes 2 unconfirmed PR
Abbreviations: 1L= first line, 2L= second line; mos= months;
NR = not reached; ORR, objective response rate; PFS, progression free survival
Source: Layman R. et. al, Lancet Oncol.,
2024
Phase 3 HR+/HER2- ABC Clinical Trial (VIKTORIA-1)
In 2022, we initiated VIKTORIA-1, a Phase 3, open-label,
randomized clinical trial to evaluate the efficacy and safety of gedatolisib in combination with fulvestrant with or without palbociclib
in adults with HR+/HER2- advanced breast cancer whose disease has progressed after prior CDK4/6 therapy in combination with an aromatase
inhibitor. This multi-center, international trial is expected to enroll approximately 701 total subjects at more than 200 clinical sites
across North America, Europe, Latin America, and Asia-Pacific. The first patient was dosed in December 2022.
The clinical trial enables separate evaluation of
subjects according to their PIK3CA status.
The clinical trial primary endpoints are progression
free survival (“PFS”), per RECIST 1.1 criteria, as assessed by blinded independent central review (“BICR”). Two
primary endpoints will be evaluated in subjects who are PI3KCA WT, and one primary endpoint will be evaluated in subjects who are PI3KCA
MT. In subjects who are PI3KCA WT, the PFS of gedatolisib in combination with palbociclib and fulvestrant (Arm A) will be compared to
fulvestrant monotherapy (Arm C), and the PFS in gedatolisib in combination with fulvestrant (Arm B) will be compared to fulvestrant monotherapy
(Arm C). In subjects who are PI3KCA MT, the PFS of gedatolisib in combination with palbociclib and fulvestrant (Arm D) will be compared
to alpelisib combined with fulvestrant (Arm E).
All subjects will receive treatment according to the
assigned study arm until objective progressive disease, unacceptable toxicity, death, or withdrawal of consent, whichever occurs first.
Subjects in Arm C will have the option to receive the treatment regimen provided in Arm A or Arm B upon radiographically confirmed disease
progression. Subjects will be followed for adverse events, safety laboratory testing, tumor assessment by RECIST v1.1, quality of life,
and overall survival.
Phase 3 HR+/HER2- ABC Clinical Trial (VIKTORIA-2)
During the third quarter of 2024, we initiated site
selection and activation activities to support a Phase 3, open-label, randomized clinical trial to evaluate the efficacy and safety of
gedatolisib plus a CDK4/6 inhibitor and fulvestrant as first-line treatment for patients with HR+/HER2- advanced breast cancer that is
endocrine treatment resistant (VIKTORIA-2). For the CDK4/6 inhibitor, investigators may choose either ribociclib or palbociclib. This
multi-center, international trial is expected to enroll approximately 12–36 evaluable subjects in the safety run-in portion of the
study to evaluate the safety of gedatolisib when combined with ribociclib and fulvestrant. In the Phase 3 portion of the study, approximately
638 subjects will be randomized and assigned to Cohort 1 (“PIK3CA WT”) or Cohort 2 (“PIK3CA MT”) based on their PIK3CA status.
Subjects in each cohort will be randomized on a 1:1 basis to either Arm A (gedatolisib with fulvestrant and ribociclib or palbociclib)
or Arm B (fulvestrant and ribociclib or palbociclib). It is expected that approximately 200 clinical sites across North America, Europe,
Latin America, and Asia-Pacific will participate. The first patient is expected to be dosed in the second quarter of 2025.
The clinical trial primary endpoints for this study
are PFS, per RECIST 1.1 criteria, as assessed by BICR. The statistical analyses of Cohort 1 and 2 are independent of the other. For each
cohort, the PFS of gedatolisib in combination with fulvestrant and either palbociclib or ribociclib (Arm A) will be compared to fulvestrant
combined with either palbociclib or ribociclib (Arm B).
Prostate Cancer Program
In the United States, prostate cancer is the second
leading cause of cancer death in men. Current estimates predict that one in eight men will be diagnosed with prostate cancer in his lifetime.
The National Cancer Institute estimates that in 2024 there will be over 299,000 new cases of prostate cancer in the United States and
approximately 35,250 deaths from the disease. Although approximately 69% of patients are diagnosed with localized prostate cancer, about
8% of patients present with metastatic disease with a 5-year survival rate of 37%. Androgen deprivation therapy (“ADT”) via
medical or surgical castration has been the mainstay treatment for metastatic prostate cancer. However, prostate cancer cells develop
resistance to ADT and progress to castration resistance, leading to poor prognosis and a median overall survival of about three to five years.
Men with mCRPC have a poor prognosis and a predicted
survival rate of fewer than two years from the initial time of progression. Treatment options for prostate cancer depend on many different
factors, including the stage of the cancer. Castration-resistant prostate cancer is defined by disease progression despite ADT and is
often indicated by rising levels of PSA. Current standard of care for men with castration-resistant prostate cancer provides that patients
should initially receive a combination of ADT and either abiraterone, which works by decreasing androgen levels, or enzalutamide, which
works by blocking androgen binding to androgen receptors (“AR”). If the disease progresses despite these second-generation
hormonal therapies, chemotherapy is considered the next treatment option. Treatment with chemotherapy is generally postponed for as long
as possible due to the potential for severe side effects including neuropathies, nausea, diarrhea, decreased mental capacity and increased
risk of infections.
Preclinical studies have demonstrated a potential
association between the PAM pathway and AR signaling in prostate cancer cells developing resistance to ADT. In these studies, the AR and
PAM pathways were shown to cross-regulate each other. This is similar to the relationship demonstrated in breast cancer with the estrogen
receptor pathway and the PAM pathway. Additionally, 70% - 100% of mCRPC tumors have PAM related pathway alterations.
Several clinical studies have shown promising results
by inhibiting the PAM pathway in combination with an AR inhibitor. In separate Phase 2 and Phase 3 trials, the AKT inhibitor, ipatasertib,
showed improvement in radiographic PFS (“rPFS”) in patients with mCRPC and tumors with phosphatase and tensin homolog (“PTEN”)
loss when ipatasertib was combined with the AR inhibitor, abiraterone, versus abiraterone alone. In a Phase 2 trial, the pan-PI3K inhibitor,
samotolisib, reported median rPFS of 10.2 when combined with enzalutamide versus 5.5 months for enzalutamide alone.
Evidence of gedatolisib’s in vivo activity in
prostate cancer was provided in a study evaluating the 22RV-1, PC3, and C4-2 prostate cancer xenograft models. As seen in the figures
below, gedatolisib induced greater than 80% tumor growth inhibition, regardless of the xenograft model’s sensitivity to the AR inhibitor,
enzalutamide and the cell lines’ PTEN or AR status. In addition, gedatolisib combined with enzalutamide induced significantly greater
tumor growth inhibition than enzalutamide alone in the enzalutamide sensitive model (“C4-2”).
Source: Sen, ASCO-GU, 2023
Phase 1b/2 mCRPC Clinical Trial (CELC-G-201)
We received approval from the FDA in mid-2023 to proceed
with the clinical development of gedatolisib in combination with Nubeqa® (darolutamide), an approved androgen receptor inhibitor,
for the treatment of patients with mCRPC. We have since initiated a Phase 1b/2 clinical trial (CELC-G-201) that will enroll up to 54 participants
with mCRPC who progressed after treatment with an AR inhibitor. We dosed our first patient in this trial in February 2024.
In the Phase 1b portion of the clinical trial, we
enrolled 36 participants randomly assigned to receive 600 mg darolutamide combined with either 120 mg gedatolisib in Arm 1 or 180 mg gedatolisib
in Arm 2. An additional 12 participants will then be enrolled in the Phase 2 portion of the study at the recommended phase 2 dose (“RP2D”)
level to enable evaluation of 30 participants treated with the RP2D of gedatolisib.
The primary objectives of the Phase 1b portion of
the trial include assessment of the safety and tolerability of gedatolisib in combination with darolutamide and determination of the recommended
Phase 2 dose of gedatolisib. The primary objective of the Phase 2 portion of the trial is to assess the rPFS at six months of patients
who received the RP2D.
Pfizer License Agreement
In April 2021, we entered into a license agreement
(“the Gedatolisib License Agreement”) with Pfizer pursuant to which we acquired exclusive (including as to Pfizer) worldwide
sublicensable rights to research, develop, manufacture, and commercialize gedatolisib for the treatment, diagnosis and prevention of all
diseases. Pursuant to the Gedatolisib License Agreement, we are obligated to use commercially reasonable efforts to develop and seek regulatory
approval for at least one product in the U.S. and if regulatory approval is obtained, to commercialize such product in the U.S. and at
least one international major market.
We paid Pfizer a $5.0 million upfront fee upon execution
of the Gedatolisib License Agreement and issued to Pfizer $5.0 million of our common stock. We are also required to make milestone payments
to Pfizer upon achievement of certain development and commercial milestone events, up to an aggregate of $335.0 million. We will pay Pfizer
tiered royalties on sales of gedatolisib at percentages ranging from the low to mid-teens, that may be subject to deductions for expiration
of valid claims, amounts due under third-party licenses and generic competition. Unless earlier terminated, the Gedatolisib License Agreement
will expire upon the expiration of all royalty obligations. The royalty period will expire on a country-by-country basis upon the later
of (a) 12 years following the date of First Commercial Sale of such Product in such country, (b) the expiration of all regulatory or data
exclusivity in such country for such Product, or (c) the date upon which the manufacture, use, sale, offer for sale or importation of
such Product in such country would no longer infringe, but for the license granted herein, a Valid Claim of a Licensed Patent Right. Capitalized
terms in this paragraph have the meanings set forth in the Gedatolisib License Agreement.
We have the right to terminate the Gedatolisib License
Agreement for convenience upon 90 days’ prior written notice. Pfizer may not terminate the agreement for convenience. Either we
or Pfizer may terminate the Gedatolisib License Agreement if the other party is in material breach and such breach is not cured within
the specified cure period. In addition, either we or Pfizer may terminate the Gedatolisib License Agreement in the event of specified
insolvency events involving the other party.
Manufacturing
We rely on third parties to manufacture gedatolisib.
We have entered into agreements with contract manufacturing organizations (“CMOs”), to produce the drug substance gedatolisib,
and produce, package and distribute finished drug product for clinical supply. We require all of our CMOs to conduct manufacturing activities
in compliance with applicable laws including current good manufacturing practice (“cGMP”), requirements. We anticipate that
these CMOs will have the capacity to support both clinical supply and commercial-scale production, and we have started negotiating agreements
at this time to cover commercial production. We may also elect to enter into agreements with other CMOs to manufacture supplies of drug
substance and finished drug product.
Sales and Marketing
If any of our product candidates are approved, we
intend to market and commercialize them in the U.S. and select international markets, either alone or in partnership with others. Cancer
patients are primarily treated by medical, surgical, or radiation oncologists, and we believe they can be reached with a targeted sales
force.
Competition for Gedatolisib
The pharmaceutical industry is characterized by rapid
evolution of technologies and intense competition. While we believe that our product candidates, technology, knowledge, experience, intellectual
property, and scientific resources provide us with competitive advantages, we face competition from major pharmaceutical and biotechnology
companies, academic institutions, governmental agencies and public and private research institutions, among others. Any product candidates
that we successfully develop and commercialize will compete with approved treatment options, including off-label therapies, and new therapies
that may become available in the future. Key considerations that would impact our ability to effectively compete with other therapies
include the efficacy, safety, method of administration, cost, level of promotional activity and intellectual property protection of our
products. Many of the companies against which we may compete have significantly greater financial resources and expertise than we do in
research and development, manufacturing, preclinical testing, conducting clinical trials, obtaining regulatory approvals and marketing
approved products.
There are several PI3K, AKT, and mTOR inhibitors approved
by the FDA, including PIQRAY and AFINITOR from Novartis AG, TRUQAP from AstraZeneca plc, Itovebi from F. Hoffmann-La Roche Ltd, COPIKTRA
from Verastem, Inc., and ZYDELIG from Gilead Sciences, Inc. We are aware that other companies are, or may be, developing products for
this indication, including BridgeBio Pharma Inc., Eli Lilly and Company, Kazia Therapeutics Limited, Relay Therapeutics, Inc., Revolution
Medicines Inc., and Takeda Pharmaceutical Company Limited. There may be additional companies with programs suitable for addressing these
patient populations that could be competitive with our efforts but that have not yet disclosed specific clinical development plans. Smaller
or early-stage companies, including oncology-focused therapeutics companies, may also prove to be significant competitors, particularly
through collaborative arrangements with large and established companies. These companies may also compete with us in recruiting and retaining
qualified scientific and management personnel, establishing clinical trial sites, enrolling patients in clinical trials and acquiring
technologies complementary to, or necessary for, our programs. The availability of reimbursement from government and private payors will
also significantly impact the pricing and competitiveness of our products. Our competitors may obtain FDA or other regulatory approvals
for their products more rapidly than we may obtain approvals for our product candidates, which could result in our competitors establishing
a strong market position before we are able to commercialize our product candidates.
CELsignia
We founded our company to develop our proprietary
CELsignia diagnostic platform and relied on the capability of this technology to identify our lead drug candidate, gedatolisib. CELsignia
characterizes the specific activity of various oncogenic signaling pathways, including the PAM pathway, in living patient tumor cells.
As previously disclosed, we made the decision to focus on the clinical development of gedatolisib and minimize our activities to support
development of CELsignia.
Intellectual Property
Our success depends in part on our ability to obtain
and maintain proprietary protection for our product candidates, manufacturing and process discoveries and other know-how, to operate without
infringing the proprietary rights of others, and to prevent others from infringing our proprietary rights. We plan to protect our proprietary
positions using a variety of methods, which include protecting current U.S. and foreign patents related to proprietary technology, inventions
and improvements and prosecuting additional U.S. and foreign patents that we determine are important to the development and implementation
of our business. For example, we, our licensors, or our collaborators currently have, or are pursuing, patents covering the composition
of matter for our drug product candidates and we plan to generally pursue patent protection covering methods-of-use for one or more clinical
programs. We also rely on trade secrets, trademarks, know-how, continuing technological innovation and potential in-licensing opportunities
to develop and maintain our proprietary position.
Gedatolisib Patents
We entered into the Gedatolisib License Agreement
with Pfizer in April 2021, pursuant to which we acquired exclusive worldwide rights under Pfizer patents and know-how to develop, manufacture
and commercialize gedatolisib. We have exclusive licenses under the Gedatolisib License Agreement to patent rights in the U.S. and numerous
foreign jurisdictions relating to gedatolisib. The patent rights in-licensed under the Gedatolisib License Agreement include 12 granted
patents in the U.S. and more than 290 patents granted in foreign jurisdictions including Australia, Canada, China, France, Germany, Spain,
United Kingdom and Japan. A U.S. patent covering gedatolisib as a composition of matter has a statutory expiration date in December 2029
(including 209 days of Patent Term Adjustment) and a U.S. patent that covers the cyclodextrin formulation of gedatolisib that is currently
in clinical development expires in January 2041 (including 578 days of Patent Term Adjustment), not including any patent term extension
that may be awarded by the FDA, and relevant foreign counterparts.
CELsignia Patents
With respect to CELsignia, we have six issued U.S.
patents and 30 issued international patents covering our diagnostic approach using cell signaling analysis in living patient cells to
guide treatment of patients with targeted therapies and cell sample preparation methods. The earliest expiration date of the patents is
2033. In addition, we have developed significant proprietary know-how and trade secrets for the various cell sample preparation and cellular
analysis methods we have developed.
Product Trademark
We have applied for trademark protection for our preferred
commercial product tradename. While we expect the trademark to issue, the FDA ultimately will determine whether we can use the trademark
with our product.
Trade Secrets
In addition to patents, we rely on trade secrets and
know-how to develop and maintain our competitive position. We typically rely on trade secrets to protect aspects of our business that
are not amenable to, or that we do not consider appropriate for, patent protection. We protect trade secrets and know-how by establishing
confidentiality agreements and invention assignment agreements with our employees, consultants, scientific advisors, contractors and partners.
These agreements generally provide that all confidential information developed or made known during the course of an individual or entity’s
relationship with us must be kept confidential during and after the relationship. These agreements also generally provide that all inventions
resulting from work performed for us or relating to our business and conceived or completed during the period of employment or assignment,
as applicable, shall be our exclusive property. In addition, we take other appropriate precautions, such as physical and technological
security measures, to guard against misappropriation of our proprietary information by third parties.
Government Regulation
Approval of Gedatolisib and Other Drug Products
Government authorities in the U.S. at the federal,
state and local level and in other countries and jurisdictions, including the EU, extensively regulate, among other things, the research,
development, testing, manufacture, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution,
post-approval monitoring and reporting, marketing and export and import of drug products, such as gedatolisib and other drugs that may
be used in combination with or compete with gedatolisib. Generally, before a new drug can be marketed, considerable data demonstrating
its quality, safety and efficacy must be obtained, organized into a format specific for each regulatory authority and submitted for review
and approved by the regulatory authority. The regulatory approval process is time-consuming and requires significant capital expenditures.
U.S. Approval Process
Overview of FDA Approval Process
In the U.S., pharmaceutical products are subject to
extensive regulation by the FDA. The Federal Food, Drug, and Cosmetic Act (the “FDC Act”), and other federal and state statutes
and regulations, govern, among other things, the research, development, testing, manufacture, storage, recordkeeping, approval, labeling,
promotion and marketing, distribution, post-approval monitoring and reporting, sampling, and import and export of pharmaceutical products.
Failure to comply with applicable U.S. requirements may subject a company to a variety of administrative or judicial sanctions, such as
FDA refusal to approve pending New Drug Applications (“NDAs”), warning or untitled letters, product recalls, product seizures,
total or partial suspension of production or distribution, injunctions, fines, civil penalties and criminal prosecution. The process required
by the FDA before a drug may be marketed in the United States generally involves the following:
● submission to the FDA of an NDA for a new drug;
● FDA review of the NDA.
The
lengthy process of seeking required approvals and the continuing need for compliance with applicable statutes and regulations require
the expenditure of substantial resources and approvals are inherently uncertain.
Preclinical and Clinical Stages
Preclinical tests include laboratory evaluation of
product chemistry, formulation and toxicity, as well as animal trials to assess the characteristics and potential safety and efficacy
of the product. The conduct of the preclinical tests must comply with federal regulations and requirements, including good laboratory
practices. The results of preclinical testing are submitted to the FDA as part of an IND along with other information, including information
about product chemistry, manufacturing and controls and a proposed clinical trial protocol. Long term preclinical tests, such as animal
tests of reproductive toxicity and carcinogenicity, may continue after the IND is submitted. A 30-day waiting period after the submission
of each IND is required prior to the commencement of clinical testing in humans. If the FDA has neither commented on nor questioned the
IND within this 30-day period, the clinical trial proposed in the IND may begin.
The clinical stage of development involves the administration
of the investigational product to healthy volunteers or disease-affected patients under the supervision of qualified investigators, generally
physicians not employed by, or under control of, the trial sponsor, in accordance with GCPs. Clinical trials are conducted under protocols
detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the
parameters to be used to monitor subject safety and assess efficacy. Each protocol, and any subsequent amendments to the protocol, must
be submitted to the FDA as part of an IND. Furthermore, each clinical trial must be reviewed and approved by an Institutional Review Board
(“IRB”), for each institution at which the clinical trial will be conducted to ensure that the risks to individuals participating
in the clinical trials are minimized and are reasonable in relation to anticipated benefits. The IRB also monitors the clinical trial
until completed. Human clinical trials are typically conducted in three sequential phases, which may overlap or be combined:
A registrational trial is a clinical trial that adequately
meets regulatory agency requirements for the evaluation of a drug candidate’s efficacy and safety such that it can be used to justify
the approval of the drug. Generally, registrational trials are Phase 3 trials but may be Phase 2 trials if the trial design provides a
reliable assessment of clinical benefit, particularly in situations where there is an unmet medical need.
Post-approval trials, sometimes referred to as Phase
4 clinical trials, may be conducted after initial marketing approval. These trials are used to gain additional experience from the treatment
of patients in the intended therapeutic indication, particularly for long-term safety follow up.
Progress reports detailing the results of the clinical
trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur. The FDA or the sponsor may
suspend or terminate a clinical trial at any time, or the FDA may impose other sanctions on various grounds, including a finding that
the research 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 requirements of the IRB or if the drug has
been associated with unexpected serious harm to patients.
There also are requirements governing the reporting
of ongoing clinical trials and completed clinical trial results to public registries. Information about most clinical trials must be submitted
within specific timeframes for publication on the www.clinicaltrials.gov website. Information related to the product, patient population,
phase of investigation, trial sites and investigators and other aspects of the clinical trial is made public as part of the registration
of the clinical trial. Sponsors are also obligated to discuss the results of their clinical trials after completion. Disclosure of the
results of these trials can be delayed in some cases for up to two years after the date of completion of the trial. Competitors may use
this publicly available information to gain knowledge regarding the progress of development programs.
FDA Review and Approval Process
After completion of the required clinical testing,
an NDA is prepared and submitted to the FDA. Prior to granting approval of the NDA, which is required before marketing of the product
may begin in the U.S., the FDA must determine whether to accept the submission and, thereafter, conduct an in-depth review. This process
may take a year or more. The NDA must include the results of all preclinical, clinical and other testing and a compilation of data relating
to the product’s pharmacology, chemistry, manufacture and controls. The cost of preparing and submitting an NDA is substantial.
The submission of an NDA to FDA, absent an applicable fee waiver, is subject to a substantial application user fee, currently $4,310,002
for Fiscal Year 2025, and the manufacturer and/or sponsor under an approved NDA are also subject to annual program fees for eligible products,
which are currently $403,889 for Fiscal Year 2025.
The FDA may also refer applications for novel drug
products, or drug 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.
The FDA is not bound by the recommendation of an advisory committee, but it generally follows such recommendations. Before approving an
NDA, the FDA will typically inspect one or more clinical sites to assure compliance with GCP. Additionally, the FDA will inspect the facility
or the facilities at which the drug is manufactured. The FDA will not approve the product unless compliance with cGMP is satisfactory