Actuate Therapeutics, Inc. Form 10-K
Table of Contents
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
_____________
FORM 10-K
_____________
(Mark One)
For the fiscal year
ended December 31, 2024
OR
Commission File Number: 001-42139
________________________
Actuate Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
________________________
Registrant’s telephone number, including area
code: (817) 887-8455
Securities registered pursuant to Section 12(b) of
the Act:
Title of each class Trading Symbol Name of each exchange on which registered
Common Stock, par value $0.000001 per share ACTU The Nasdaq Stock Market LLC
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by check mark if the registrant is a well-known seasoned issuer, as defined in Rule 405 of the Securities Act. Yes ☐ No ☒
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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. YesýNo ☐
Indicate
by check mark whether the registrant has submitted electronically every Interactive Data File required to be submitted and posted pursuant
to Rule 405 of Regulation S-T (§ 229.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit and post such files). YesýNo
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As of August 30, 2024, the
aggregate market value of the registrant’s common stock held by non-affiliates of the registrant was approximately $48 million,
based on the closing price of the registrant’s common stock on the Nasdaq Global Market of $8.05 per share. The registrant has elected
to use August 30, 2024 as the calculation date because, as on June 28, 2024 (the last business day of the registrant’s most recently
completed second fiscal quarter) the registrant was a privately held company until its initial public offering in August 2024.
On
March 10, 2025, 19,531,636shares
of common stock, $0.000001 par value per share, were outstanding.
DOCUMENTS INCORPORATED BY REFERENCE
None.
Table of Contents
Page
PART I
Item 1. Business 1
Item 1A. Risk Factors 44
Item 1B. Unresolved Staff Comments 100
Item 1C. Cybersecurity 100
Item 2. Properties 101
Item 3. Legal Proceedings 101
Item 4. Mine Safety Disclosures 101
PART II
Item 6. [Reserved] 103
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 118
Item 8. Financial Statements and Supplementary Data 118
Item 9A. Controls and Procedures 118
Item 9B. Other Information 119
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 119
PART III
Item 10. Directors, Executive Officers and Corporate Governance 120
Item 11. Executive Compensation 124
Item 14. Principal Accountant Fees and Services 137
PART IV
Item 15. Exhibit and Financial Statement Schedules 139
i
Unless the context requires otherwise, references
in this Annual Report on Form 10-K to “Actuate,” the “Company,” “we,” “us,” and “our”
refer to Actuate Therapeutics, Inc.
CAUTIONARY NOTE REGARDING FORWARD-LOOKING STATEMENTS
This Annual Report on Form 10-K
(“Report” or “Annual Report”) contains forward-looking statements about us and our industry. In addition, from
time to time, we or our representatives have made or will make forward-looking statements. The forward-looking statements involve substantial
risks and uncertainties. All statements, other than statements related to present facts or current conditions or of historical facts,
contained in this Report, including statements regarding our strategy, future operations, future financial position, future revenues,
and projected costs, prospects, plans and objectives of management, research and development plans, the anticipated timing, costs, design
and conduct of our ongoing and planned clinical trials and preclinical studies for elraglusib and any future product candidates, the timing
and likelihood of regulatory filings and approvals for elraglusib and any future product candidates, our ability to commercialize elraglusib
and any future product candidates, if approved, the pricing and reimbursement of elraglusib and any future product candidates, if approved,
the potential to develop future product candidates, the potential benefits of strategic collaborations and potential to enter into any
future strategic arrangements, the timing and likelihood of success, plans and objectives of management for future operations, and future
results of anticipated product development efforts, are forward-looking statements. The words “anticipate,” “believe,”
“continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,”
“ongoing,” “plan,” “potential,” “predict,” “project,” “should,”
“target,” “will,” “would,” or the negative of these terms or other comparable terminology are intended
to identify forward-looking statements, although not all forward-looking statements contain these identifying words. These statements
involve estimates, assumptions and uncertainties which could cause actual results to differ materially from those expressed in them. In
addition, any forward-looking statements are qualified in their entirety by reference to the factors summarized under the heading “Risk
Factor Summary” and discussed further under the heading “Risk Factors” in this Report.
You should assume that the information
appearing in this Report is accurate as of its date only. Because the risk factors referred to above could cause actual results or outcomes
to differ materially from those expressed in any forward-looking statements made by us or on our behalf, you should not place undue reliance
on any forward-looking statements. Further, any forward-looking statement speaks only as of the date on which it is made. New factors
emerge from time to time, and it is not possible for us to predict which factors will arise. In addition, we cannot assess the impact
of each factor on our business or the extent to which any factor, or combination of factors, may cause actual results to differ materially
from those contained in any forward-looking statements. All written or oral forward-looking statements attributable to us or any person
acting on our behalf made after the date of this Report are expressly qualified in their entirety by the risk factors and cautionary statements
contained in this Report. Unless legally required, we do not undertake any obligation to release publicly any revisions to such forward-looking
statements to reflect events or circumstances after the date of this Report or to reflect the occurrence of unanticipated events.
In addition, statements that “we
believe” and similarly qualified statements reflect our beliefs and opinions on the relevant subject. These statements are based
upon information available to us as of the date of this Report, and while we believe such information forms a reasonable basis for such
statements, such information may be limited or incomplete, and our statements should not be read to indicate that we have conducted an
exhaustive inquiry into, or review of, all potentially available relevant information. These statements are inherently uncertain and you
are cautioned not to rely unduly upon them.
The discussion of the Company’s
financial condition and results of operations should be read in conjunction with the Company’s consolidated financial statements
and the related notes thereto included in this Report.
ii
PART I
Item 1. Business.
Overview
We are a clinical stage biopharmaceutical
company focused on developing therapies for the treatment of high impact, difficult to treat cancers through the inhibition of glycogen
synthase kinase-3 (GSK-3). We are developing elraglusib (formerly 9-ING-41), an ATP-competitive small molecule that is designed to enter
cancer cells and block the function of the enzyme glycogen synthase kinase-3 beta (“GSK-3β”), a master regulator of complex
biological signaling cascades, including those mediated by oncogenes, that lead to tumor cell survival, growth, migration, and invasion.
We believe that the blockade of GSK-3β signaling ultimately results in the death of the cancer cells and the regulation of anti-tumor
immunity.
We have exclusively licensed a
portfolio of GSK-3 inhibitors developed in a collaboration between The Board of Trustees of the University of Illinois-Chicago (“UIC”)
and Northwestern University (“NU”). Elraglusib is the lead drug in our portfolio and is being evaluated in a randomized Phase 2
trial in patients with metastatic pancreatic ductal adenocarcinoma (“mPDAC”), our most advanced clinical indication to date.
We are also advancing a Phase 1/2 clinical trial in refractory pediatric malignancies, including Ewing sarcoma (“EWS”).
Elraglusib represents a broad
opportunity for us to potentially initiate and advance multiple drug development programs around our lead asset based on data emerging
from completed or ongoing Phase 1/2 trials and non-clinical biological, cellular, and animal data. Animal tumor model data, Phase 1/2
clinical data and AI-based computational approaches have identified a number of areas of unmet clinical need in cancer treatment where
elraglusib may play an interventional role, including pancreatic, metastatic melanoma, lung, colon, breast, renal, and ovarian cancer,
leukemias and lymphomas, as well as some pediatric cancers including Ewing sarcoma, neuroblastoma and pediatric leukemias.
Elraglusib Injection
Our lead clinical program, referred
to as Actuate-1801, is an intravenous (“IV”) injection solution of elraglusib (“Elraglusib Injection”) that we
are evaluating for the treatment of first-line mPDAC.
To date, we have treated over
500 patients with Elraglusib Injection in Phase 1 and Phase 2 studies. Elraglusib Injection is currently being evaluated in a Phase 2
study (as part 3B of our Actuate 1801 protocol) as a weekly IV infusion in combination with gemcitabine/nab-paclitaxel (“GnP”).
Overall survival (“OS”) has been summarized throughout the study by following and reporting 1 year survival rate. The primary
endpoint at the end of the study will be summarized as median overall survival (“mOS”). The study completed enrollment in
January 2024, and top-line results are expected to be presented in the second quarter of 2025. As further described below, we conducted
a preliminary analysis of interim data in the pre-specified safety population as of November 15, 2024, at the point when >70% of death
events occurred in the GnP control arm. Log-rank analysis will be used to determine statistical significance when comparing the elraglusib/GnP
and GnP arms of the study.
The analysis of interim data demonstrated
that treatment with elraglusib in combination with GnP resulted in statistically significant increases in 1-year survival rate (p-value
of 0.002) and mOS (hazard ratio of 0.63, p-value of 0.016) versus treatment with GnP alone. The combination treatment also resulted in
increased Objective Response Rates (“ORR”) and Disease Control Rates (“DCR”) in the elraglusib/GnP combination
arm versus the GnP control arm. As depicted in Figure 1 and below, interim data highlights from the predefined safety population as of
the November 15, 2024 cutoff date include:
Figure 1: Actuate-1801 Part 3B:
Draft unaudited Phase 2 data of elraglusib in mPDAC (as of November 15, 2024).
As with all preliminary analyses
of interim data, this data should not be relied upon as a final analysis and is subject to change once full data analysis is complete.
At the completion of this Phase
2 study, we plan to meet with the U.S. Food and Drug Administration (the “FDA”) and discuss the design and execution of a
Phase 3 registration study. In addition, we plan to discuss the use of the Phase 2 data to support potential registration.
As discussed in more detail below
under “History of Elraglusib Clinical Development,” the Phase 2 trial followed the evaluation of Elraglusib Injection in a
Phase 1 dose escalation study (Actuate-1801 Part 1) in 238 adult patients with refractory advanced cancers when given as a single
agent (n=67) or in combination with chemotherapy (n=171). The objective of this study was to establish the safety profile of elraglusib
when used alone or in combination with chemotherapy and to identify either a maximum tolerated dose (“MTD”) or recommended
Phase 2 dose (“RP2D”) to then inform the design of exploratory efficacy studies in Phase 2. Subjects in this study were
diagnosed with a variety of cancer types and most patients had received two or more previous lines of chemotherapy prior to enrollment
in the study. Objective responses and durable disease control were observed in both the single agent and combination treatment arms of
the study. The most common TEAEs attributed to elraglusib were transient visual disturbance (patients described lights as brighter and
skin tones as darker, which resolved spontaneously) and fatigue across both study parts. The majority (>99%) of TEAEs that occurred
in ≥ 20% of patients were reported as Grade 1 or 2 (mild or moderate). In combination with chemotherapy, no new safety signals
were observed. While the elraglusib/GnP combination appears to be well-tolerated and well-managed in the clinic, we do not yet know whether
any increase in the number or severity of toxicities will be attributable to elraglusib and thus the elraglusib/GnP combination will have
its own safety profile that will need to be evaluated and discussed with regulators.
Based on the results of the Phase 1
study, we initiated a single arm Phase 2 study (“Actuate-1801 Part 3A” or “Part 3A”) in patients with
previously untreated mPDAC. This study was originally designed as a single arm exploratory Simon two-stage trial (and therefore not designed
or powered to demonstrate statistical significance). The elraglusib dose was started at the RP2D evaluated in the latter part of the Phase
1 trial (15 milligrams of drug per kilogram of body weight (mg/kg) administered twice weekly). No new safety signals were observed with
the elraglusib/GnP combination, but investigators observed that GnP toxicities may have occurred earlier and may have been more intense
in some patients than would be anticipated for GnP alone. For these reasons, the dose of elraglusib was proactively reduced near the end
of the Part 3A study to 9.3 mg/kg administered twice weekly. After an analysis conducted following the completion of Part 3A, which showed
an mOS of 15.3 months in the efficacy evaluable (n=29) patient population, we amended and expanded the second stage of the study
to a randomized, controlled trial now powered for statistical significance (“Actuate-1801 Part 3B” or “Part 3B”)
that would allow a comparison of the safety and efficacy of the combination of Elraglusib Injection plus GnP versus GnP alone in 286 patients.
In addition, Elraglusib Injection
is also being evaluated in pediatric cancer patients with recurrent/refractory solid cancers. This study, Actuate-1902, is a Phase 1/2
study that evaluated escalating doses of elraglusib as a single agent as well as in combination with irinotecan or cyclophosphamide/topotecan
in the Phase 1 portion. This study was based off the RP2D from the Actuate-1801 adult cancer study using twice weekly dosing of elraglusib.
Patients in this Actuate-1902 study also experienced a number of objective responses in the combination chemotherapy arms, and based on
this data, we identified Ewing sarcoma as a potential second indication for further development of Elraglusib Injection. Currently, the
Actuate-1902 study is open but only accruing patients with refractory Ewing sarcoma into the Phase 1 portion of the study. Subject
to future funding, we plan to further investigate the activity of elraglusib in the Ewing sarcoma patient population.
Elraglusib Oral Tablet Development Plans
We have developed several oral
dosage forms of elraglusib, which we believe will allow us to expand the number of cancer indications that we are able to target and allow
us to further explore more convenient dose delivery options for patients. A clinical candidate tablet, the Elraglusib Oral Tablet, has
been selected for further development and we are planning a Phase 1 study (Actuate-2401) to identify the MTD and RP2D for Elraglusib Oral
Tablet in adult patients with advanced, refractory cancers, subject to future funding. Subject to additional funding, several Phase 2
studies have been identified for further clinical development of Elraglusib Oral Tablet based on data from the Actuate-1801 study in indications,
including but not limited to, refractory, metastatic melanoma and refractory, metastatic colorectal cancer.
Our Market Opportunity
Treatment of Metastatic Pancreatic Ductal
Adenocarcinoma (“mPDAC”)
According to the American Cancer
Society, the annual incidence of pancreatic cancer is expected to exceed 67,000 patients in the United States in 2025 and approximately
70% of these patients will present with metastatic disease. A recent review of clinical trials in Future Oncology1
showed that the mOS in patients with mPDAC treated with GnP ranged from approximately 3.6 to 9.8 months with an unweighted mOS of 6.9
months. Therefore, we believe the ability to extend survival by even a few months would be considered meaningful in this patient
population.
We are developing elraglusib
for patients with mPDAC who have not previously received systemic treatment for their metastatic disease. Due to lack of early symptoms,
approximately 80-90% of all patients with pancreatic cancer are unresectable, and present with advanced or metastatic disease. In addition,
80-90% of PDAC cases do not have a high tumor mutational burden in general, and are unlikely to respond to checkpoint inhibitors such
as pembrolizumab. Pembrolizumab has been approved for patients with metastatic solid cancer with high tumor burden but is rarely used
in metastatic pancreatic cancer for this reason. However, frequent mutations in KRAS and TP53 oncogenes drive pancreatic tumor growth
and treatment resistance, often making PDAC refractory to chemotherapy.
Current first-line therapies
for mPDAC consist of GnP, FOLFIRINOX, or irinotecan liposomal injection given with oxaliplatin, fluorouracil, and leucovorin (“NALIRIFOX”).
NALIRIFOX was recently approved (February 2024) and may provide an alternative to FOLFIRINOX with a somewhat improved safety profile.
The mOS in mPDAC patients
is 11.1 months with NALIRIFOX, 11.2 months with FOLFIRINOX and 7 to 10 months with GnP, respectively, in the first-line setting. NALIRIFOX
demonstrated superiority to GnP in the NAPOLI-3 trial (mOS 11.1 vs 9.2 months). However, safety profiles between these three chemotherapy
backbones are quite different: FOLFIRINOX leads to higher rates of neutropenia and nausea, NALIRIFOX has more gastrointestinal and constitutional
toxicity such as nausea, diarrhea and fatigue, and GnP treatment leads to increased myelosuppression and neurotoxicity. An analysis of
an insurance claims database indicated that first-line treatment from 2014-2018 was split between FOLFIRINOX and GnP. We believe it is
too early to predict how NALIRIFOX will fit into clinical use in patients with mPDAC.
Our management believes
elraglusib may improve outcomes in first-line mPDAC regardless of the chemotherapy backbone used. Patients with mPDAC are often resistant
or become resistant to the first-line chemotherapy backbones currently used to treat them. Part of elraglusib’s mechanism of action
is the ability to enhance chemotherapy activity even in resistant tumors and we believe this has been demonstrated in multiple animal
tumor models. In addition, elraglusib has shown the ability to enhance the activity of several chemotherapy drugs that comprise the current
first-line backbones in mPDAC including gemcitabine, nab-paclitaxel and irinotecan, suggesting the potential for elraglusib to be used
in combination with multiple first-line mPDAC treatments. In addition to the activity observed in our 1801 Part 3B study evaluating the
activity of elraglusib/GnP combination in mPDAC, an additional exploratory Phase 2 study is ongoing through an investigator initiated
trial (“IIT”) in patients with mPDAC evaluating the combination of elraglusib/FOLFIRINOX/losartan combination in up to 65
patients. Early evidence of increased clinical activity in patients receiving this combination was recently presented at the AACR Special
Conference on Advances in Pancreatic Cancer Research. This trial is being led by Dr. Colin Weekes at Massachusetts General Hospital (“MGH”)
and is supported by the Lustgarten Foundation as well as Actuate. Additional sites participating in the study include The University of
Colorado and the University of Washington’s Fred Hutchinson Cancer Center. Thus, our plan, subject to available funding, is to develop
elraglusib in combination with the present first-line chemotherapy regimens used in the treatment of mPDAC, as exemplified by our lead
program of elraglusib/GnP combination and later moving to combinations with either FOLFIRINOX or NALIRIFOX pending results of the FOLFIRINOX
combination trial. If shown to be clinically active, elraglusib/chemotherapy combinations could eventually be used to treat a large segment
of mPDAC patients.
Elraglusib has been granted Fast
Track and Orphan Drug Designations from the FDA for pancreatic cancer in the United States and Orphan Drug Designation for soft tissue
sarcomas in the United States. Elraglusib received Orphan Medicinal Product Designation (“OMPD”) for both pancreatic cancer
and sarcoma from the European Medicines Agency (“EMA”). Actuate is planning a Type D meeting with the FDA to discuss Phase
3 design and an End of Phase 2 (Type B) meeting to discuss future development plans in 2025.
____________________
1 Cockrum P, Dennen S, Brown A, Briggs
J, Paluri R. Real-world clinical outcomes and economic burden of metastatic pancreatic ductal adenocarcinoma: a systematic review. Future
Oncol. 2025; 21: 241-260. doi: 10.1080/14796694.2024.2435253. Epub 2024 Dec 8.
Treatment of Ewing Sarcoma
An estimated 9,550 children (ages
0-14 years) and 5,140 adolescents (ages 15-19 years) are expected to be diagnosed with cancer in the United States in 2025. It was also
estimated that 1,050 children and 600 adolescents will die from the disease in the United States in 2025. While death rates for pediatric
and adolescent cancers have declined by more than 50% over the last five decades due to improved treatment options, there is still room
for improvement. Despite the improved survival offered by current therapies, approximately 40% of childhood cancer survivors have severe,
life-threatening or fatal complications within 30 years of diagnosis and up to 90% of survivors will have a chronic health condition by
the age of 45. These long-term effects are related to the type of treatment used such as chemotherapy and radiation which can have a material
adverse impact on developing organs. Work is ongoing to determine how to more effectively identify underlying mechanisms of pediatric
cancers in an effort to develop and administer more targeted, more effective and less toxic treatments.
Based on extensive preclinical
work in pediatric malignancies showing excellent synergy between elraglusib and standard of care chemotherapy in neuroblastoma, sarcoma,
glioma and others, we initiated the Actuate-1902 Phase 1 study to evaluate the safety of elraglusib +/- chemotherapy in pediatric patients
with refractory malignancies in 2020. The dose escalation part of the study assigned patients to elraglusib alone, elraglusib/irinotecan
or elraglusib/cyclophosphamide and topotecan (“CT”). As of December 31, 2024, 40 patients had been enrolled and received at
least one dose of elraglusib. No SAEs were observed with elraglusib monotherapy at the first two dose levels and positive results were
observed for some patients as discussed under “Our Solution – Current Elraglusib Development - Developing Elraglusib IV for
the Treatment of Ewing Sarcoma – Actuate 1902” below. Upon determination of RP2D for monotherapy and combination therapy,
we had originally intended to initiate a Phase 2 study in neuroblastoma. However, recently approved anti-GD2 antibodies have shown considerable
improvement of response rate, progression-free survival (“PFS”), and survival, making development in this population much
more challenging.
Based on the positive response
from a Ewing sarcoma patient further discussed below under “Developing Elraglusib Injection for the Treatment of Ewing Sarcoma –
Phase 1 and Phase 2 Plans – Actuate-1902,” six additional patients with metastatic, refractory Ewing and Ewing-like sarcoma
were enrolled in the elraglusib/CT combination arm. There are currently no known treatment regimens that meaningfully extend life in Ewing
sarcoma patients with metastatic, refractory disease. The five-year survival rate for patients who have recurrent (relapsed) disease is
<30%. Patients who are refractory and have metastases and disease progression despite two or more chemotherapy regimens generally have
a very short survival of 3-8 months. Twelve patients including ten Ewing sarcoma patients, one patient with desmoplastic small round cell
tumors (“DSRCT”) and one patient with CIC rearranged sarcoma were enrolled in our Actuate-1902 trial. All twelve patients
appear to have metastatic disease and had disease progression prior to joining the study despite undergoing previous treatment combinations
including chemotherapy, radiation, and/or surgical procedures. Eight patients received two or more previous chemotherapy regimens, prior
to entering the 1902 study. All patients received the combination of elraglusib and cyclophosphamide/topotecan. We believe this exploratory
Ewing sarcoma data, discussed further under “Developing Elraglusib IV for the Treatment of Ewing Sarcoma – Actuate 1902”
below, is sufficiently positive in this orphan pediatric cancer indication to consider additional development in Ewing sarcoma. The Actuate-1902
Phase 1 arm of the study is open to enrollment, focusing on recruitment of patients with refractory Ewing sarcoma.
The FDA has granted Rare
Pediatric Disease Designation (“RPDD”) to elraglusib for our treatment of EWS. Rare Pediatric Disease Designation is granted
by the FDA for serious or life-threatening diseases that affect fewer than 200,000 people in the United States and in which the serious
or life-threatening manifestations primarily affect individuals less than 18 years of age. If, in the future, a New Drug Application (“NDA”)
for elraglusib for the treatment of Ewing sarcoma is approved by the FDA, we may be eligible to receive a Priority Review Voucher (“PRV”)
that could be utilized by us or potentially sold to another company for its use.
Our Pipeline and Development Timeline
Our initial focus is on the development
of GSK-3 inhibitors for the treatment of cancers with ineffective treatment options and poor overall survival. Given our ability to formulate
elraglusib in both the Elraglusib Injection and Elraglusib Oral Tablet forms, if adequate funding is secured, and given the potential
to use it in different ways depending on the cancer type, we believe that elraglusib represents a pipeline in a molecule, as shown in
the Figure 2 below. We are currently focused on advancing our trials in mPDAC with Elraglusib Injection. Our ability to advance our ongoing
and planned clinical trials listed in Figure 2 will depend on whether we have or raise sufficient capital to support those trials.
Figure 2: Ongoing and planned clinical trials.
Our Strengths
We believe that we have several
strengths that support our vision of developing therapies for the treatment of high impact, difficult to treat cancers through the inhibition
of GSK-3, including:
· Phase 1 dose escalation study planned in advanced cancer patients.
Our Business Strategies
Subject to available financing,
we intend to develop elraglusib in a broad list of advanced cancer indications, initially in patients with refractory disease and with
an initial focus on metastatic pancreatic cancer. We believe that our two product candidates, Elraglusib Injection and Elraglusib Oral
Tablet, will provide us with two different dosage forms of drug product with different attributes that will allow us to tailor each dosage
form to a specific cancer type to potentially improve outcomes and compliance. Key elements of our strategy to accomplish this objective
include:
About Elraglusib (9-ING-41)
There are no approved high-affinity
inhibitors of GSK-3β and we believe elraglusib is one of the most advanced GSK-3β inhibitors in clinical development. Elraglusib
was originally known as 9-ING-41 but was granted the elraglusib International Nonproprietary Names (“INN”) and United States
Adopted Names (“USAN”) generic name in 2021. The known major mechanisms of action of elraglusib are summarized in Figure 4
and emphasize the therapeutic potential of this drug in multiple cancer types. For these reasons, elraglusib represents a “pipeline
in a molecule” depending on the dosage form and how it is used in a particular cancer type. Our lead development program is seeking
to treat mPDAC in combination with GnP. Our clinical data to date and the development plan are also further discussed below.
Elraglusib may exert anticancer
activity through a variety of mechanisms that may be context and cancer type specific. For example, GSK-3β mediates signaling of
oncogenic PI-3K but if this oncogene is not expressed in a particular tumor, this would not be a pathway that could be targeted by elraglusib
in that tumor. Potential antitumor activity through GSK-3β inhibition may occur through the following six mechanisms of action (see
Figure 3 below):
(1) Immune modulation;
(2) Inhibiting cell proliferation;
(3) Reducing tumor fibrosis;
(4) Decreasing immune evasion;
(5) Increasing apoptosis and disrupting DNA damage repair; and
(6) Inhibition of epithelial-mesenchymal transitions (“EMT”).
Figure 3:Elraglusib mechanisms
of action.
(1) Immune modulation and inhibition of immune evasion
GSK-3β plays an important
role in immune cell function, as inhibition of GSK-3β can facilitate immune cell expansion, differentiation and activation including
T and natural killer (“NK”) cells. GSK-3β inhibition increases the ability of effector T cells to kill tumors in vivo
through the induction of effector proteins granzyme B and FasL in gastric cancer models. Additionally, inhibition of GSK-3β, with
both small molecules and small interfering RNA (“siRNA”), downregulates programmed cell death protein 1 (“PD-1”)
expression in CD8 and cytolytic T cells and enhances their function. GSK-3β inhibition also lowers PD-1 expression and promotes long-term
survival and generation of memory CAR-T cells in vivo. These memory T cells enabled 100% clearance of cancer cells after rechallenging
during tumor remission. Recently, inhibition of GSK-3β with small molecules was shown to reduce the expression of T cell immunoreceptor
with immunoglobulin and ITIM domain (“TIGIT”) and lymphocyte activation gene-3 (“LAG-3”), additional immune system
suppressing molecules that work in concert with PD-L1 (Programmed Death-Ligand 1) to reduce anti-tumor surveillance by the system. Combining
GSK-3β inhibition and LAG-3 blockade significantly enhanced clearance of melanoma tumors compared to either treatment alone. LAG-3
was recently validated as a cancer therapeutic target when the first anti-LAG-3 antibody, relatlimab, was approved in March 2022
by the FDA for treatment of patients with unresectable or metastatic melanoma.
Blocking GSK-3 in NK cells leads
to enrichment of mature NK cells and primes them for enhanced cytokine production and anti-tumor function in vivo. GSK-3β expression
was increased in the NK cells of patients with acute myeloid leukemia (“AML”) and inhibition of GSK-3β led to increased
cell directed cytotoxicity in these patient-derived samples. Inhibition of GSK-3 also decreased LAG-3 expression on NK cells.
GSK-3β activity has also
been tied to transforming growth factor β (“TGF-β”) expression. TGF-β released by cancer cells, stromal fibroblasts
and other cells in the tumor microenvironment further promotes cancer progression by shaping the architecture of the tumor and by suppressing
the anti-tumor activities of immune cells, thus generating an immunosuppressive environment that prevents or attenuates the efficacy of
anticancer immunotherapies. Therefore, blocking GSK-3β may reduce TGF-β-mediated immunosuppression.
Elraglusib has now been demonstrated
to decrease expression of PD-1, TIGIT and LAG-3 and to enhance the anti-tumor effects of anti-PD-1 checkpoint inhibition in animal tumor
models. Thus, elraglusib blockade of GSK-3β activity may improve immune response to tumors by augmenting the responsiveness of a
patient’s immune system in addition to the direct anti-tumor effects of elraglusib within the cancer cells themselves.
(2) Inhibiting cell proliferation
Inhibition of GSK-3β leads
to inhibition of tumor cell proliferation. This has been shown in multiple tumor model systems using elraglusib. A number of pathways
have been implicated in the inhibition of cell proliferation mediated by GSK-3 inhibitors including MYC, Cyclin D1, TGFα, epidermal
growth factor receptor, Ras, PI3K/Akt, and NF-κB. Given GSK-3’s role as an adapter of multiple signaling pathways, elraglusib
may exert its antiproliferative effects through the inhibition of one or more of these pathways.
(3) Reducing tumor fibrosis and (4) decreased immune evasion
A chronic inflammatory microenvironment
is conducive to tumorigenesis (e.g., pancreatitis patients are known to have increased risk of pancreatic cancer) and tumors can undergo
EMT, leading to increased metastasis, under inflammatory conditions. Moreover, several profibrotic cytokines (e.g., TGF-β, TNF-α
and IL-1) are secreted by inflammatory cells and tumor cells and converge to activate pathways that regulate EMT. Further, GSK-3β
has also been demonstrated to be a mediator of EMTs. Therefore, the inflammatory response designed to fight tumor progression also ends
up promoting metastasis and tumor-associated fibrosis. Tumor fibrosis presents multiple challenges to drug delivery and tumor immune recognition
and contributes to drug resistance by presenting physical barriers in the tumor microenvironment to drug and immune cell access. Elraglusib
has been shown to reduce the inflammation and signaling that contribute to immune system evasion in multiple animal models, including
lung and liver, suggesting another mechanism through which elraglusib may interfere in cancer growth.
(5) Increasing apoptosis and disrupting DNA damage repair
GSK-3 inhibits apoptosis pathways.
A number of studies have suggested that the primary mechanism of GSK-3-mediated apoptosis is through the NF-κB pathway. Apoptosis
is a mechanism of cell death that is often suppressed in cancer cells leading to cancer cell survival and resistance even after treatment
with chemotherapeutic drugs or radiation. Studies have shown that eliminating or inhibiting GSK-3β in cancer cells is able to restore
apoptosis to cells, leading to tumor cell death. These findings support GSK-3β as a potential therapeutic target to potentiate apoptosis
in cancer cells.
In addition to GSK-3β’s
role in regulating NF-κB activity, it has also been shown to modulate DNA damage repair (“DDR”) pathways. DDR pathways
are integral in both normal and cancer cells to maintain genomic integrity by sensing and responding to DNA damage. In normal cells, DDR
helps to identify and repair mutations or breaks in DNA and restore the normal, intact sequence. If the cell is unable to repair a DNA
lesion, these DDR pathways can then initiate cell death signaling to prevent neoplastic growth. In cancer, DNA repair has been subverted
to protect tumor cells from repairing DNA damage that would otherwise lead to spontaneous apoptosis. Cancers will often have mutations
in at least one DNA repair pathways leading to dysregulated cell growth and replication. Our collaborators have shown that elraglusib
inhibition of GSK-3β sensitizes pancreatic cancer cells to gemcitabine by disrupting TopBP1/ATR mediated cell-cycle arrest and DNA
repair. GSK-3β’s emerging role in regulating DDR pathways supports its use in combination with DNA damaging chemotherapy.
Inhibition of DDR pathways have
also been shown to enhance tumor immune recognition by immune checkpoint inhibitors such as anti-PD-1, creating neoantigens in tumors
that lead to recruitment of tumor infiltrating immune cells, decreased immune evasion and increased anti-tumor immune response. This provides
the link that couples the various elraglusib-related mechanisms of action through the targeting of GSK-3.
(6) Inhibition of epithelial-mesenchymal transition (EMT)
GSK-3β has been shown to
be a mediator of a number of signaling pathways that regulate the transition of tumor cells from an epithelial to mesenchymal phenotype
potentially contributing to tumor progression, a process known as EMT. Signaling through Wnt, Notch, TGF-β and Snail are known mediators
of EMT and their signaling is regulated through GSK-3β. Several toolkit GSK-3β inhibitors have been shown to inhibit EMT in
tumor models suggesting that this is a class effect and highlighting a similar mechanism for elraglusib.
Our Solution – Current Elraglusib Development
Elraglusib represents a broad
opportunity for us to potentially initiate and advance multiple drug development programs around our lead asset based on data emerging
from completed or ongoing Phase 1/2 trials. Our lead program is developing Elraglusib Injection for the first-line treatment of mPDAC.
mPDAC remains one of the highest unmet needs in oncology as the 5-year survival rate for PDAC (<10%) is one of the lowest of any cancer
type.
Developing Elraglusib Injection for the Treatment
of mPDAC – Phase 2 Studies
Actuate-1801 Part 3B
We are currently evaluating elraglusib
through the second part of a Phase 2 study, referred to as Actuate-1801 Part 3B, which was initiated under the Actuate-1801 Master
Protocol in patients with mPDAC who had not previously received systemic treatment for their metastatic disease.
This study was designed as a randomized,
controlled study with a run-in to explore two different dosing schedules of elraglusib/GnP (once weekly vs. twice weekly) in the hope
of potentially providing clinical support for moving to a more convenient, commercially viable elraglusib schedule. Pharmacokinetics were
also included in this study to address the potential for drug-drug interactions (“DDI”) between elraglusib and gemcitabine
or nab-paclitaxel. Management believes that confirmation of the Actuate-1801 Part 3A result discussed below in an adequately powered,
randomized study, would compare favorably with the recently approved irinotecan liposomal injection and would complement the other first-line
regimens currently used to treat mPDAC and provide a basis for approval for use in patients with mPDAC who had not previously received
systemic treatment for their metastatic disease.
Actuate-1801 Part 3B enrolled
its first patients in October 2021 and the run-in part of the trial demonstrated the weekly dosing of elraglusib was equivalent to
twice weekly dosing of elraglusib. All patients randomized to the elraglusib/GnP arm now receive weekly elraglusib in addition to GnP.
The trial accrued more readily than projected and enrollment was completed in January 2024. Below are the key inclusion criteria
and clinical endpoints in the study:
Inclusion Criteria:
· ≥ 18 years old with metastatic pancreatic adenocarcinoma
· Participants must have measurable disease as defined by RECIST1.1
· No prior therapy
· Total enrollment: 286
Endpoints:
· Primary endpoints: 1 year OS/mOS
· Secondary endpoints: ORR, DCR, PFS
We conducted a preliminary analysis
of interim data in the pre-specified safety population as of November 15, 2024. As with all preliminary analyses of interim data, this
data should not be relied upon as a final analysis and is subject to change once full data analysis is complete. For this preliminary
analysis, we used data based on a cut-off date corresponding to the date when >70% of death events occurred in the GnP control arm.
The analysis of interim data demonstrated
treatment with elraglusib in combination with GnP resulted in statistically significant increases in 1-year survival rate (p-value of
0.002) and mOS (hazard ratio of 0.63, p-value of 0.016) versus treatment with GnP alone. The combination treatment also resulted in increased
ORR and DCR in the elraglusib/GnP combination arm versus the GnP control arm. Interim data highlights include the following:
Figure 4 provides additional details
regarding the demographics and disease history of the enrolled patient population (draft unaudited data as of November 15, 2024).
Demographics GnP (n=78) Elraglusib + GnP (n=155)
Sex
Age (years)
Race
Black or African American 6 (7.7%) 7 (4.5%)
Multiracial 0 1 (0.6%)
Unknown/Not Reported 5 (6.4%) 14 (9.0%)
Ethnicity
Hispanic or Latino 0 8 (5.2%)
Unknown/Not Reported 1 (1.3%) 6 (3.9%)
Body Surface Area (BSA) (m2)
Eastern Cooperative Oncology Group Performance Status
Disease Status
Site of Metastases
Figure 4:Actuate-1801 Part 3B: Demographics
for patients in study (as of November 15, 2024).
Additional data from the preliminary
analysis of interim data as of November 15, 2024 are shown in Figures 5 – 11. These figures represent draft unaudited data
as of November 15, 2024 and the final data and results may change as the study continues through completion. As with all interim data,
this data should not be relied upon as a final analysis and is subject to change once full data analysis is complete.
Figure 5 summarizes primary
and secondary endpoints and patients remaining on study for each treatment arm as well as landmark OS endpoints of 18- and 24-months.
A large number of patients are still on treatment with 38% still remaining on the elraglusib/GnP combination arm versus 19% still remaining
on the GnP only arm as of November 15, 2024. This is also shown at the patient level for each treatment cohort in the swim plots in Figure
9 that show patients still on treatment, patients with a response including stable disease, and patients still on study as well as those
that have reached an event. Interim safety data is shown in Figure 11.
Outcome GnP (n=78) Elraglusib/GnP (n=155)
Primary Endpoint: mOS (months) HR=0.63; log-rank p=0.016 7.2 9.3
Figure 5: Actuate-1801 Part 3B: Primary and
secondary study endpoints (as of November 15, 2024).
Figure 6 below represents interim
Kaplan-Meier estimate for mOS. The administrative analysis of interim data indicates that >80% of the patients in the GnP control arm
progressed and were no longer receiving GnP.
Figure 6: Actuate-1801 Part 3B: Interim
Kaplan-Meier Estimate for mOS (as of November 15, 2024).
Figure 7 below depicts the best overall response
(“BOR”) of patients enrolled in the Phase 2 study (Actuate-1801 Part 3B) in the GnP control arm who received at least one
radiographic scan.
Figure 7: Actuate-1801 Part 3B: GnP Best Overall
Response (as of November 15, 2024).
Figure 8 below depicts the BOR of patients enrolled
in the Phase 2 study (Actuate-1801 Part 3B) in the elraglusib/GnP combination arm who received at least one radiographic scan.
Figure 8: Actuate-1801 Part 3B: GnP/Elraglusib
combination Best Overall Response (as of November 15, 2024).
Figure 9 below is a graphical
representation of survival (“mOS Swim Plot’”) of patients enrolled in the Phase 2 study (Actuate-1801 Part 3B) in the
elraglusib/GnP combination arm compared to the GnP control arm.
Figure 9: Actuate-1801 Part 3B: Administrative Analysis
of mOS Swim Plot (as of November 15, 2024).
This is an open-label study and
therefore, the study could not be used to support accelerated approval which would be based on evaluation of surrogate endpoints.
Management expects top-line data
will be presented in the second quarter of 2025 based on the completion of enrollment in January 2024.
At the conclusion of Phase 2 trial
(Actuate-1801 Part 3B), we expect to have survival data on the elraglusib/GnP combination arm and GnP arm in patients with mPDAC
who had not previously received systemic treatment for their metastatic disease. At the completion of this study, we plan to meet with
the FDA and discuss the design and execution of a Phase 3 registration study, if justified by the results this study. In addition,
we plan to discuss the use of the Actuate-1801 Part 3B data for regulatory support and to support possible registration if the study
achieves its primary endpoint of showing improved survival over GnP alone. Moreover, while the elraglusib/GnP combination appears to be
well-tolerated and well-managed in the clinic, we do not yet know whether any increase in the number or severity of toxicities will be
attributable to elraglusib and thus the elraglusib/GnP combination will have its own safety profile that will need to be evaluated and
discussed with regulators. Figure 11 is a summary of the safety events reported as of November 15, 2024.
Actuate-1801 Part 3A
Actuate-1801 Part 3A is a single
arm Phase 2 trial that was initiated in patients with mPDAC who had not previously been treated with any systemic chemotherapy including
GnP (first-line study) and which built on the results of Actuate-1801 Part 2 described below, allowing a comparison of the safety
and efficacy of the combination of Elraglusib Injection plus GnP as compared to GnP alone. By moving our development into the first line
setting, we increased our ability to deliver the elraglusib/GnP combination to many more patients since more than 70% of patients with
mPDAC never go on to a second-line treatment once they have progression on first-line treatment. In addition, we believe that the safety
profile of elraglusib/GnP provides a strong basis for testing this combination in first-line patients. We also received a number of commercialization
incentives (e.g. ODD, FTD) through registration for pancreatic cancer including mPDAC. Results from the Actuate-1801 Part 3A study formed
the basis for the initiation of Actuate-1801 Part 3B trial.
In Part 3A of the Phase 2
study under the Actuate-1801 Master Protocol, the efficacy evaluable (“EE”) patient population was pre-defined as the efficacy
analysis population and the modified intent to treat (“mITT”) was the safety population. The elraglusib dose was started at
the RP2D evaluated in Part 2 (15 mg/kg dosed twice weekly).
The original study design proposed
to enroll 23 consecutively evaluable patients who met the definition for the EE. These patients could be replaced at the discretion of
the independent data monitoring committee (“IDMC”). Consequently, six patients were replaced such that there were 29 EE patients
in the study. No new safety signals were observed with the elraglusib/GnP combination, but investigators observed that GnP toxicities
may have occurred earlier and may have been more intense in some patients than would be anticipated for GnP alone. For these reasons,
the dose of elraglusib was proactively reduced near the end of the study to 9.3 mg/kg dosed twice weekly, with the final four patients
enrolled being treated at this dose.
Figure 10 below is a summary of
the response of patients with mPDAC treated with the elraglusib/GnP combination in Part 3A (data cutoff as of March 2023) in the
29 EE patients.
Response EE population (n=29)
CR, n (%) 2 (6.9)
PR, n (%) 9 (31)
Progressive disease, n (%) 3 (10.1)
mPFS 5.4 months (4.9 months ITT)
mOS 15.3 months (11.9 months ITT)
Confidence Interval (“CI”); Stable Disease (“SD”)
Figure 10:Response of EE patients
with mPDAC treated with elraglusib/GnP combination in Part 3A (data cutoff as of March 2023).
The mOS for the EE and ITT were
15.3 months and 11.9 months, respectively. These compare favorably with the mOS for GnP alone of 8.5 months in the MPACT
trial or more recently 9.2 months in NAPOLI-3 trial, which evaluated irinotecan liposomal injection (Onivyde®) in combination
compared to GnP, in the first-line mPDAC setting.
Elraglusib Injection was initially
evaluated in Actuate-1801 Part 1/2, a dose escalation study in adult patients with refractory advanced cancers when given as a single
agent or in combination with chemotherapy. The objective of this study was to establish the safety profile of elraglusib when used alone
or in combination with chemotherapy and to identify either an MTD or RP2D to then inform the design of exploratory efficacy studies in
Phase 2. Figure 14, which shows the study design process, and additional information regarding Actuate 1801 Master Protocol and potential
future development opportunities (for which funding would need to be raised) identified through Actuate 1801 Parts 1 and 2 are set forth
under “History of Elraglusib Clinical Development” below.
Overview of Interim Safety Profile from Phase 2 Trial (Actuate-1801
Part 3B)
Figure 11 provides safety
data as of November 15, 2024 from the Actuate-1801 Part 3B trial. TEAEs broadly encompass all adverse events observed while a patient
is on study and could be due to the drug or drugs (if used in combination), the disease or something specific to a particular patient
such as other diseases or illness. It is then up to individual clinical investigator to decide which toxicities are due to elraglusib.
The most common TEAEs attributed to elraglusib were transient visual disturbance and fatigue across both study parts, and the majority
of TEAEs that occurred in ≥ 20% of patients were reported as Grade 1 or 2 (Figure 11). Visual disturbance affected 66.5% of patients
(n=103/155) receiving elraglusib plus GnP and 9.0% of patients (n=7/78) receiving GnP alone. Commonly reported symptoms were darkened
vision, where patients described lights as brighter and skin tones darker. Greater than 99% of visual disturbance cases were reported
as mild or moderate (Grade 1 or 2). These visual disturbances were considered dose-dependent, occurring more frequently and lasting longer
at higher doses. All cases of visual disturbance were transient, resolved completely, and lacked any associated retinal, ocular, or systemic
toxicity. Fatigue, while also observed in ≥ 20% of patients, was also reported as mild or moderate (Grade 1 or 2) and did not interfere
with daily life.
Some of the key findings from the interim safety analysis
as of November 15, 2024 include:
o No permanent changes to eye structure or vision.
Figure 11 below is a summary of
TEAEs of any grade reported in >20% of patients treated with elraglusib as of November 15, 2024 in Actuate 1801 Part 3B (trial
ongoing).
Patients, n (%)
Adverse event Elraglusib + GnP (n=155) GnP (n=78)
Any Grade Grade ≥3 Any Grade Grade ≥3
TEAEs of any Grade in 320% of Patients
Figure 11:Actuate 1801