ACTUATE THERAPEUTICS, INC. 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, 2025
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
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. YesýNo ☐
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 (§ 229.405 of this chapter) during the preceding 12 months (or for such shorter period that the registrant
was required to submit such files). YesýNo
☐
Indicate by check
mark whether the registrant is a large accelerated filer, an accelerated filer, a non-accelerated filer, 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 ý Smaller reporting company ý
Emerging growth company ý
If
an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying
with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. ☐
Indicate by check
mark whether the registrant has filed a report on and attestation to its management’s assessment of the effectiveness of its internal
control over financial reporting under Section 404(b) of the Sarbanes-Oxley Act (15 U.S.C. 7262(b)) by the registered public accounting
firm that prepared or issued its audit report. ☐
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 Exchange Act). Yes ☐ No ý
Aggregate market
value of registrant’s common stock held by non-affiliates of the registrant on June 30, 2025, the last business day of the registrant’s
most recently completed second fiscal quarter, based upon the closing price of the registrant’s common stock on such date as reported
by Nasdaq Global Market, was approximately $42.1 million. Shares of common stock held by each officer and director and by each person
who is known to own 10% or more of the outstanding common stock have been excluded in that such persons may be deemed to be affiliates
of the registrant. This determination of affiliate status is not necessarily a conclusive determination for other purposes.
The number of shares of registrant’s
common stock outstanding as of March 25, 2026 was 23,709,943.
DOCUMENTS INCORPORATED BY REFERENCE
The registrant intends
to file a definitive proxy statement pursuant to Regulation 14A within 120 days after the end of the fiscal year ended December 31, 2025.
Portions of such proxy statement are incorporated by reference into Part III of this Annual Report on Form 10-K.
Table of Contents
Page
PART I
Item 1. Business 1
Item 1A. Risk Factors 35
Item 1B. Unresolved Staff Comments 65
Item 1C. Cybersecurity 65
Item 2. Properties 66
Item 3. Legal Proceedings 66
Item 4. Mine Safety Disclosures 66
PART II
Item 6. [Reserved] 68
Item 7A. Quantitative and Qualitative Disclosures About Market Risk 79
Item 8. Financial Statements and Supplementary Data 79
Item 9A. Controls and Procedures 79
Item 9B. Other Information 80
Item 9C. Disclosure Regarding Foreign Jurisdictions that Prevent Inspections 80
PART III
Item 10. Directors, Executive Officers and Corporate Governance 81
Item 11. Executive Compensation 81
Item 14. Principal Accountant Fees and Services 81
PART IV
Item 15. Exhibit and Financial Statement Schedules 82
SIGNATURES 84
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” within the meaning of Section
27A of the Securities Act of 1933, as amended (the "Securities Act") and Section 21E of the Securities Exchange Act of 1934,
as amended (the "Exchange Act") about us and our industry. 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. The forward-looking statements in
this Report include, but are not limited to, statements concerning the following:
· our future financial and operating results;
· the timing and success of our plan of commercialization.
These forward-looking statements
are subject to a number of risks, uncertainties and assumptions, including those 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
RISK FACTOR SUMMARY
The following is a summary
of the key risks and uncertainties that make an investment in our securities speculative and risky. The summary below does not contain
all of the information that may be important to you, and you should read this summary together with the more detailed description of the
risks set forth under "Item 1A. Risk Factors" of this Annual Report.
Risks Related to Our Limited Operating History,
Financial Condition and Capital Requirements
Risks Related to the Development and Commercialization
of Our Product Candidates
Risks Related to Our Reliance on Third Parties
iii
Risks Related to Our Intellectual Property
Risks Related to Our Business Operations and
Industry
Risks Related to our Common Stock
iv
PART I
Item 1.Business.
Overview
Class-Leading GSK-3β Inhibitor
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, 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. 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.
Exclusive Rights
We have exclusively licensed
elraglusib, a proprietary and patent protected GSK-3 inhibitor developed in a collaboration between The Board of Trustees of the University
of Illinois-Chicago (“UIC”) and Northwestern University (“NU”).
Broad Therapeutic Potential
We believe elraglusib represents
a “pipeline in a molecule” with a broad opportunity for us to potentially initiate and advance multiple drug development programs
around our lead asset based on its multimodal mechanisms of action, data emerging from completed or ongoing clinical trials and non-clinical
biological, cellular, and animal data. Animal tumor model data, clinical trial 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.
Figure 1 shows the broad therapeutic
potential of elraglusib where evidence of preclinical and clinical activity has been observed.
Figure 1: GSK-3β inhibitors and elraglusib’s
potential to treat numerous cancer histologies.
Significant Clinical Experience and Promising
Phase 2 Data in mPDAC
To date, we have treated over
500 patients with elraglusib as an IV injection (“Elraglusib Injection”) in Phase 1 and Phase 2 studies.
Our most advanced clinical
indication is first-line metastatic pancreatic ductal adenocarcinoma (“mPDAC”). Our Phase 2 study in mPDAC, known as Actuate-1801
Part 3B study, is a randomized, controlled Phase 2 trial that enrolled 286 patients with no prior systemic treatment for metastatic disease.
The primary endpoint for this study was median overall survival (“mOS”), with overall survival (“OS”) summarized
throughout the study by estimates of 1-year survival. Updated data results presented at the American Society of Clinical Oncology (“ASCO”)
Genitourinary Cancers Symposium (“ASCO GI”) in January 2026 utilizing a data cutoff as of November 22, 2025 showed that the
trial met its primary endpoint, demonstrating a statistically significant improvement in mOS with elraglusib plus gemcitabine/nab-paclitaxel
(“GnP”) versus GnP alone.
Data presented at ASCO GI
included:
Elraglusib Injection Shows Promise in the Treatment
of Pediatric Cancers
In addition to mPDAC, 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 of the trial. 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 and neuroblastoma as new indications for further development of
Elraglusib Injection, further expanding the potential of elraglusib.
Elraglusib Oral Dose Tablet Allows Us to Expand
into New Indications
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, subject to future funding, we are planning a Phase 1 study to identify the maximum tolerated
dose and recommended Phase 2 dose (“RP2D”) for Elraglusib Oral Tablet in adult patients with advanced, refractory cancers.
Once we have determined a RP2D, several Phase 2 studies have been identified for further clinical development of Elraglusib Oral Tablet,
subject to additional funding, based on data from previous studies, including but not limited to, refractory, metastatic melanoma and
refractory, metastatic colorectal cancer, and non-small cell lung cancer.
Pancreatic Cancer Represents a High Unmet Need
with Limited Treatment Options for Patients
According to the American
Cancer Society, the annual incidence of pancreatic cancer is expected to exceed 67,000 patients in the United States in 2026. Pancreatic
ductal adenocarcinoma (“PDAC”) is considered one of the most aggressive malignancies, with approximately 90% of patients presenting
with advanced disease. Despite advances in the treatment therapies over the last 30 years, the 5-year survival rate for Stage IV disease
is less than 5%. The standard of care for first-line treatment of mPDAC generally includes one of the following two chemotherapy regimens:
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.
Our Strategy and 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-3β, including:
Our strategy is to develop
elraglusib for multiple advanced cancer indications with high unmet medical need and significant commercial potential, initially in patients
with metastatic pancreatic cancer, pediatric cancers, and metastatic melanoma, subject to available financing and/or funding from potential
strategic collaborations. 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:
_______________________
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.
Our Solution
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.
Despite advances in the treatment therapies over the last 30 years, the 5-year survival rate for Stage IV mPDAC remains at less than 5%,
representing one of the lowest of any cancer type.
Our Advancing Pipeline
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, and given the potential to administer this
molecule as an IV or oral formulation depending on the cancer type and existing standard of care, we believe that elraglusib represents
a pipeline in a molecule that can be broadly developed if adequate funding is secured. We are focused on advancing trials in mPDAC, Ewing
sarcoma, and neuroblastoma with Elraglusib Injection while also advancing the Elraglusib Oral Tablet in a Phase I trial in advanced solid
tumors. Our ability to advance our ongoing and planned clinical trials listed in Figure 2 will depend on whether we can raise sufficient
capital to support those trials, including potential support from strategic collaborations.
Figure 2: Ongoing and planned clinical trials.
Developing Elraglusib Injection for the Treatment
of mPDAC
Our lead clinical program
is focused on evaluating Elraglusib Injection for the treatment of first-line mPDAC. The Phase 2 trial is a randomized, controlled Phase
2 trial of elraglusib in combination with GnP versus GnP alone in first-line mPDAC. The trial enrolled 286 patients with mPDAC and no
prior systemic treatment for metastatic disease. Patients were randomized 2:1 to the elraglusib/GnP combination arm or the GnP arm, respectively.
This study included a run-in to explore two different dosing schedules of elraglusib/GnP (once weekly versus twice weekly) to evaluate
the potential of moving to a more convenient, commercially viable elraglusib dosing schedule. The Phase 2 trial enrolled its first patient
in October 2021 and the run-in part of the trial demonstrated that the weekly dosing of elraglusib was equivalent to twice weekly dosing
of elraglusib with no meaningful clinical difference in safety or efficacy. After the dose run-in part of the trial, all patients that
were randomized to the elraglusib/GnP arm received weekly elraglusib in addition to GnP. Last patient was enrolled in the first quarter
of 2024.
Key inclusion criteria included
patients that were 18 years or older with metastatic pancreatic adenocarcinoma and no prior therapy with measurable disease as defined
by RECIST1.1.
The primary endpoint for this
study was mOS, with OS summarized throughout the study by estimates of 1-year survival. Secondary endpoints were overall response rates
(“ORR”), median progression-free survival (“mPFS”), disease control rate (“DCR”) and adverse events.
Updated study results were
presented at the ASCO GI conference in January 2026 utilizing a data cutoff of November 22, 2025. Log-rank analysis was used to determine
statistical significance when comparing the two arms of the study. Data presented in the pre-specified safety population showed that the
trial met its primary endpoint of improved mOS in patients in the elraglusib/GnP arm versus the GnP control arm. The analysis of updated
data demonstrated treatment with elraglusib/GnP resulted in statistically significant increases in 1-year survival rate (p-value of 0.0004)
and mOS (10.1 months vs 7.2 months, HR=0.62, log-rank p=0.02) with a 38% reduction in the risk of death versus treatment with GnP alone.
The following table provides
additional Phase 2 study results as of the November 22, 2025 cutoff date:
Safety Population Elraglusib/GnP (n=155) GnP (n=78)
Primary Endpoint: mOS (months) HR=0.62; log-rank p=0.02* 10.1 7.2
_____________________ *statistically significant
In addition, updated data showed there were numerically
improved ORR, mPFS, and DCR in the elraglusib/GnP combination arm versus the GnP arm as noted in the below table.
Safety Population Elraglusib/GnP (n=155) GnP (n=78)
mPFS (months) 5.6 5.1
Figure 3 depicts the interim
Kaplan-Meier estimate for mOS as of November 22, 2025 cutoff and other endpoints in the study, including primary and secondary endpoints
and patients remaining on study for each treatment arm as well as landmark OS endpoints at 18- and 24-months.
Figure 3: Unaudited Phase 2 data of elraglusib
in mPDAC (data as of November 22, 2025 cutoff).
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.
Treatment-emergent adverse
events (“TEAEs”) and Serious Adverse Events (“SAEs”) in the elraglusib/GnP combination arm were similar to those
observed in the GnP arm, indicating a favorable risk-benefit profile for the elraglusib/GnP combination. 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 the 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 4). Visual disturbance
affected 68.4% of patients (n=106/155) receiving elraglusib/GnP and 9.0% of patients (n=7/78) receiving GnP alone. Commonly reported
symptoms were darkened vision, where patients described lights visually appearing brighter and skin tones visually appearing darker.
Greater than 99% of visual disturbance cases were reported as mild or moderate (Grade 1 or 2). 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.
Figure 4 below is a summary
of TEAEs of any grade reported in ≥20% of patients treated with elraglusib/GnP versus GnP alone as of November 22, 2025 data cutoff.
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 4:TEAEs
of Any Grade Reported in ≥20% of Patients Treated.
Additional updated data
as of November 22, 2025 are shown in Figures 5 and 6. 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
additional details regarding the demographics and disease history of the enrolled patient population in each arm of the study.
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 5:Patient demographics and disease history
as of November 22, 2025 cutoff.
Figure 6 below is a
graphical representation of survival (“mOS Swim Plot’”) of each patient enrolled in the Phase 2 study in the
elraglusib/GnP arm versus the GnP control arm.
Figure
6: mOS Swim Plot as of November 22, 2025.
During the first half of 2026,
we plan to meet with the FDA and EMA to discuss the design and execution of a Phase 3 global registration study to support potential
product registration.
Elraglusib Injection for the Treatment of Pediatric
Cancers
Elraglusib Injection is also
being evaluated in pediatric cancer patients with recurrent/refractory solid cancers. The Actuate-1902 study was an open-label, multicenter
Phase 1/2 study evaluating the safety and efficacy of elraglusib in 40 pediatric patients ages 3 – 21 with relapsed (>2 remissions)/refractory
cancers, including EWS, neuroblastoma, Central Nervous System (“CNS”) tumors, non-EWS sarcomas, and other refractory pediatric
malignancies. This trial evaluated escalating doses of elraglusib as a single agent as well as in combination with irinotecan or cyclophosphamide/topotecan
in the Phase 1 portion of the trial. The Phase 1 dose escalation portion of the trial was designed primarily to determine the maximum
tolerated dose (“MTD”) and/or RP2D of elraglusib as a single agent and in combination with chemotherapy. While an MTD was
not reached, initial evidence of anti-tumor activity was observed, particularly when elraglusib was administered with a standard cyclophosphamide
and topotecan regimen. Two Complete Metabolic Responses (“CMRs”) were observed in patients with relapsed/refractory metastatic
EWS and one Complete Response (“CR”) was observed in a patient with relapsed/refractory metastatic neuroblastoma. The Phase
1 portion of this study was closed in July 2025. Key highlights from the Actuate-1902 study include:
Elraglusib in combination with cyclophosphamide
and topotecan regimen:
Elraglusib in combination with irinotecan regimen:
Based on these data, we identified
Ewing sarcoma and neuroblastoma as new indications for further development of Elraglusib Injection. Given that Ewing sarcoma and neuroblastoma
are very rare pediatric cancer indications, an international consortium of investigators and sites will be needed to advance this program
to registration. In addition, we plan to pursue a number of development incentives in the United States and parallel programs in the EU.
In July 2024, we received ODD from the FDA for elraglusib for the treatment of soft tissue sarcomas in the United States and Orphan Medical
Product Designation from the EMA for the treatment of sarcoma. In October 2024, we received Rare Pediatric Disease Designation (“RPDD”)
from the FDA for the treatment of EWS. The ability to engage in further development in pediatric cancers will depend on our ability to
raise sufficient additional capital to support this path. We believe that pursuing this development could be an efficient and rapid path
to registration in the United States and Marketing Authorization in the EU.
Elraglusib Oral Tablet for the Treatment of
Solid Tumors
We initially developed an
oral liquid that was evaluated for bioavailability in a Phase 1 healthy volunteer study (Actuate-2203) in a single dose cross-over
design such that each subject on the study received IV, oral liquid after fasting and oral liquid with food. Elraglusib oral liquid was
greater than 50% bioavailable when given with food and was very well tolerated by healthy volunteers.
Consequently, we developed several oral tablet prototype formulations that were evaluated for bioavailability in dogs, and an oral tablet
candidate was identified with greater than 95% orally bioavailable when given with food. In the study, the oral drug had an AUC24 (Area
Under the serum Concentration vs. time curve for 0-24 hours) of 77,000 ng•h/mL (nanograms times hours per milliliter) after a single
250 mg oral tablet and 137,000 ng•h/mL after oral administration of 500 mg (2 x 250 mg tablets). We expect that steady state exposures
of 77,000 ng•h/mL or greater will be possible with the Elraglusib Oral Tablet at well-tolerated doses in humans. We believe that
we will be able to administer the Elraglusib Oral Tablet daily, which may allow the drug to achieve steady state levels in plasma in
patients resulting in continuous inhibition of the target GSK-3 in the tumor and tumor-associated cells. Based on the potential for daily
dosing, we believe this will allow for additional opportunities to explore the anti-tumor activity of elraglusib with the oral tablet
that could not be achieved with Elraglusib Injection.
Our lead clinical candidate
tablet, the Elraglusib Oral Tablet, has been selected for further development, and we are planning a Phase 1/2 dose escalation study to
identify the MTD and RP2D for Elraglusib Oral Tablet in adult patients with advanced, refractory cancers, subject to future funding. Once
we have determined a RP2D, 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, and non-small lung cancer.
Investigator-Initiated Trials
In addition to company-sponsored
trials, we have collaborated with a number of investigators through investigator-initiated trials (“IIT”) to evaluate elraglusib
in new indications and with new drug combinations. Two of these IITs will provide exploratory data on the combination of elraglusib and
FOLFIRINOX as a first-line treatment for mPDAC and may provide a rationale for developing elraglusib in combination with FOLFIRINOX or
NALIRIFOX as another first-line treatment for mPDAC. Since either GnP or FOLFIRINOX are currently used to treat the majority of patients
with mPDAC, we believe that elraglusib has the potential to treat a large segment of patients diagnosed with mPDAC.
In August 2025, we supported
commencement of a Phase 1b IIT with UPMC Hillman Cancer Center. The trial is evaluating elraglusib in combination with Incyte’s
PD-1 inhibitor, retifanlimab, and modified FOLFIRINOX (“mFOLFIRINOX”) as front-line therapy in advanced pancreatic adenocarcinoma
in up to 12 patients. This IIT is an open-label, single-arm RiLEY (NCT06896188) trial, led by Anwaar Saeed, MD, Associate Professor of
Medicine, and Chief of the Gastrointestinal Medical Oncology at UPMC Hillman Cancer Center. The primary objective of the trial is to determine
the RP2D for the combination regimen, while the secondary objectives include evaluation of ORR, DCR, mPFS, OS, and assessment of safety
and tolerability. The trial is currently open for enrollment, and four patients have been enrolled as of February 28, 2026.
In February 2022, we supported
commencement of a Phase 2 IIT to determine the safety, tolerability, and progression-free survival of the combination of elraglusib with
FOLFIRINOX and losartan in adults with untreated metastatic pancreatic adenocarcinoma. The IIT is being led by Colin Weekes, MD Ph.D.
at Massachusetts General Hospital and is supported by us and the Lustgarten Foundation. Additional sites participating in the study include
The University of Colorado and the University of Washington’s Fred Hutchinson Cancer Center. This study administers elraglusib by
IV infusion twice weekly in combination with FOLFIRINOX administered once every 14 days and daily losartan in adults with pancreatic
cancer who have not received any prior systemic therapy for advanced disease. A total of 49 patients have been enrolled in the study.
We expect to receive all final data from this study, which is considered exploratory and may inform future development of elraglusib in
2026.
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 2026, and the
majority of these patients will present with metastatic disease. The Pancreatic Cancer Treatment Market Size Report, 2030 by Grand View
Research, estimates the current global market for treating pancreatic cancer was approximately $2.9 billion in 2024 and is expected to
grow to $5.8 billion by 2030 based on the growing aging population and associated rise in lifestyle-related diseases.
Current first-line therapies
for mPDAC consist of GnP, FOLFIRINOX, or irinotecan liposomal injection given with oxaliplatin, fluorouracil, and leucovorin (“NALIRIFOX”).
NALIRIFOX was approved in February 2024 and may provide an alternative to FOLFIRINOX with a somewhat improved safety profile.
We are developing elraglusib
for patients in 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.
A recent review of real-world
clinical trials in Future Oncology 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 believe elraglusib may
improve outcomes in first-line mPDAC regardless of the chemotherapy backbone used by doctors. Patients with mPDAC are often resistant
or become resistant to the first-line chemotherapy backbones currently used to treat them. One of the mechanisms of action of elraglusib
is the ability to enhance chemotherapy activity even in resistant tumors, and we believe this has been demonstrated in multiple animal
tumor models. 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.
Treatment of Pediatric Cancers
EWS is a rare malignancy that
occurs primarily in the bone or in the soft tissue around a bone. The tumor is most common in older children and adolescents, but it can
occur at any age. According to American Cancer Society, Ewing sarcoma accounts for about 1% of all childhood cancers and approximately
200 children and adolescents in the United States are diagnosed annually with EWS. Treatment options include surgery, radiotherapy, chemotherapy,
and tyrosine kinase inhibitors. The response to therapy is dependent on the stage of the tumor. Overall, the 5-year survival rates range
from 81% for patients with localized disease to 41% for patients with metastatic disease. The five-year survival rate for patients who
have recurrent (relapsed) disease is <30% with no known treatment regimens that meaningfully extend life in Ewing sarcoma patients
with metastatic, refractory disease.
Neuroblastoma is a rare cancer
of the early nerve cells, called neuroblasts, that make up the nerves in our bodies. According to American Cancer Society, neuroblastoma
is the most common cancer in infants who are less than 1 year old. There are about 600 to 800 new cases of neuroblastoma each year in
the United States. The 5-year survival rates range from 95% for lower risk patients to 60% for patients with higher risk disease per the
American Cancer Society, and neuroblastoma claims more lives of children under the age of 5 than any other cancer.
The FDA has granted RPDD to
elraglusib for our treatment of EWS and neuroblastoma. 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 or neuroblastoma 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.
About GSK-3β
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.
GSK-3β inhibition 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 multimodal mechanisms of action,
including:
(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”).
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. Inhibition of GSK-3β leads to inhibition of tumor cell proliferation as shown in multiple
tumor model systems using elraglusib. A number of pathways have been implicated in the inhibition of cell proliferation mediated by GSK-3β
inhibitors including MYC, Cyclin D1, TGFα, epidermal growth factor receptor, Ras, PI3K/Akt, and NF-κB. Also, 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. 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. In addition, a number of studies have suggested that the primary mechanism of GSK-3β -mediated apoptosis
is through the NF-κB pathway. 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. 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.
License Agreements
Northwestern University License Agreement
We licensed the exclusive
worldwide rights to materials and non-exclusive rights to certain know-how relating to the use for therapeutic, diagnostic and commercial
research purposes of elraglusib and related compounds in cancer and combination therapies from NU pursuant to that certain royalty-free
license agreement between us and NU dated March 31, 2015, as amended on April 29, 2019 (as amended, the “NU License Agreement”).
Pursuant to the NU License
Agreement, NU granted us (i) a nonexclusive license to certain technical information developed in the laboratory of Dr. Mazar,
and (ii) an exclusive license to all results obtained by Dr. Mazar and his collaborators at NU on the use of the GSK-3β
inhibitor 9-ING-41 and related compounds used for the treatment of cancer and combination therapies. The term of the NU License Agreement
continues in effect until the expiration of the last to expire of patent rights covering 9-ING-41 and related GSK-3 inhibitors (see the
discussion under “Intellectual Property” below for a discussion of our expected patent terms), unless earlier
terminated by NU due to our making a general assignment for the benefit of creditors, initiation of bankruptcy proceedings by or against
us or the appointment of a receiver or trustee to take possession of our property, or by either party following 90 days’ notice
of a material breach of the NU License Agreement that is not then cured. The NU License Agreement terms are subject to the provisions
of the Bayh-Dole Act, including requiring us to substantially manufacture products related to the license in the United States, unless
waived. While the drug substance (“DS”) for elraglusib is manufactured by a supplier in China, the end drug product is substantially
manufactured in the United States.
In consideration of the license
granted by NU, we issued 27,778 shares of our common stock to NU, which represented 5% of our then-outstanding fully-diluted shares and
agreed to customary confidentiality and progress update obligations and to indemnify NU for any claims arising from our use of the licensed
rights under the NU License Agreement.
UIC Exclusive License Agreement with Equity
The exclusive rights to Patent
Rights (as defined in the UIC License Agreement and described further below) and Technical Information (as defined in the UIC License
Agreement) surrounding GSK-3 inhibitors for Neurodegenerative Disorders were licensed through an Exclusive License Agreement with Equity
between us and UIC, dated April 6, 2015, as amended on April 24, 2019 (as amended, the “UIC License Agreement”).
Under the UIC License Agreement, the Patent Rights relate to certain patents relating to 3-Benzofuranyl-4-Indolyl Maleimides, the last
of which is scheduled to expire on March 16, 2028, not including any Patent Term Extension (“PTE”), which we may apply
for under Title II of the Drug Price Competition and Patent Term Restoration Act of 1984 (“Hatch-Waxman”), 35 U.S.C. §156.
The following summarizes the key terms set forth in the UIC License Agreement.
Pursuant to the UIC License
Agreement, UIC granted us (i) an exclusive, nontransferable license, with the right to sublicense under UIC’s rights in the
Patent Rights, and (ii) a non-exclusive, non-transferable license, with the right to sublicense, to use UIC’s rights in the
Technical Information within the specified territory (which is where the Patent Rights exist for such rights and worldwide for the Technical
Information) for all uses other than rights reserved by UIC for non-commercial purposes, including teaching, research and public service
and publishing information included in the Patent Rights and the Technical Information. The term of the UIC License Agreement continues
in effect until the later of (x) expiration of the last to expire of the Patent Rights, (y) notice from us that the use of the
Technical Information has ceased, and (z) the expiration of the last form of market exclusivity for products using the licensed technology.
The UIC License Agreement may also be earlier terminated by UIC in the event of certain breaches of its terms that are not cured following
a notice period or initiation of bankruptcy proceedings by or against us or the imposition of any lien or encumbrance on the licensed
technology. We may also terminate the UIC License Agreement for any reason following 90 days’ notice.
In consideration of the license
granted under the UIC License Agreement, we issued 46,528 shares of our common stock to UIC, which represented 5% of our capital stock
on a fully-diluted basis as defined in the UIC License Agreement, and agreed to pay UIC (i) development milestones of up to $1.25 million,
of which, up to $0.25 million is due upon the progress of clinical trials and $1.0 million is due upon the initiation of commercial
sales (ii) increasing annual minimum royalty payments reaching $50,000 in year six and thereafter, (iii) royalty on net sales
for product covered under the Patent Rights in the low single digits with a 50% reduction in royalties for products solely utilizing Technical
Information, (iv) a declining percentage of sublicensing revenue based on the escalating stage of development upon a sublicensing
event, and (v) the reimbursement of all patent and related expenses incurred by UIC covering the Patent Rights. We also agreed to
customary confidentiality and progress update obligations, to indemnify UIC for any claims arising from our use of the licensed rights
under the UIC License Agreement.
The UIC License Agreement
obligates us or a sublicensee to commercialize the licensed technology, including to achieve the development events specified in the agreement,
including progress through clinical trials and achieving commercialization. UIC may also identify feasible uses of the licensed technology
and, unless we demonstrate that we are pursuing such development or such development is not feasible within a specified period, UIC may
terminate the UIC License Agreement or the exclusivity of the licensed rights. As of the date hereof, we have met all existing milestones
as provided for in the UIC License Agreement. We are also responsible for the prosecution and maintenance of the licensed patents, at
our expense and using commercially reasonable efforts. We have the sole right to enforce the licensed patents, at our expense. The UIC
License Agreement terms are subject to the provisions of the Bayh-Dole Act, including requiring us to substantially manufacture products
related to the license in the United States, unless waived. While the DS for elraglusib is manufactured by a supplier in China, the end
drug product is substantially manufactured in the United States.
In addition, we entered into
a sublicense and collaboration agreement dated August 28, 2017 with an unrelated entity that was covered under the UIC License Agreement,
which sublicense agreement was later terminated on January 31, 2018. Under the UIC License Agreement, the Company owed UIC a certain percentage
of amounts received under the sublicense agreement in the amount of $449,990. The Company paid UIC 10% of the sublicense fees in the amount
of $44,999 and the remaining unpaid balance of $404,991 (“Deferred Amount”) was originally due and payable to UIC in two installments:
50% due and payable on the one-year anniversary from the first commercial sale and 50% due on the second-year anniversary from the first
commercial sale. The Deferred Amount is treated as debt and continues to accrue interest at a rate of five percent (5%) per annum, representing
the prime rate as of the date of the agreement plus 1%, payable annually within 30 days following the second anniversary of the closing
of the IPO and annually thereafter. On July 16, 2024, the Company and UIC entered an amendment to the UIC License Agreement (“UIC
Amendment”). Pursuant to the UIC Amendment, the payment of the Deferred Amount and any accrued interest thereon is due upon the
sooner of (i) termination of the UIC License Agreement by the Company, (ii) the Company ceases development of the licensed UIC technology,
(iii) the Company consummates a Change in Control (as defined in the UIC License Agreement), (iv) the Company sublicenses the licensed
technology or the developed product, (v) the one-year anniversary following approval of a NDA of a licensed product, or (vii) the Company
executes a partnership agreement with any entity resulting in the payment to us above a specified milestone amount or the Company secures
cumulative financing equal to or exceeding $200 million. In addition, the UIC Amendment provides that to the extent the Company secures
equity financing equal to or exceeding $85 million through its IPO or otherwise, 50% of the Deferred Amount is due and payable within
30 days. The remaining 50% of the Deferred Amount shall be due and payable upon the first to occur of any of the events noted above in
clauses (i) through (vii). Finally, the UIC Amendment provides that for as long as the Company or a sublicensee is selling the licensed
product, the Company will pay all consideration provided for in the original UIC License Agreement and described above until the last
to expire market exclusivity date, the period of which for all products in a jurisdiction will not exceed a total of seven (7) years beginning
with the date regulatory approval is granted for the first licensed product in the jurisdiction, and such obligation will survive termination
of the UIC License Agreement.
Collaboration Agreement
We entered into a Collaboration
Agreement with Lantern Pharma in 2021 under which the parties are collaborating on utilization of Lantern Pharma’s platform to develop
novel biomarker-derived signatures for use with our product candidates. As part of the collaboration, Lantern Pharma received 13,889 restricted
shares of our common stock, which vested upon meeting certain conditions of the collaboration, as well as the potential to receive additional
shares if results from the collaboration are utilized in future development efforts. Certain affiliates of the Bios Equity Affiliated
Funds (as defined below), which is our largest stockholder, beneficially owned greater than 10% of Lantern Pharma’s common stock
as of December 31, 2025. Through December 31, 2025, no revenue has been recognized by either party under this agreement.
Intellectual Property
The proprietary nature of,
and protection for, our product candidates and their methods of use and compositions of matter are an important part of our strategy to
develop and commercialize novel medicines, as described in more detail below. Our policy is to file patent applications to protect technology,
inventions and improvements to inventions that are commercially important to the development of our product candidates and our business.
We seek U.S. and foreign patent protection for a variety of technologies. We also intend to seek patent protection or rely upon trade
secret rights to protect other technologies that may be used to discover and validate targets and identify and develop novel products.
We seek protection, in part, through confidentiality and proprietary information agreements. We are a party to various other license agreements
that give us rights to use specific technologies in our research and development.
As of December 31, 2025,
we own or have licensed 119 issued patents and pending patent applications worldwide, including four pending international Patent Cooperation
Treaty (“PCT”) patent applications, which are material to the programs described in this Report. Three of these issued worldwide
patents are owned by UIC, which has granted us exclusive license rights to the technology.
With respect to our elraglusib
program, as of December 31, 2025, we own or exclusively in-license one patent family focused on the elraglusib molecule and/or related
compounds. The exclusively in-licensed patent family for elraglusib and related compounds (the original patent in-licensed from UIC) includes
one granted U.S. patent, one granted European patent (with validation in 5 countries) and one granted Canadian patent, which are directed
to 3-Benzofuranyl-4-Indolyl Maleimides compounds. The U.S. patent is expected to expire in 2028.
Actuate subsequently discovered