Core Viewpoint - Actuate Therapeutics, Inc. plans to conduct an underwritten public offering of its common stock to raise funds for working capital and general corporate purposes [1][2]. Company Overview - Actuate Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on developing therapies for high-impact, difficult-to-treat cancers through the inhibition of glycogen synthase kinase-3 beta (GSK-3β) [1][5]. - The company's lead investigational drug, elraglusib, targets molecular pathways involved in tumor growth and resistance to conventional cancer treatments, potentially enhancing anti-tumor immunity [5]. Offering Details - The company intends to offer shares of its common stock and may grant underwriters a 30-day option to purchase an additional 15% of the shares at the public offering price [1]. - The offering is subject to market conditions, and there is no assurance regarding the completion, size, or terms of the offering [1][6]. - The offering will be made under a shelf registration statement previously filed with the SEC, and a preliminary prospectus supplement has been filed [3].

Financial Performance - The company reported net losses of $27,285,328 and $24,744,620 for the years ended December 31, 2024 and 2023, respectively, and $12,266,429 and $14,868,278 for the six months ended June 30, 2025 and 2024, respectively[113]. - As of June 30, 2025, the company had an accumulated deficit of $144,646,278[113]. - The company has incurred significant operating losses and expects to continue incurring substantial expenses as it develops elraglusib and seeks regulatory approval[113][114]. - Total operating expenses for the three months ended June 30, 2025, were $5,968,877, an increase of $533,428 compared to $5,435,449 in 2024[131]. - Net loss for the three months ended June 30, 2025, was $5,949,405, a decrease of $622,814 compared to a net loss of $6,572,219 in 2024[131]. - For the six months ended June 30, 2025, total operating expenses were $12,334,461, a decrease of $874,242 from $13,208,703 in 2024[137]. - The company reported a net loss of $12,266,429 for the six months ended June 30, 2025, which was offset by non-cash stock-based compensation expense of $2,704,372[154]. - The company anticipates an increase in general and administrative expenses in the future due to operational expansion and increased headcount[126]. Cash Position and Financing - As of June 30, 2025, the company had cash and cash equivalents of $6,492,656, which are expected to be insufficient to meet operational and capital requirements beyond October 2025 without additional capital[117]. - The company entered into a common stock purchase agreement allowing it to sell up to $50 million of newly issued shares over a 36-month period, with net proceeds of $2,148,506 received for 256,429 shares sold under this facility[115]. - The company received net proceeds of $4,621,546 from a private placement of common stock and warrants in June 2025[145]. - The company anticipates that its existing cash and cash equivalents will not satisfy operational and capital requirements beyond October 2025, necessitating additional financing[148][149]. - During the six months ended June 30, 2025, the company provided net cash of $6,643,535 from financing activities, compared to $5,314,270 in the same period of 2024[153]. Clinical Development - The Actuate-1801 trial enrolled 286 patients with metastatic pancreatic ductal adenocarcinoma, showing a median overall survival of 10.1 months for the elraglusib/GnP combination versus 7.2 months for GnP alone, representing a 37% reduction in the risk of death[104][105]. - The 12-month overall survival rate was 44.1% for the elraglusib/GnP group compared to 22.3% for the GnP group, with a p-value of 0.0005 indicating statistical significance[105]. - The company plans to advance the clinical program for elraglusib in Ewing sarcoma towards a Phase 2 study in 2026, subject to funding availability[109]. - The company has developed oral dosage forms of elraglusib and plans to conduct a Phase 1 study to identify the maximum tolerated dose for the Elraglusib Oral Tablet[110]. - The topline data from the Actuate-1801 trial indicated improved overall response rates of 29.0% for elraglusib/GnP compared to 21.8% for GnP alone[107]. - The company is continuing to invest in clinical trials for elraglusib, with costs dependent on the size, number, and length of these trials[151]. Operating Expenses - Research and development expenses decreased by $1,608,000 to $2,764,805 for the three months ended June 30, 2025, primarily due to lower external clinical trial expenses[134]. - General and administrative expenses increased by $2,141,428 to $3,204,072 for the three months ended June 30, 2025, mainly driven by a rise in personnel-related expenses[135]. - Research and development expenses for the six months ended June 30, 2025, were $5,985,124, down $5,248,111 from $11,233,235 in 2024[138]. - General and administrative expenses for the six months ended June 30, 2025, increased by $4,373,869 to $6,349,337, largely due to higher personnel-related expenses[141]. - The company expects stock-based compensation expense to increase in future periods due to continued equity-based awards[165]. Other Financial Information - Interest income for the three months ended June 30, 2025, was $24,534, an increase of $15,889 compared to $8,645 in 2024[131]. - The company recorded a change in estimated fair value of warrant liability of $240,339 for the three months ended June 30, 2024, which is included in other income (expense)[136]. - The company recognized an increase in the fair value of warrant liability of $272,854 for the six months ended June 30, 2024[147]. - The company incurred a loss of $400,000 on the issuance of Related Party Convertible Notes Payable for the six months ended June 30, 2024[147]. - The company currently has no off-balance sheet arrangements as defined by SEC regulations[166]. - The company is classified as an emerging growth company under the JOBS Act, allowing for an extended transition period for new accounting standards[168]. - The company qualifies as a smaller reporting company, enabling it to utilize scaled disclosures as long as certain revenue and stock thresholds are met[169]. - The company is not required to provide quantitative and qualitative disclosures about market risk due to its smaller reporting company status[170].

Core Viewpoint - Actuate Therapeutics has initiated a Phase 1b clinical trial to evaluate the combination of elraglusib, retifanlimab, and modified FOLFIRINOX as a frontline therapy for advanced pancreatic adenocarcinoma, aiming to address unmet medical needs in this challenging cancer type [1][4]. Group 1: Clinical Trial Details - The Phase 1b trial, named RiLEY (NCT06896188), will enroll up to 12 patients initially, with plans for expansion based on interim efficacy results [2]. - The primary objective is to determine the recommended phase 2 dose (RP2D) for the combination regimen, while secondary objectives include evaluating overall response rate (ORR), disease control rate (DCR), median progression-free survival (mPFS), overall survival (OS), and safety [2]. Group 2: Mechanism and Previous Results - The combination therapy is expected to provide a synergistic immune-modulatory approach, enhancing anti-tumor responses by targeting multiple immune checkpoints [3]. - Previous studies indicated that elraglusib combined with gemcitabine/nab-paclitaxel resulted in a significant increase in median overall survival, a 37% reduction in the risk of death, and a doubling of the 12-month survival rate in patients with metastatic pancreatic adenocarcinoma [3]. Group 3: Company Strategy and Future Plans - The collaboration with UPMC Hillman Cancer Center and Incyte aims to explore new synergistic opportunities for patients who have not yet received systemic therapy, enhancing both efficacy and durability of response [4]. - Actuate is also conducting a separate Phase 2 trial (NCT05077800) studying elraglusib in combination with FOLFIRINOX and losartan, with initial data showing promising results in patients with extensive liver metastases [4].

As filed with the Securities and Exchange Commission on July 25, 2025 Registration No. 333- UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 FORM S-1 REGISTRATION STATEMENT UNDER THE SECURITIES ACT OF 1933 Actuate Therapeutics, Inc. (Exact name of registrant as specified in its charter) Delaware 8731 47-3044785 (State or other jurisdiction of incorporation or organization) (Primary Standard Industrial Classification Code Number) (I.R.S. Employer Identification Number) 1751 River Run, ...

Core Insights - Actuate Therapeutics has completed the Phase 1 study of elraglusib in pediatric patients, showing promising results in treating refractory Ewing Sarcoma (EWS) [1][2][3] - The company plans to advance to a Phase 2 trial for elraglusib in children, adolescents, and adults with relapsed/refractory EWS due to the observed complete responses [1][3] Company Overview - Actuate Therapeutics is a clinical-stage biopharmaceutical company focused on developing therapies for high-impact, difficult-to-treat cancers, specifically through the inhibition of glycogen synthase kinase-3 beta (GSK-3β) [1][6] - Elraglusib, the company's lead investigational drug, targets molecular pathways involved in tumor growth and resistance to conventional cancer treatments [6] Clinical Study Details - The Phase 1/2 trial (NCT 04239092), known as Actuate-1902, is an open-label, multicenter study evaluating the safety and efficacy of elraglusib in pediatric patients with relapsed/refractory malignancies, including EWS [2][3] - The study enrolled ten patients with relapsed/refractory EWS, with two patients achieving complete responses and two others showing stable disease [3] Future Plans - The company is planning to initiate a Phase 2 trial in 2026, subject to funding availability, and will engage with regulators to discuss the potential registration path for elraglusib [3][1] - Actuate is collaborating with key opinion leaders and consortiums to ensure the upcoming study design meets patient needs and regulatory expectations [3]

Core Insights - Actuate Therapeutics, Inc. reported significant clinical benefits of elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) for patients with first-line metastatic pancreatic adenocarcinoma, showing a near doubling of 1-year overall survival (OS) and a 43% reduction in risk of death compared to GnP alone [1][2][7] Company Overview - Actuate Therapeutics is a clinical-stage biopharmaceutical company focused on developing therapies for difficult-to-treat cancers, with elraglusib as its lead investigational drug targeting GSK-3β to inhibit tumor growth and enhance anti-tumor immunity [9] Clinical Trial Results - In the Phase 2 trial (Actuate-1801 Part 3B), patients receiving elraglusib plus GnP achieved a median overall survival (mOS) of 12.5 months compared to 8.5 months in the control group, with a disease control rate (DCR) of 53.4% versus 44.8% and an overall response rate (ORR) of 37.9% versus 29.3% [2][5] - Patients with liver metastases experienced a 2.5-fold increase in 1-year OS and a 38% reduction in risk of death, with a survival probability of 13.6% at 18 months for those treated with elraglusib [5][7] Efficacy Metrics - Additional efficacy metrics for patients with liver metastases included a DCR of 36.8% versus 27.9%, an ORR of 29.8% versus 19.7%, and a median progression-free survival (PFS) of 4.9 months compared to 3.9 months in the control group [5][7]

Core Insights - Actuate Therapeutics, Inc. announced promising biomarker data from the Phase 2 trial of elraglusib in combination with gemcitabine/nab-paclitaxel for first-line metastatic pancreatic adenocarcinoma, highlighting the potential for improved patient stratification based on pre-dose plasma biomarkers [1][2][3] Group 1: Study Findings - The analysis of 40 cytokines, chemokines, soluble cell receptors, and growth factors identified 7 significant biomarkers predicting favorable survival in the elraglusib-treated cohort, particularly highlighting CXCL2's unique survival trend [2][3] - Univariate analysis showed that elevated levels of CXCL2 and TRAIL were associated with improved overall survival, while lower levels of CCL3, IL-1α, IL-18, TGF-β, and TRAIL R3 were linked to better survival outcomes [3] - Multivariate machine learning models were developed to accurately predict patients likely to survive over one year when treated with elraglusib and GnP [3] Group 2: Company Strategy and Future Plans - The results support the use of non-invasive blood-based markers to identify patients who may benefit from elraglusib, indicating a significant advancement in the company's biomarker strategy [4] - The company plans to prospectively test the identified biomarkers in future trials and focus on optimizing patient stratification and predictive accuracy through refined machine learning models [4] - Actuate aims to apply this biomarker identification approach to guide the development of elraglusib in metastatic pancreatic cancer and other advanced cancer indications [4] Group 3: Company Overview - Actuate Therapeutics is a clinical-stage biopharmaceutical company focused on developing therapies for difficult-to-treat cancers, with elraglusib as its lead investigational drug targeting pathways involved in tumor growth and resistance to conventional therapies [5] - Elraglusib may also enhance anti-tumor immunity by regulating immune checkpoints and immune cell functions, indicating its potential in cancer treatment [5]

Core Insights - Actuate Therapeutics, Inc. will be added to the Russell 3000® Index and automatically included in the Russell 2000® Index effective after the U.S. market close on June 27, 2025, marking a significant milestone for the company [1][3] - The inclusion reflects the company's strong momentum following positive topline Phase 2 data in metastatic pancreatic ductal adenocarcinoma (mPDAC), demonstrating a clinically meaningful increase in median overall survival (mOS) of 10.1 months compared to 7.2 months, with a 37% reduction in the risk of death [3] Company Overview - Actuate is a clinical-stage biopharmaceutical company focused on developing therapies for high-impact, difficult-to-treat cancers, with its lead investigational drug, elraglusib, targeting molecular pathways involved in tumor growth and resistance to conventional cancer treatments [4] - Elraglusib is a novel glycogen synthase kinase-3 beta (GSK-3β) inhibitor that may also mediate anti-tumor immunity through the regulation of immune checkpoints and immune cell function [4] Industry Context - The Russell 3000® Index tracks the performance of the largest 3,000 publicly traded U.S. companies and serves as a broad benchmark for the U.S. equity market, with approximately $10.6 trillion in assets benchmarked against the Russell U.S. Indexes as of May 2025 [2]

Core Insights - Actuate Therapeutics announced positive topline results from the Phase 2 trial of elraglusib in combination with gemcitabine/nab-paclitaxel for treating metastatic pancreatic ductal adenocarcinoma, indicating a significant improvement in overall survival [1][2][5] Study Results - The study achieved its primary endpoint with a median overall survival of 10.1 months for the elraglusib/GnP group compared to 7.2 months for the GnP group, resulting in a 37% reduction in the risk of death (HR = 0.63) [2][8] - The 12-month survival rate was 44.1% in the elraglusib/GnP arm versus 22.3% in the GnP arm, demonstrating a doubling of survival rates [2][8] - Continued survival benefits were observed at 18 and 24 months, with survival rates of 19.7% vs 4.4% and 13.8% vs 0% for elraglusib/GnP compared to GnP alone, respectively [8] - The overall response rate was numerically improved at 29.0% for the elraglusib/GnP arm compared to 21.8% for the GnP arm [8] Safety Profile - The trial met its primary safety endpoint, with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) in the elraglusib/GnP arm being similar to those in the GnP arm, indicating a favorable risk-benefit profile [8] - Most treatment-related adverse events (TRAEs) were Grade 1-2, with transient visual impairments being the most common [8] Mechanism of Action - Elraglusib works by inhibiting GSK-3β, which may enhance chemotherapy activity, activate anti-tumor immunity, and regulate gene expression, potentially leading to improved survival outcomes [10][11] Clinical Context - The KOL event highlighted the unmet need in mPDAC and the potential of elraglusib to reshape treatment paradigms, emphasizing the importance of new drugs with unique mechanisms [4][5]

Core Insights - Actuate Therapeutics, Inc. presented topline results from the Phase 2 trial of elraglusib in combination with gemcitabine/nab-paclitaxel for treating metastatic pancreatic ductal adenocarcinoma, demonstrating significant improvements in overall survival [1][2][5] Efficacy - The trial met its primary endpoint, showing a median overall survival (mOS) of 10.1 months for the elraglusib combination group compared to 7.2 months for the control group, with a hazard ratio (HR) of 0.63 and a log-rank p-value of 0.01, indicating a 37% reduction in the risk of death [2][4][5] - The 12-month survival rate for patients receiving elraglusib with GnP was 44.1%, which is double that of the GnP alone group at 22.3% [2][5] - Continued survival benefits were observed at 18 and 24 months, with survival rates of 19.7% vs 4.4% and 13.8% vs 0% for the elraglusib/GnP combination versus GnP alone, respectively [10] - The overall response rate was numerically improved at 29.0% for the elraglusib combination compared to 21.8% for GnP alone [10] Safety Profile - The trial met its primary safety endpoint, with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) in the elraglusib combination arm being similar to those in the GnP arm, indicating a favorable risk-benefit profile [10] - Most treatment-related adverse events (TRAEs) were Grade 1-2, with transient visual impairments being the most common [10] - Grade 3 or higher neutropenia was observed, but rates of febrile neutropenia and sepsis were similar across both treatment arms [10] Future Plans - Based on the positive clinical results and manageable safety profile, the company plans to engage with the FDA and EMA in the second half of 2025 to discuss a path towards product registration [3][5] - Actuate will host a Key Opinion Leader (KOL) event to discuss the trial results, featuring prominent experts in the field [8]