8-K: Actuate Therapeutics Reports Positive Phase 2 Elraglusib Data in Metastatic Pancreatic Cancer, Doubling One-Year Survival

Actuate Therapeutics announced compelling topline Phase 2 results for elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) for first-line metastatic pancreatic cancer, demonstrating a statistically significant improvement in median overall survival and a doubling of the one-year survival rate.

Summary

• Actuate Therapeutics presented topline Phase 2 (Actuate-1801 Part 3B) data for elraglusib combined with gemcitabine/nab-paclitaxel (GnP) in first-line metastatic pancreatic cancer (mPDAC) at the ASCO 2025 Annual Meeting.
• The trial met its primary endpoint, showing a statistically significant increase in median overall survival (mOS) to 10.1 months for the elraglusib/GnP arm compared to 7.2 months for GnP alone (HR=0.63, log-rank p=0.01), representing a 37% reduction in the risk of death.
• The 12-month overall survival rate for the elraglusib/GnP combination was 44.1%, more than double the 22.3% observed with GnP alone (p=0.0005).
• Survival benefits continued at 18 and 24 months, with rates of 19.7% vs 4.4% and 13.8% vs 0% respectively, for the elraglusib/GnP combination versus GnP alone.
• Numerically improved overall response rates (ORR) of 29.0% vs 21.8%, median progression-free survival (PFS) of 5.6 months vs 5.1 months, and disease control rates (DCR) of 61.3% vs 56.4% were observed in the combination arm.
• The trial also met its primary safety endpoint, with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) in the elraglusib/GnP arm being similar to the GnP arm, indicating a favorable risk-benefit profile.
• Most frequent treatment-related adverse events (TRAEs) were transient visual impairments (Grade 1-2), which were reversible and non-progressive.
• Subgroup analysis showed significant OS benefits for patients treated for one cycle (mOS 12.5 months vs 8.5 months, HR=0.57, p=0.018) and for patients with liver metastases (mOS 8.3 months vs 6.6 months, HR=0.62, p=0.008).
• Exploratory biomarker analysis confirmed elraglusib's proposed immune modulating mechanism of action, showing increased CD8-positive and granzyme B-positive T cells, increased NK cells, and decreased myeloid-derived suppressor cells in tumor biopsies from elraglusib-treated patients.
• The company plans to engage with the FDA and EMA in the second half of 2025 to discuss a path towards product registration.
• Actuate's financial condition raises substantial doubt about its ability to continue as a going concern, requiring additional capital beyond Q2 2025.

Sentiment

Score: 7

Explanation: The clinical trial results are highly positive and represent a significant advancement in a difficult-to-treat cancer, indicating strong therapeutic potential. However, the explicit disclosure of substantial doubt regarding the company's ability to continue as a going concern due to immediate capital needs introduces a significant financial risk, tempering the overall positive sentiment.

Positives

• Elraglusib/GnP combination achieved a statistically significant increase in median overall survival (mOS) to 10.1 months, a 37% reduction in the risk of death compared to GnP alone (7.2 months).
• The 12-month overall survival rate for elraglusib/GnP was 44.1%, doubling the 22.3% seen with GnP alone, demonstrating a clinically meaningful advance.
• Survival benefits extended to 18 months (19.7% vs 4.4%) and 24 months (13.8% vs 0%) for the combination arm.
• The treatment showed a favorable risk-benefit profile, with a safety profile similar to GnP alone and mostly mild-to-moderate, reversible adverse events.
• Significant overall survival benefits were observed in key subgroups, including patients treated for at least one cycle and those with liver metastases.
• Exploratory biomarker data supports elraglusib's immune-modulating mechanism of action, indicating a potential for broader applicability.
• The company plans to engage with regulatory bodies (FDA, EMA) in 2H 2025 to discuss a path to registration, indicating progress towards commercialization.

Negatives

• The company's financial condition raises substantial doubt about its ability to continue as a going concern.
• Actuate requires additional capital to finance its operations beyond the second quarter of fiscal year 2025.
• Failure to obtain necessary capital in the near term could force delays, reductions, or termination of development programs and commercialization efforts.
• Preliminary and unaudited data are subject to change upon full data analysis.

Risks

• Preliminary and unpublished data may be subject to change and further interpretation.
• Clinical trial data are subject to differing interpretations and assessments by regulatory authorities and the medical community.
• Clinical and preclinical drug development is a lengthy and expensive process with uncertain timelines and outcomes.
• Results of prior preclinical studies and early clinical trials are not necessarily predictive of future results.
• Elraglusib may not achieve positive clinical results or favorable preclinical results.
• The company may not be able to make regulatory submissions or receive regulatory approval on a timely basis, if at all.
• The company may not successfully enroll additional patients or establish or advance plans for further development, including through conversations with the FDA or EMA.
• Elraglusib could be associated with side effects, adverse events, or other properties or safety risks, which could delay or preclude regulatory approval, cause suspension or discontinuation of clinical trials, or result in other negative consequences.
• Reliance on third parties to conduct non-clinical studies and clinical trials.
• Reliance on third-party licensors and ability to preserve and protect intellectual property rights.
• Significant competition from other biotechnology and pharmaceutical companies.
• The company's financial condition raises substantial doubt as to its ability to continue as a going concern.
• Failure to obtain necessary additional capital in the near term on acceptable terms, or at all, could force the company to delay, limit, reduce, or terminate development programs, commercialization efforts, or other operations.
• High risk of never generating revenue or becoming profitable, or sustaining profitability if achieved.
• Business is highly dependent upon receiving approvals from various U.S. and international governmental agencies.
• The company currently depends entirely on the success of elraglusib, its only product candidate.
• The company may not be successful in efforts to investigate elraglusib in additional indications.
• Termination of third-party licenses could adversely affect rights to important compounds or technologies.

Future Outlook

Actuate Therapeutics plans to request a pre-NDA meeting with the FDA and engage with the EMA in the second half of 2025 to align on a path towards product registration for elraglusib in mPDAC. The company also intends to initiate planning for a Phase 3 or Confirmatory Trial in the second half of 2025, contingent on future funding. Rolling/RTOR NDA submission and DO3 IND submission are anticipated in 2026.

Management Comments

• Dr. Deva Mahalingam, MD, PhD, Northwestern University Feinberg School of Medicine, and lead principal investigator of the 1801 Part 3B trial commented: 'Pancreatic cancer continues to represent one of the highest unmet medical needs with no major treatment advances in recent years, bar some molecular targets in small subsets of patients. New mechanisms of action are urgently needed. The addition of elraglusib to the existing chemotherapy backbone of gemcitabine and nab-paclitaxel is promising and may represent a meaningful therapeutic advance for patients with pancreatic cancer.'
• Daniel Schmitt, President & Chief Executive Officer of Actuate added: 'We significantly improved mOS, cut the risk of death by 37%, and doubled the 12-month survival rate. Combined with a manageable safety profile and strong emerging mechanistic insights, these results reinforce the transformative potential of our GSK-3 inhibitor program. Based on the clear clinical benefit and well-tolerated safety profile, we intend to engage with the FDA and EMA in the second half of this year to align on a path to registration. We believe this enables us to move rapidly towards commercialization and delivery of this first-in-class therapy to patients with an urgent unmet need.'

Industry Context

Metastatic pancreatic cancer (mPDAC) remains a highly aggressive disease with a poor prognosis, characterized by a 5-year survival rate of less than 10% and median overall survival typically under one year with current standard treatments like FOLFIRINOX and gemcitabine with nab-paclitaxel (GnP). The market for pancreatic cancer treatments is projected to exceed $5 billion by 2030, highlighting the urgent unmet medical need for more effective therapies. Elraglusib's novel multimodal mechanism of action as a GSK-3 inhibitor, impacting tumor progression, immune evasion, and chemotherapy resistance, positions it as a potentially significant advancement in this challenging therapeutic area.

Comparison to Industry Standards

• Actuate's elraglusib/GnP combination achieved a median overall survival (mOS) of 10.1 months, which is significantly better than the 7.2 months observed in the control GnP arm of their trial.
• Compared to historical data for GnP alone, such as the MPACT study (Von Hoff et al. 2013) which reported an mOS of 8.5 months for GnP, Actuate's 10.1 months mOS for the combination arm represents a notable improvement.
• The 12-month overall survival rate of 44.1% for elraglusib/GnP is substantially higher than the 22.3% for GnP alone in Actuate's trial, and also surpasses the 35.0% 1-year OS reported for GnP in the MPACT study.
• While the NAPOLI-3 study (Wainberg et al., 2024) showed NALIRIFOX achieving an mOS of 11.1 months compared to GnP's 9.2 months, elraglusib's 10.1 months mOS demonstrates a competitive efficacy profile when added to GnP, particularly given the significant improvement over GnP alone.
• Real-world reviews, such as Cockrum et al. (2025), indicate mOS for GnP typically ranges from 6.9 months, further underscoring the clinical benefit demonstrated by elraglusib's addition.

Stakeholder Impact

• **Shareholders**: Positive clinical data could increase share price, but significant financial risk due to capital needs could lead to dilution or solvency concerns.
• **Patients**: Potential for a new, more effective treatment option for metastatic pancreatic cancer, a disease with high unmet needs.
• **Employees**: Continued employment and potential growth if capital is secured and development progresses, but uncertainty due to financial condition.
• **Creditors**: Increased risk due to the 'going concern' warning and need for additional capital.
• **Suppliers/Partners**: Continued engagement and potential for future collaborations if the company secures funding and advances towards commercialization.

Next Steps

• Request a Type B pre-NDA meeting with the FDA in 2H 2025 to align on a path towards product registration.
• Engage with the EMA in 2H 2025 to discuss a path to registration.
• Initiate planning for a Phase 3 or Confirmatory Trial in 2H 2025 (contingent upon future funding).
• Start Rolling / RTOR NDA (P2 Data) in 2026 (contingent on future discussions with the FDA and future funding).
• Submit DO3 IND in 2026.

Key Dates

Recommendation

Keywords

Actuate Therapeutics, elraglusib, pancreatic cancer, mPDAC, Phase 2 clinical trial, overall survival, GSK-3 inhibitor, oncology, biopharmaceutical, clinical-stage, cancer treatment, ASCO, FDA, EMA, drug development