Actuate Therapeutics, Inc. has announced positive interim results from its Phase 2 trial evaluating elraglusib in combination with gemcitabine/nab-paclitaxel (GnP) for the first-line treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). The data, which triggered a pre-specified analysis due to reaching >70% death events in the GnP control arm, demonstrated statistically significant improvements in both one-year survival rate and median overall survival compared to GnP alone.
The combination of elraglusib and GnP resulted in a one-year survival rate of 43.6% compared to 22.5% in the GnP control arm (p=0.002). Furthermore, the median overall survival (mOS) increased to 9.3 months in the elraglusib-GnP arm versus 7.2 months in the GnP arm, with a hazard ratio of 0.63 (p=0.016), indicating a 37% reduction in the risk of death. The treatment also demonstrated encouraging objective response rates (ORR) and disease control rates (DCR) compared to the control arm.
Impact on Survival Rates
The study's findings extend beyond the one-year mark, with 18- and 24-month survival rates also showing a benefit in the elraglusib-GnP combination arm (20.9% and 16.7%, respectively) compared to the GnP arm (0% for both). As of the data cutoff on November 15, 2024, 38% of subjects in the elraglusib-GnP arm were still alive, compared to 19% in the GnP control arm.
Safety Profile
The trial also met its primary safety endpoint, with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) in the elraglusib-GnP combination arm being similar to those observed in the GnP arm. This suggests a favorable risk-benefit profile for the combination therapy.
Clinical Significance
Pancreatic cancer remains one of the most aggressive and lethal cancers, with a five-year survival rate of less than 5% in the US. The current standard of care, gemcitabine and nab-paclitaxel, offers limited benefit, highlighting the urgent need for more effective treatments. These interim results suggest that elraglusib, a novel GSK-3β inhibitor, could potentially improve outcomes for patients with mPDAC.
Daniel Schmitt, President & Chief Executive Officer of Actuate, expressed optimism about the potential of elraglusib, noting its favorable risk-benefit profile and the possibility of improved outcomes for patients with limited treatment alternatives. Actuate plans to engage with the FDA in the first half of 2025 to discuss the topline data and potential next steps, including a proposed Phase 3 registration trial.
Study Design
The Actuate-1801 Part 3B study (NCT03678883) is a randomized, controlled Phase 2 trial of elraglusib with GnP versus GnP alone in first-line mPDAC. The trial enrolled 286 mPDAC patients with no prior systemic treatment for metastatic disease, who were randomized 2:1 to the elraglusib treatment arm (elraglusib + GnP) or the control arm (GnP alone). Elraglusib is administered at a dose of 9.3 mg/kg by IV infusion on Day 1 of each week of a 28-day cycle. The primary endpoint is 1-year survival rate, with mOS as the primary parameter for summarization of survival data at the end of the study. Secondary endpoints include DCR, ORR, PFS, and AE.
Mechanism of Action
Elraglusib inhibits glycogen synthase kinase-3 beta (GSK-3β), a molecular target involved in promoting tumor growth and resistance to conventional cancer drugs. Inhibition of GSK-3β may inhibit tumor growth and improve survival through several complimentary mechanisms that include enhancement of chemotherapy activity, activation of innate anti-tumor immunity and regulation of gene expression, leading to alterations in tumor metabolism and Epithelial-to-Mesenchymal Transition (EMT).
Complete and Partial Responses
Notably, the trial has seen complete and partial responses in patients treated with the elraglusib combination. Two patients with previously inoperable metastatic lesions experienced reductions in target lesions and were referred for successful resection, one of whom achieved a 100% reduction in total tumor burden after surgery. Additionally, there have been 1 Complete Response and 1 Partial Response with 100% reduction in target lesions in the elraglusib GnP combination arm versus 0 in the control arm to date.
Dr. Andrew Mazar, Actuate’s Scientific Co-Founder and Chief Operating Officer, highlighted the consistent evidence of significant clinical benefit and anti-tumor activity in the elraglusib combination arm across multiple endpoints. He also noted that the favorable risk-benefit profile observed to date may provide a treatment option for many patients with metastatic pancreatic cancer who may not tolerate more aggressive and less tolerable chemotherapy approaches.
