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 GSK-3ß, 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-3ß signaling ultimately results in the death of the cancer cells and the regulation of anti-tumor immunity. The enzyme GSK-3ß, a serine/threonine protein kinase, is understood to be an essential positive regulator of nuclear factor kappa B (NF-kB) transcriptional activity. Studies have demonstrated that the inhibition of GSK-3ß decreases cancer cell survival via suppression of the transcriptional activity of its downstream effector NF-kB. In light of these findings, we believe that the inhibition of GSK-3ß may overcome and/or reverse NF-kB-mediated cancer cell survival and chemoresistance to conventional chemotherapeutic drugs in a range of human cancers. Research has also demonstrated that aberrant nuclear GSK-3ß accumulation is limited to cancer cells, making GSK-3ß a potential candidate for specific and targeted cancer therapy. Additionally, GSK-3 regulates the expression of immune modulators such as pro-inflammatory cytokines and checkpoint molecules in tumor and immune cells. We believe blocking GSK-3 in these cells leads to improved immune cell function, which can ultimately result in better, longer clinical responses in patients. Our Lead Product Candidate We have exclusively licensed a portfolio of GSK-3 inhibitors developed in a collaboration between the University of Illinois-Chicago (UIC) and Northwestern University (NU). The lead drug in our portfolio is called elraglusib (9-ING-41), which is being evaluated in a randomized Phase 2 trial in patients with metastatic pancreatic cancer, our most advanced clinical indication to date. 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 in pediatric and adult patients with advanced, refractory cancers. Many of the pathological processes that drive cancer are controlled by GSK-3ß and thus, by targeting GSK-3ß, we are pursuing the development of products designed to intervene in the progression of multiple cancer types. Animal tumor model data and Phase 1/2 clinical data have identified a number of areas of unmet clinical need in cancer where elraglusib may play an interventional role, including pancreatic, colon, lung, breast, renal, ovarian, leukemias and lymphomas, and melanoma, as well as some pediatric cancers including Ewing sarcoma, neuroblastoma and pediatric leukemias. Our lead program, Elraglusib Injection, is an intravenous solution of elraglusib that we are evaluating for the treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). Elraglusib Injection has been evaluated 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 treatment-emergent adverse events (TEAEs) attributed to elraglusib were transient visual disturbance (patients described lights as brighter and skin tones 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. Based on the results of the Phase 1 study, which established 15 mg/kg as the RP2D when combined with chemotherapy, we initiated a single arm Phase 2 study (Actuate-1801 Part 2) 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), but after an analysis conducted following the completion of Stage 1, which showed a median overall survival (mOS) of 15.3 months in the efficacy evaluable (n=29) patient population, we amended and expanded the Stage 2 of the study to a randomized, controlled trial now powered for statistical significance (Actuate-1801 Part 3B) that would allow a comparison of the safety and efficacy of the combination of Elraglusib Injection plus gemcitabine/nab-paclitaxel (GnP) as compared to GnP alone. The primary endpoint for Actuate-1801 Phase 2 is overall survival (OS). Elraglusib is currently being evaluated as a weekly intravenous (IV) infusion in combination with the approved dosing regimen for GnP. This study completed enrollment four months faster than predicted and top line results are expected in the first quarter of 2025. In April 2024, we carried out a preliminary analysis of interim data from Actuate-1801 Part 3B in the pre-specified safety population. This preliminary analysis and overall results may change as the study continues through completion. For this preliminary analysis, we used data based on a cut-off date corresponding to the date when >50% of the patients in the GnP control group had progressed. As of this cut-off date, our preliminary analysis indicates that patients in the (i) GnP control group arm exceeded 50% death events (the outcome measure for survival analysis) at 53.8% and (ii) elraglusib/GnP combination therapy arm were below 50% death events at 34.2%. Based on this interim data, the Kaplan-Meier preliminary analysis demonstrates a mOS of 12.2 months in the elraglusib combination therapy arm versus 7.3 months in the GnP control group arm (HR=0.60; log-rank p=0.012). 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. We were incorporated in Delaware on January 16, 2015, as Apotheca Therapeutics, Inc. and changed our name to Actuate Therapeutics, Inc. on October 1, 2015. Our principal executive offices are located at 1751 River Run, Suite 400, Fort Worth, Texas.
