Cogent Biosciences Reports Positive Phase 2 APEX Trial Data on Bezuclastinib for Advanced Systemic Mastocytosis

Cogent Biosciences, Inc., a biotechnology company specializing in precision therapies for genetically defined diseases, has reported promising data from Part 1 of its Phase 2 APEX clinical trial. This trial focuses on evaluating the efficacy and safety of bezuclastinib in patients with advanced systemic mastocytosis (AdvSM). These findings were presented at the 66th American Society of Hematology (ASH) Annual Meeting & Exposition, held in San Diego, CA from December 7-10, 2024.

Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, expressed optimism about bezuclastinib’s potential to significantly improve treatment options for AdvSM patients. He highlighted the impressive rapid and deep clinical responses observed, combined with a favorable safety profile that mitigates many of the common side effects associated with current AdvSM treatments.

Andrew Robbins, President and CEO of Cogent Biosciences, emphasized their enthusiasm in sharing these updated clinical data. He noted that the results underscore the potential of bezuclastinib, a highly potent, selective, non-brain penetrant KIT inhibitor, to benefit patients with AdvSM. Robbins also expressed anticipation for completing enrollment in APEX Part 2 and sharing results by mid-2025.

The APEX trial is a global, open-label, multi-center, two-part Phase 2 study evaluating various safety, efficacy, pharmacokinetic, and pharmacodynamic profiles of bezuclastinib. Part 1 involved 32 patients treated at one of four dose levels (50 mg BID, 100 mg BID, 200 mg BID, or 400 mg QD). Cogent announced earlier this year that Part 2 would use an optimized 150 mg QD dose, approximating the exposure of the 100 mg BID dose in Part 1. The median age of participants was 68 years, with a range from 33 to 87 years. The patient cohort included seven individuals with aggressive systemic mastocytosis (ASM), 23 with systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and two with mast cell leukemia (MCL). Five patients had prior avapritinib treatment, and ten had previous midostaurin therapy.

As of October 11, 2024, the data cutoff date, 32 patients were evaluated for clinical activity, with 27 being mIWG-MRT-ECNM evaluable. The clinical activity data revealed a 52% overall response rate (ORR) per mIWG criteria, including an 83% ORR for patients on the 100 mg BID dose. Per pure pathological response (PPR) criteria, an 88% ORR was observed, with a full 100% ORR for those on the 100 mg BID dose. The median time to response was 2.2 months, with the median duration of response and progression-free survival (PFS) yet to be reached. The PFS rate at 24 months was reported at 82%.

Pharmacodynamic data demonstrated significant biomarker improvements related to disease burden. Among evaluated patients, 94% achieved a reduction of 50% or more in serum tryptase levels, with all patients receiving at least two cycles showing this reduction. Additionally, 66% of patients reached serum tryptase levels below 20 ng/mL. A substantial 93% of KITD816V-positive patients achieved a 50% or greater reduction in the KIT D816V variant allele fraction (VAF), and all evaluable patients saw a similar reduction in bone marrow mast cell burden, with 83% achieving complete clearance of mast cell aggregates.

Safety data as of the cutoff date indicated that bezuclastinib maintained a favorable safety and tolerability profile across various doses. Most hematological adverse events were mild and reversible, with no new treatment-related serious adverse events or discontinuations reported since the last update at ASH 2023. One previous case of drug-induced liver injury (DILI) was reassessed as a Grade 4 gamma-glutamyl transferase (GGT) elevation due to underlying medical conditions. Dose reductions were necessary for twelve patients, primarily those on the 400 mg daily dose.

Cogent Biosciences continues to enroll patients for APEX Part 2, with enrollment expected to conclude by Q1 2025 and top-line results anticipated in mid-2025. Additionally, Cogent will present 24-week follow-up data from the SUMMIT trial, a Phase 2 trial evaluating bezuclastinib in patients with Nonadvanced Systemic Mastocytosis (NonAdvSM), at the ASH meeting on December 9, 2024.