FDA Accepts Bezuclastinib NDA for Advanced Systemic Mastocytosis

The FDA has accepted a new drug application (NDA) for the selective KIT D816V inhibitor bezuclastinib for the treatment of adult patients with advanced systemic mastocytosis (AdvSMz), assigning the NDA a Prescription Drug User Fee Act (PDUFA) target action date of June 29, 2027.¹

The NDA is primarily supported by data from the phase 2 APEX trial (NCT04996875) in which treatment with bezuclastinib led to an overall response rate (ORR) of 65% among 68 patients with AdvSM who were able to be evaluated per modified International Working Group–Myeloproliferative Neoplasms Research and Treatment–European Competence Network on Mastocytosis criteria. Of the 68 patients, 57% had a complete response (CR), complete response with incomplete hematologic recovery (CRh), or partial response (PR).^1,2

Across all 81 patients treated in the APEX population the ORR was 81% per pure pathological response criteria, which combines CR, CRh, and PR. The study also showed substantial reductions in objective markers of mast cell burden. Among 80 patients assessed for serum tryptase, 89% experienced a reduction of at least 50%. The same proportion achieved at least a 50% reduction in bone marrow mast cells or clearance of mast cell aggregates. Among 43 patients evaluable for KIT D816V variant allele frequency (VAF), 91% achieved a reduction of at least 50%. Approximately one-third of treated patients had KIT D816V VAF become undetectable.

The treatment was also associated with changes in bone marrow pathology. Improvements were reported in abnormal CD25 and CD30 expression, mast cell morphology, overall bone marrow cellularity, and myelofibrosis. These effects were observed as early as 8 weeks in the pathobiology analyses, while most patients also achieved normalization of serum tryptase.

“With the FDA’s acceptance of our NDA in Advanced Systemic Mastocytosis, we have reached another important regulatory milestone for bezuclastinib and are one step closer to potentially bringing this therapy to patients with AdvSM,” Andrew Robbins, president and chief executive officer, Cogent, stated in a news release.¹ “Together with the NDAs currently under review for NonAdvSM and GIST patients, this milestone further reinforces the potential of bezuclastinib across multiple patient populations with KIT-driven diseases. With an excellent commercial and medical team in place, we are excited and ready for the potential launches later this year.”

At the March 31, 2026, cutoff, the 12-month progression-free survival (PFS) rate was 79%, while the 12-month overall survival (OS) rate was 87%. Median PFS and OS had not yet been reached, indicating that follow-up remained immature for these time-to-event outcomes.

Safety of Bezuclastinib

Bezuclastinib was generally well tolerated in the APEX population, with relatively few patients requiring treatment-related dose reductions or discontinuation. The most frequently reported treatment-related adverse events (TRAEs) were hair color changes and neutropenia, each occurring in 31% of patients, followed by altered taste in 28%, thrombocytopenia in 25%, and increased alanine aminotransferase/aspartate aminotransferase levels in 21%. Most transaminase elevations were low grade, asymptomatic, and reversible.^1,2

Two patients experienced grade 3 transaminase elevations. One discontinued bezuclastinib, while the other continued treatment after a dose reduction.

Earlier APEX Part 1 data provided additional safety information during dose optimization. In that cohort, treatment-related adverse events were reported in 91% of patients, with 44% experiencing grade 3 or higher events.³ The most common events occurring in more than 10% of patients included hair color changes in 34%, increased alanine aminotransferase/aspartate aminotransferase levels in 28%, neutropenia and thrombocytopenia in 25% each, fatigue in 16%, periorbital edema and peripheral edema in 13% each, and dysgeusia in 13%. No treatment-related cognitive impairment, intracranial bleeding, or deaths were reported. Eleven patients, or 34%, required dose reductions and 2 patients, or 6%, discontinued treatment because of TRAEs.

APEX Trial Design

APEX is an open-label, multicenter phase 2 study evaluating bezuclastinib as a single agent in adults with AdvSM, including aggressive systemic mastocytosis, systemic mastocytosis with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). The trial includes patients who previously received systemic therapy as well as treatment-naive patients.^1,2

The study was conducted in multiple parts. Part 1 evaluated different bezuclastinib doses to establish an exposure and dose level for further development. Earlier data from this phase showed that 100 mg twice daily of the original formulation provided favorable exposure, efficacy, and safety characteristics. An optimized formulation was subsequently selected at 150 mg once daily, with pharmacokinetic analyses indicating comparable exposure to the original 100-mg twice-daily regimen.³

In part 2, 81 patients received bezuclastinib at 150 mg once daily. The population included 57 patients with SM-AHN, 11 with aggressive systemic mastocytosis, and 13 with MCL. Sixty-eight patients were evaluable under the mIWG-MRT-ECNM criteria for the primary response endpoint, while all 81 patients were evaluable for the PPR analysis.

Bezuclastinib is also being evaluated across other KIT-driven diseases. The company's NDA for nonadvanced systemic mastocytosis is under FDA review with a PDUFA target action date of December 30, 2026, while an NDA for gastrointestinal stromal tumors has a target action date of November 30, 2026. Cogent has also established expanded access programs for eligible US patients with systemic mastocytosis or gastrointestinal stromal tumors who may benefit from bezuclastinib or bezuclastinib in combination with sunitinib (Sutent).¹

REFERENCES

1. Cogent Biosciences announces FDA acceptance of new drug application (NDA) for bezuclastinib in patients with advanced systemic mastocytosis (AdvSM). News release. Cogent Biosciences, Inc. September 15, 2026. Accessed September 15, 2026. https://tinyurl.com/wmutphvf

2. DeAngelo D, Radia D, George T, et al. Efficacy and safety of bezuclastinib in patients with advanced systemic mastocytosis: results from the Apex study. Presented at: European Hematology Association 2026 Congress; June 11-14, 2026; Stockholm, Sweden.

3. DeAngelo DJ, Gotlib J, Pullarkat V, et al. Apex Part 1: updated assessment of bezuclastinib (CGT9486), a selective KIT D816V tyrosine kinase inhibitor, in patients with advanced systemic mastocytosis (AdvSM). Blood. 2024;144(suppl 1):659. doi:10.1182/blood-2024-193678.