A new drug application (NDA) has been submitted to the FDA seeking the approval of bezuclastinib (CGT0486) for the treatment of patients with non-advanced systemic mastocytosis.1
NDA Submission of Bezuclastinib for Non-Advanced Systemic Mastocytosis : Highlights
- An NDA for bezuclastinib has been submitted to the FDA for the treatment of non-advanced systemic mastocytosis following positive results from the SUMMIT trial.
- The SUMMIT trial achieved its primary end point by demonstrating that patients treated with bezuclastinib experienced a statistically significant reduction in TSS compared with those receiving placebo.
- Bezuclastinib showed high efficacy in reducing key biological markers of the disease, with 95.4% of evaluable patients achieving at least a 50% reduction in serum tryptase levels.
This NDA submission was based on findings from the phase 2 SUMMIT trial (NCT05186753). Data presented at the 2025 ASH Annual Meeting showed statistically significant improvements with bezuclastinib vs placebo across several symptom domains. The trial achieved its primary end point, demonstrating a significantly higher mean change in total symptom score (TSS) at week 24 with bezuclastinib, at –24.32 (95% CI, –27.56 to –21.08) vs –15.41 (95% CI, –19.58 to –11.24) with placebo (difference, –8.91; 95% CI, –13.56 to –4.26; P < .001).2 Significantly greater proportions of patients in the bezuclastinib arm achieved reductions in TSS of at least 30% (65.4%) and at least 50% (34.3%) compared with 38.6% (P < .001) and 18.1% (P = 01), respectively, among patients in the placebo arm.
“This NDA is the first of 3 planned submissions for bezuclastinib based on positive clinical data from 3 pivotal trials completed in 2025 for patients with systemic mastocytosis and gastrointestinal stromal tumor,” Andrew Robbins, president and chief executive officer of Cogent Biosciences, the developer of bezuclastinib, stated in a news release.1 “Building on the exceptional results from the SUMMIT trial, this filing moves us closer to delivering an important disease-modifying therapy to patients with non-advanced systemic mastocytosis. We extend our deep appreciation to the patients, families, clinicians, collaborators, and our Cogent team, who all helped make this possible.”
Previously, in October 2025, the FDA granted breakthrough therapy designation to bezuclastinib for the treatment of patients with smoldering systemic mastocytosis, as well as for those with non-advanced systemic mastocytosis who have previously been treated with avapritinib (Ayvakit).
What was the design of the SUMMIT trial?
SUMMIT enrolled patients with indolent systemic mastocytosis, bone marrow mastocytosis, or smoldering systemic mastocytosis based on World Health Organization 2022 classification who had inadequate symptom control (defined as moderate-to-severe symptoms) despite receiving at least 2 anti-mediator therapies.2 Part 1 was a dose-optimization portion consisting of a 12-week double-blind treatment period to determine the recommended dose of bezuclastinib.
Part 2 was an expansion portion to determine the efficacy of bezuclastinib at the selected dose from part 1. In part 2, 179 patients were randomly assigned 2:1 to receive bezuclastinib at 100 mg daily plus best supportive care (BSC; n = 119) or placebo plus BSC (n = 60) for a double-blind treatment period of 24 weeks. The primary end point of part 2 was mean change from baseline in mastocytosis symptom severity daily diary (MS2D2) TSS. Key secondary end points included at least 50% reductions in serum tryptase levels, KIT p.D816V variant allele frequency (VAF), bone marrow mast cell burden, and MS2D2 TSS; as well as at least a 30% reduction in TSS.
What additional findings were seen with bezuclastinib in the SUMMIT trial?
Among evaluable patients, 95.4% of those in the bezuclastinib arm (n = 109) reached at least a 50% reduction in serum tryptase levels at 24 weeks vs 0% of those in the placebo arm (n = 57; P < .0001). Additionally, 88.2% of evaluable patients in the bezuclastinib arm (n = 102) achieved at least a 50% reduction in bone marrow mast cell burden vs 25.5% of those in the placebo arm (n = 60). Furthermore, a significant reduction in KIT p.D816V VAF was seen with bezuclastinib vs placebo at 24 weeks, at 85.7% (n = 78/91) vs 0% (n = 0/48), respectively.
References
- Cogent Biosciences announces submission of new drug application for bezuclastinib in nonadvanced systemic mastocytosis. News release. Cogent Biosciences, Inc. December 30, 2025. Accessed January 2, 2025. https://investors.cogentbio.com/news-releases/news-release-details/cogent-biosciences-announces-submission-new-drug-application
- Rein L, Boggs N, Rose P, et al. Efficacy and safety results from the primary analysis of the pivotal summit trial: bezuclastinib in adults with non-advanced systemic mastocytosis. Blood. 2025;146(suppl 1):80. doi:10.1182/blood-2025-80
