FDA Receives NDA Submission for Bezuclastinib in Systemic Mastocytosis

The FDA has received a new drug application (NDA) submission for bezuclastinib, a selective type 1 tyrosine kinase inhibitor, for the treatment of patients with nonadvanced systemic mastocytosis, according to a news release from the developer, Cogent Biosciences, Inc.¹

Support for the submission is based on findings from the phase 2 SUMMIT trial (NCT05186753), the results of which were presented at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.²Therein, the trial met all primary and key secondary end points.

Specifically, treatment with bezuclastinib was associated with a significant reduction in mast cell (MC) aggregates by week 24 compared with placebo; from weeks 1 to 24, MC aggregates dropped from 74% to 13% by week 24 in the investigational group vs 78% to 60% in the placebo group. Additionally, a significant difference in the reduction of MC percentage by week 24 was observed with bezuclastinib compared with placebo; from weeks 1 to 24, it dropped from 18% to 5% with bezuclastinib and from 16% to 14% with placebo (P <.0001). Furthermore, a more pronounced reduction was observed in the percentage of spindle shaped MCs by week 24 with bezuclastinib; the week 1 and 24 totals in each arm were 76% and 50% vs 75% and 70%, respectively (P <.0001).

Moreover, patients treated with bezuclastinib saw a greater reduction in the mean percentage of MCs with CD25 or CD30 expression by week 24. Among patients treated with the investigational agent or placebo, the baseline percentages of MCs with CD25 expression were 89% vs 87%, and the week 24 percentages were 23% vs 93%. The baseline percentages of MCs with CD30 expression dropped from 13% at baseline to 3% at 24 weeks with bezuclastinib, and from baseline to week 24 in the placebo arm, they increased from 12% to 16%.

The overall response rate (ORR) among patients evaluable for exploratory pure pathologic response (PPR) by 24 weeks of treatment was 91% in the bezuclastinib group—including 67% of patients experiencing a complete remission—and 0% in the placebo group. Additionally, 55% of patients treated with bezuclastinib no longer met the WHO diagnostic criteria at 24 weeks of treatment vs 4% of the placebo group.

“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 tumors (GIST)]. Building on the exceptional results from the SUMMIT trial, this filing moves us closer to delivering an important disease-modifying therapy to patients with [nonadvanced systemic mastocytosis],” Andrew Robbins, president and chief executive officer of Cogent, stated in the news release.¹ “We extend our deep appreciation to the patients, families, clinicians, collaborators, and our Cogent team, who all helped make this possible.”

Patients with indolent or smoldering systemic mastocytosis or bone marrow mastocytosis based on WHO 2022 classification with inadequate symptom control were enrolled and randomly assigned 2:1 to receive best standard care plus bezuclastinib at 100 mg daily or placebo for a 24-week double-blind treatment period. In each respective arm, 62.2% vs 73.3% of patients were female, 81.5% vs 83.3% had indolent histology, and 55.0% in each had grade 1 myelofibrosis.

The primary end point of the trial was mean change from baseline to week 24 in mastocytosis symptom severity score. Key secondary end points included mean changes in serum tryptase, KIT p.D816V VAF, bone marrow MC burden, and total symptom score from baseline to week 24.

Updated data through 48 weeks of the SUMMIT trial displayed a continued deepening of symptomatic improvement. According to the developers, the favorable safety profile of bezuclastinib in this group supports its potential use among patients with chronic nonadvanced systemic mastocytosis.

In October 2025, the FDA granted breakthrough therapy designation to bezuclastinib in patients with smoldering systemic mastocytosis and those with nonadvanced systemic mastocytosis previously treated with avapritinib (Ayvakit).

References

1. 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, 2026. https://tinyurl.com/3htvw4n9
2. Rein L, Boggs N, Bose 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