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FDA Accepts NDA for Bezuclastinib in Non-Advanced Systemic Mastocytosis
The FDA has set a PDUFA date of December 30, 2026.
Cogent Biosciences announced March 16 that the United States Food and Drug Administration (US FDA) has accepted its new drug application (NDA) for bezuclastinib in adults with non-advanced systemic mastocytosis (NonAdvSM) and set a PDUFA target action date of December 30, 2026.1 The agency communicated that it does not plan to hold an advisory committee meeting and has not identified any potential review issues. The acceptance marks the first potential therapy specifically targeting the KIT D816V mutation in this population.
The NDA is supported by results from the pivotal SUMMIT trial (NCT05186753), in which bezuclastinib met its primary endpoint and all key secondary endpoints with statistical significance.2 Extended 48-week data presented at the 2026 American Academy of Allergy, Asthma & Immunology (AAAAI) annual meeting show continued deepening of benefit across all symptom domains and across biomarker endpoints.3
Background: NonAdvSM and KIT D816V
Systemic mastocytosis encompasses a spectrum of subtypes defined by neoplastic mast cell infiltration of tissues and pathologic mast cell mediator release. Non-advanced subtypes — indolent SM (ISM), smoldering SM (SSM), and bone marrow mastocytosis (BMM) — are the most prevalent forms and are distinguished from advanced SM by the absence of an associated hematologic neoplasm or mast cell leukemia.1
The gain-of-function somatic KIT p.D816V mutation drives pathology in up to 95% of SM patients and is the primary therapeutic target for kinase inhibitor development in this space. Bezuclastinib (CGT9486) is an oral, potent, selective type 1 tyrosine kinase inhibitor with activity specifically against KIT D816V. Its type 1 binding conformation targets the active kinase state, differentiating it mechanistically from avapritinib, the only currently approved KIT D816V inhibitor, which is indicated for advanced SM only.
Despite its substantial symptom burden — which can include flushing, urticaria pigmentosa, anaphylaxis, bone pain, and gastrointestinal and neurocognitive manifestations — NonAdvSM has no approved therapy targeting the underlying mutation.
SUMMIT Trial
SUMMIT is a multicenter, randomized, double-blind, placebo-controlled phase 2 trial in adults with NonAdvSM and inadequate symptom control on best supportive care (BSC).1 Patients were randomized 2:1 to bezuclastinib 100 mg once daily plus BSC or placebo plus BSC, with the dose established from SUMMIT Part 1. As of the May 22, 2025 data cutoff, 179 patients were enrolled: 119 to bezuclastinib and 60 to placebo.
The primary endpoint was 24-week mean change from baseline in the Mastocytosis Symptom Severity Daily Diary (MS2D2) total symptom score (TSS; range 0–110), a fit-for-purpose patient-reported outcome tool. Key secondary endpoints included proportions achieving ≥50% reductions in serum tryptase, KIT p.D816V variant allele frequency (VAF), bone marrow mast cell burden, and MS2D2 TSS, as well as ≥30% TSS reduction.
The enrolled population was representative of the real-world NonAdvSM population: median age 51 years (range, 23–78); 65.9% female; mean baseline MS2D2 TSS 55.6. By subtype, 82% had ISM, 11% BMM, and 7% SSM. Median baseline serum tryptase was 40 ng/mL.2
24-Week Efficacy Results
Bezuclastinib demonstrated statistically significant superiority over placebo on the primary endpoint and all key secondary endpoints.2
MS2D2 TSS change at week 24: LS mean –24.3 points (95% CI, –27.6 to –21.1) with bezuclastinib vs –15.4 points (95% CI, –19.6 to –11.2) with placebo; placebo-adjusted difference of –8.9 points (P =.0002).2
Serum tryptase ≥50% reduction: 87.4% of bezuclastinib patients vs 0% placebo (P <.0001).2
KIT D816V VAF ≥50% reduction, bone marrow mast cell ≥50% reduction, MS2D2 TSS ≥50% and ≥30% reductions: All significantly favored bezuclastinib vs placebo (P <.0001 for VAF, tryptase, and BM burden; P =.01 for TSS ≥50% reduction; P =.0004 for TSS ≥30% reduction).2
Deepening Responses in 48-Week Data
Extended data presented at AAAAI 2026 demonstrate continued and deepening improvement through 48 weeks across all 13 MS2D2 symptom domains, with mean changes from the baseline score of 8.1 observed for itching (–5.2), flushing (–5.1), skin papules (–5.2), fatigue (–6.0), cognitive concentration (–7.3), memory (–5.7), nausea (–5.5), abdominal pain (–3.3), headache (–4.3), bone pain (–4.0), diarrhea (–5.6), brain fog (–3.0), and dizziness (–3.4) — each representing further improvement beyond the 24-week timepoint.3
By week 48, 86% of bezuclastinib-treated patients (81/94) achieved a ≥30% reduction in MS2D2 TSS, and 56.4% (53/94) achieved ≥50% reduction.3
Biomarker deepening was also pronounced. Serum tryptase ≥50% reduction was achieved in 98.9% of bezuclastinib patients (88/89) at week 48. Among patients who had crossed over from placebo, 96.1% (49/51) achieved the same threshold, with median serum tryptase of 5.8 ng/mL. In the bezuclastinib arm, median tryptase fell to 4.7 ng/mL; 91.7% (66/72) fell below 20 ng/mL and 83.3% (70/84) fell below 11.4 ng/mL. KIT p.D816V VAF in peripheral blood fell to a median of 0.04% in bezuclastinib-treated patients vs 0.07% in placebo crossovers, with 98.4% (61/62) of the ITT population achieving ≥50% VAF reduction.3
"These interviews were conducted before they were enrolled in the trial, and they focused on different domains, like skin, gastrointestinal, neurocognitive domains and there are some sentences taken directly from the patient interview that kind of tells you the impact of these patients are experiencing. And some of them are really very severe. And I think for somebody who is new to the field, it is absolutely eye opening to recognize what the patient's going through,” investigator Cem Akin, MD, Professor of Medicine, University of Michigan Division of Allergy and Immunology, told HCPLive at the AAAAI meeting.
Safety
The 24-week safety profile was consistent with KIT inhibitor class effects, with 70% of TEAEs grade 1.2 TEAEs occurring in ≥10% of bezuclastinib patients and at greater frequency than placebo included hair color changes (69.5% vs 5.0%), altered taste (23.7% vs 0%), nausea (22.0% vs 13.3%), ALT/AST elevation (22.0% vs 6.6%), headache (17.8% vs 11.7%), alopecia (11.9% vs 3.3%), and ALP elevation (10.2% vs 3.3%).2
Grade ≥3 ALT/AST elevations occurred in 5.9% of bezuclastinib patients. All hepatic adverse events were transient laboratory abnormalities; none required hospitalization. Dose reductions due to treatment-related adverse events occurred in 11% of bezuclastinib patients. All discontinuations due to treatment-related adverse events (5.9%) were attributable to transaminase elevations, all of which fully resolved.2
Through 48 weeks, the tolerability profile remained favorable: serious TEAEs occurred in just 1.7% of bezuclastinib-treated patients, and discontinuations due to TEAEs were 9.2% (11/119) during the double-blind period.3
Cogent Biosciences also noted that a separate NDA submission for advanced SM (AdvSM) that remains on track for the first half of 2026.1
