Cogent Biosciences announced breakthrough results from the SUMMIT trial of bezuclastinib in patients with non-advanced systemic mastocytosis (NonAdvSM), achieving statistical significance across all primary and key secondary endpoints. The registration-directed Phase 2 trial demonstrated clinically meaningful improvements in both patient-reported symptoms and objective measures of mast cell burden, positioning the company to submit its first New Drug Application (NDA) to the FDA by the end of 2025.
Primary Endpoint Success Establishes New Treatment Benchmark
The SUMMIT trial achieved its primary endpoint with highly statistically significant results in the mean change in total symptom score (TSS) at 24 weeks (p=0.0002). Patients treated with bezuclastinib showed a mean reduction of 24.3 points in TSS compared to 15.4 points in the placebo arm, resulting in a placebo-adjusted improvement of 8.91 points. The TSS was assessed using the Mastocytosis Symptom Severity Daily Diary (MS2D2).
"We have been eagerly awaiting this day and are thrilled to announce bezuclastinib's performance in the SUMMIT trial, demonstrating clinically meaningful and statistically significant results across all trial endpoints," said Andrew Robbins, Cogent's President and CEO.
Dramatic Impact on Mast Cell Burden
The trial demonstrated bezuclastinib's powerful effect on mast cell burden, with 87.4% of patients achieving at least 50% reduction in serum tryptase compared to 0% of patients in the placebo group (p<0.0001). All secondary endpoints showed statistically significant benefits favoring bezuclastinib over placebo, including:
- ≥50% reduction in KIT D816V VAF (p<0.0001)
- ≥50% reduction in TSS (p=0.0142)
- ≥50% reduction in bone marrow mast cell aggregates (p<0.0001)
- ≥30% reduction in TSS (p=0.0004)
- Mean change in most severe symptom at baseline (p=0.0001)
Favorable Safety Profile Supports Chronic Use
The safety analysis revealed that the majority of treatment emergent adverse events (TEAEs) were of low grade, with 98.3% in the bezuclastinib arm versus 88.3% in the placebo arm. The most frequent TEAEs on bezuclastinib treatment included hair color change (69.5% vs. 5.0% placebo), altered taste (23.7% vs. 0% placebo), nausea (22.0% vs. 13.3% placebo), and ALT/AST elevations (22.0% vs. 6.6% placebo).
Serious adverse events occurred in 4.2% of bezuclastinib-treated patients compared to 5.0% of placebo patients. Treatment discontinuations due to treatment-related adverse events occurred in 5.9% of bezuclastinib patients, all due to ALT/AST elevations, and all patients fully resolved. No hepatic adverse events were reported beyond transient and manageable laboratory abnormalities.
Clinical Expert Perspectives
"People living with NonAdvSM experience debilitating symptoms with enormous impact on their physical and psychological quality of life," said Nathan Boggs, MD, PhD, Allergy Division Director at Uniformed Services University, Walter Reed National Military Medical Center. "It is extremely encouraging to see the results of the SUMMIT trial, which match my own experience treating patients with bezuclastinib, as these results suggest there will soon be a new standard of care available for this patient population with significant unmet medical need."
Lindsay Rein, MD, Associate Professor of Medicine in the Division of Hematologic Malignancies and Cellular Therapy at Duke University, emphasized the drug's chronic use potential: "In addition to its impressive effects on improving patient symptoms, the safety and tolerability profile of bezuclastinib is very attractive for a patient population anticipating taking this disease-modifying agent on a chronic basis."
Regulatory Timeline and Financial Position
Based on these results, Cogent is on track to submit its first NDA to the FDA for bezuclastinib in NonAdvSM by the end of 2025. The company maintains a strong financial position with $237 million in current cash balance and access to an additional $350 million through a recently announced debt facility with SLR Capital Partners.
Mechanism of Action and Development Pipeline
Bezuclastinib is a selective tyrosine kinase inhibitor designed to potently inhibit the KIT D816V mutation and other mutations in KIT exon 17. The KIT D816V mutation drives systemic mastocytosis, a serious disease caused by unchecked proliferation of mast cells. Cogent remains on track to provide top-line results from both the PEAK Phase 3 trial in gastrointestinal stromal tumors (GIST) and the APEX trial in advanced systemic mastocytosis during the second half of 2025.
The company plans to present detailed results from the SUMMIT trial at an upcoming major medical conference later this year and has announced a Bezuclastinib Expanded Access Program to provide early access to patients with non-advanced systemic mastocytosis.
