Cogent Biosciences (COGT) investor relations material

Key study results and clinical impact

• SUMMIT trial in non-advanced systemic mastocytosis (NonAdvSM) met its primary endpoint, showing rapid, durable, and statistically significant symptom improvement with bezuclastinib versus placebo, including broad reductions across all symptom domains and objective disease markers, with a mean TSS reduction of -24.32 at week 24 vs -15.41 for placebo (p<0.001).

• 95.4% of patients on bezuclastinib achieved ≥50% reduction in serum tryptase, 88.2% had ≥50% reduction in bone marrow mast cell burden, and 97.5% had ≥50% reduction in KIT D816V variant allele frequency, with 55% no longer meeting diagnostic criteria for SM after 24 weeks.

• 65.4% of bezuclastinib patients achieved ≥30% symptom reduction and 38.6% achieved ≥50%, both significantly higher than placebo; 86% reported clinically meaningful symptom improvement at 48 weeks, with continued deepening of response over time.

• Correlation established between reduction in disease burden markers and symptom improvement, a first in this patient population, supporting bezuclastinib's disease-modifying potential.

• Bezuclastinib demonstrated a favorable safety profile, with most adverse events low-grade and reversible, most common being hair color changes, altered taste, nausea, and mild hepatic lab abnormalities, and low rates of dose reduction or discontinuation.

Advanced SM (APEX trial) findings

• APEX trial in advanced SM showed a 57% overall response rate (ORR) per mIWG criteria and 80% ORR per pure pathological response (PPR) criteria, with rapid and deep reductions in mast cell burden and serum tryptase.

• 89% of patients experienced at least a 50% reduction in bone marrow mast cells or clearance of aggregates; median time to response was two months, with ongoing deep and durable responses.

• Bezuclastinib was well tolerated, with only 14.8% of patients requiring dose reduction, no discontinuations due to treatment-related adverse events, and most adverse events being low grade and reversible.

• Most frequent adverse events included hair color change, neutropenia, altered taste, thrombocytopenia, and ALT/AST elevations, with only one grade 3 transaminase elevation resolving with dose reduction.

• Bezuclastinib's selectivity for KIT D816V mutation allows for potent activity without the off-target toxicities seen with other agents, supporting its use across a broad SM population, including those with prior avapritinib exposure.

Study design and patient population

• Pivotal phase 2, multicenter, randomized, double-blind, placebo-controlled SUMMIT trial evaluated bezuclastinib in NonAdvSM patients with moderate to severe symptoms despite ≥2 anti-mediator therapies; 179 patients were randomized 2:1 to bezuclastinib 100 mg QD plus best supportive care or placebo.

• Improvements were consistent in subgroups, including smoldering SM and those previously treated with avapritinib.

• Bezuclastinib treatment led to reversal of key bone marrow pathology, including reduction of mast cell aggregates, normalization of mast cell phenotype, and decreased bone marrow cellularity.

• 91% achieved pure pathologic response at 24 weeks.