Bezuclastinib Program - Bezuclastinib is a potential best-in-class selective KIT mutant inhibitor, showing promise in pre-clinical studies and Phase 1/2 trials for GIST patients[10, 115] - KIT mutations drive up to 80% of GIST and over 90% of SM cases[27] - Bezuclastinib exhibits minimal brain penetration, with a brain to plasma ratio of 007, compared to 20 for avapritinib[37] - Cogent is conducting a Phase 2 clinical study (APEX) of Bezuclastinib in patients with Advanced Systemic Mastocytosis, with initial clinical results expected in 1H 2022[47, 48] FGFR2 Program - FGFR2 and FGFR3 are collectively altered in up to 41% of cancers[55] - Cogent is developing FGFR2 selective inhibitors with a target profile of <10 nM FGFR2 Cell IC50 and >200 nM FGFR1 Cell IC50[64] - CGT0292, a lead compound, demonstrates ~30x selectivity between FGFR1 and FGFR2 in cellular assays[80] - CGT0292 does not show serum phosphorus increase at a 5 mg/kg dose in the SD Rat Model of Hyperphosphatemia[84] ErbB2 Program - Significant unmet need remains for patients with non-exon 20 ErbB2 mutations[95] - Cogent is developing an ErbB2 mutant selective drug which covers key mutations while sparing wtEGFR, with a target Mutant Cell IC 50 of <10 nM and EGFR WT Cell IC 50 of >200 nM[104, 105] - Cogent has identified several novel series with promising enzyme selectivity for ErbB2 over EGFR WT[114] Financial Status - Cogent Biosciences had a cash balance of $2197 million as of December 31, 2021[12, 117]

Bezuclastinib Clinical Programs - Bezuclastinib combined with sunitinib demonstrated a 12-month median Progression-Free Survival (mPFS) in heavily pre-treated Gastrointestinal Stromal Tumors (GIST) patients[10] - In the APEX study, initial data in Advanced Systemic Mastocytosis (AdvSM) patients shows promising clinical activity with Bezuclastinib[10] - In Apex study, the Overall Response Rate (ORR) of CR + CRh + PR + CI was 73% (8 out of 11 patients) per CRRC assessment in TKI therapy-naïve AdvSM patients[27] - In Apex study, 88% of patients achieved a ≥ 50% reduction in serum tryptase levels[35] - In Apex study, 100% of patients with at least 2 cycles of treatment achieved a ≥ 50% reduction in bone marrow mast cell burden[35] - In Apex study, 92% of patients with at least 2 cycles of treatment achieved a ≥ 50% reduction in KIT D816V VAF[35] Market Opportunity - The global Total Addressable Market (TAM) potential for Bezuclastinib exceeds $3.5 billion, including $1.5 billion for NonAdvSM, $700 million for 2nd-line GIST, and $300 million for AdvSM[14] - Approximately 90% of Systemic Mastocytosis (SM) patients present with non-advanced systemic mastocytosis (NonAdvSM)[18] - Approximately 10% of patients present with advanced systemic mastocytosis (AdvSM)[18] Pipeline and Financials - The company's research pipeline includes novel, small-molecule targeted therapies for rare diseases, including an FGFR1-sparing, pan-mutant FGFR2 and a CNS-penetrant ErbB2[7] - The company's cash runway is expected to fund operations into 2025, with $289.1 million in cash as of September 30, 2022[7, 83]

Clinical Programs & Catalysts - Cogent Biosciences has multiple clinical and preclinical programs with upcoming catalysts, including top-line results for Bezuclastinib in AdvSM expected in July 2025, NonAdvSM in 2H 2025, and GIST by EOY 2025 [7, 8, 11] - The company is conducting a registration-directed study of Bezuclastinib in NonAdvSM with 179 patients, using a 24-week MS2D2 primary endpoint [11] - A registration-directed study of Bezuclastinib monotherapy is underway in AdvSM with 58 patients, using ORR as the primary endpoint [11] - PEAK Part 2 is a global Phase 3 trial of Bezuclastinib in 2nd-line GIST, with top-line results expected by the end of 2025 [8] Financial Position - As of Q1 2025, Cogent Biosciences has $245.7 million, expected to fund operations into late 2026 [9] Market Opportunity - The aggregate US annual sales opportunity for Bezuclastinib across AdvSM, NonAdvSM, and GIST is greater than $3 billion with limited competition [12] - The US annual market opportunity for NonAdvSM is estimated at $2 billion, with differentiated symptom improvement potentially leading to market leadership [11] - The US annual market opportunity for 2nd-line GIST is estimated at over $1 billion, with limited competition [11] - The US annual market opportunity for AdvSM is estimated at $300 million, with differentiated safety/tolerability results potentially leading to market leadership [11] Competitive Landscape - Cogent believes Bezuclastinib offers a best-in-class KIT inhibitor opportunity with minimal late-stage competitive activity [10, 13, 30] Safety and Efficacy - In ISM patients, only 25% of Ayvakit patients achieved clinically meaningful improvement [18] - In PIONEER Part 2, low-dose Ayvakit (25 mg once daily) was associated with an improved safety profile, with 13% experiencing eye edema and dizziness [19]