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SUMMIT Trial: Bezuclastinib in NonAdvSM Patients Top - Line Results Investor Webcast July 7, 2025
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Forward Looking Statements and Risk Factors 2 This presentation and the accompanying oral commentary contain forward-looking statements that involve risks, uncertainties and assumptions. If the risks or uncertainties ever materialize or the assumptions prove incorrect, our results may differ materially from those expressed or implied by such forward looking statements. All statements other than statements of historical fact could be deemed forward-looking, including, but not limited to, any statements of the plans, strategies, and objectives of management for future operations, including our clinical development, regulatory and commercialization plans and timelines; any projections of financial information; any statement about historical results that may suggest trends for our business; any statement of expectation or belief regarding future events; potential markets or market size, technology developments, our clinical and research pipelines, clinical and pre-clinical data or the implications thereof, enforceability of our intellectual property rights, competitive strengths or our position within the industry; any statements regarding the anticipated benefits of our collaborations or other strategic transactions; and any statements of assumptions underlying any of the items mentioned. These statements are based on estimates and information available to us at the time of this presentation and are not guarantees of future performance. Actual results could differ materially from our current expectations as a result of many risks and uncertainties, including but not limited to, risks associated with: the potential impacts of raising additional capital, including dilution to our existing stockholders, restrictions our operations or requirements that we relinquish rights to our technologies or product candidates; the success, cost, and timing of our product development activities and clinical trials; the timing of our planned regulatory submissions to the FDA for our product candidate bezuclastinib and feedback from the FDA as to our plans; our ability to obtain and maintain regulatory approval for our bezuclastinib product candidate and any other product candidates we may develop, and any related restrictions, limitations, and/or warnings in the label of an approved product candidate; the potential for our identified research priorities to advance our bezuclastinib product candidate; the ability to license additional intellectual property relating to our product candidates from third-parties and to comply with our existing license agreements and collaboration agreements; the ability and willingness of our third-party research institution collaborators to continue research and development activities relating to our product candidates; our ability to commercialize our products in light of the intellectual property rights of others; our ability to obtain funding for our operations, including funding necessary to complete further development and commercialization of our product candidates; the; the commercialization of our product candidates, if approved; our plans to research, develop, and commercialize our product candidates; our ability to attract collaborators with development, regulatory, and commercialization expertise; our expectations regarding our ability to obtain and maintain intellectual property protection for our product candidates; among others. For a further description of the risks and uncertainties that could cause actual results to differ from those expressed in these forward-looking statements, as well as risks relating to our business in general, see our periodic filings filed from time to time with the Securities and Exchange Commission. Unless as required by law, we assume no obligation and do not intend to update these forward-looking statements or to conform these statements to actual results or to changes in our expectations. All of Cogent Biosciences, Inc. (“Cogent”) product candidates are investigational product candidates and their safety and efficacy have not yet been established. Cogent has not obtained marketing approval for any product, and there is no certainty that any marketing approvals will be obtained or as to the timelines on which they will be obtained.
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Agenda and Speakers 3 Andrew Robbins President and Chief Executive Officer Nathan A. Boggs, MD, PhD Allergist Immunologist, Walter Reed Allergy Division Director, Dept of Medicine School of Medicine, Uniformed Services University Jessica Sachs, MD Chief Medical Officer Lindsay A.M. Rein, MD Associate Professor of Medicinein the Division of Hematologic Malignancies and Cellular Therapy, Duke University • Introduction Andrew Robbins • NonAdvSM Disease Overview • SUMMIT Top-Line Results • Patient Case Studies Dr. Nathan Boggs and Dr. Lindsay Rein • Summary Andrew Robbins • Q&A All
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Phase 3 study in 2nd-line GIST sunitinib +/- bezuclastinib n=413, mPFS primary endpoint Registration-directed study in NonAdvSM bezuclastinib vs. placebo n=179, 24-week MS2D2 primary endpoint Registration-directed study in AdvSM bezuclastinib monotherapy n=58, ORR primary endpoint LPFV TLR LPFV TLR LPFV TLR 2024 2025 $2 billion+ US annual market opportunity; differentiated symptom improvement provides path to market leadership $1 billion+ US annual market opportunity, limited competition for 2nd-line GIST population $300 million US annual market opportunity; differentiated safety/tolerability results provides path to market leadership Aggregate US annual sales opportunity >$3 billion with limited competition Bezuclastinib Offers Potential Best-in-Class KIT Inhibitor Opportunity 4 LPFV: Last patient, first visit TLR: Top-line results including primary endpoint EOY 2H Enrolled ~6 months early Enrolled ~6 months early Enrollment complete Today
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SUMMIT Part 2 Top - line Results Full Results Expected to be Presented at an Upcoming Medical Meeting
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Neurocognitive Difficulty Concentrating, Difficulty Remembering, Brain Fog, Cognitive Dysfunction, Anxiety, Depression Skin Itching, Flushing, Skin Redness, Spots Gastrointestinal Nausea, Abdominal Pain, Diarrhea, Vomiting, Bloating, Gastroesophageal Reflux Disease (GERD) Fatigue Tiredness Figure 1. Symptoms of Nonadvanced Systemic Mastocytosis1 Pain Headache, Bone Pain, Joint Pain • Nonadvanced SM (NonAdvSM)2 includes indolent SM (ISM), bone marrow mastocytosis (BMM), as well as smoldering SM (SSM).3 • Patients with NonAdvSM experience a variety of disabling, potentially serious and severe symptoms which may significantly reduce health-related quality of life. Symptoms are caused by mast cell reactions and can include life-threatening anaphylaxis.4 • Agents targeting KIT D816V are used to treat Advanced SM (AdvSM) and NonAdvSM, but unmet need remains.5-7 – AEs like cognitive impairment, bleeding, and edema can limit dosing of other agents6 – Available medications do not adequately control symptoms for patients1,8 – SSM has no disease modifying therapies approved 6 1. Pardanani A. AmJ Hematol 2021; 96(4):508-525. 2. NORD 2021. Mastocytosis; available at: https://rarediseases.org/rare-diseases/mastocytosis/. 3. Trizuljak J, et al. Allergy 2020 Aug;75(8):1927-1938. 4. Pyatilova P and Siebenhaar F. Immunol Allergy Clin North Am 2023; 43(4):751-762. 5. DeAngelo D, et al. Nat Med, 2021, 27(12):2183-2191. 6. Ayvakit (avapritinib) [product information]. Cambridge, MA: Blueprint Medicines Corporation; May 2023. 7. DeAngelo et al. [abstract] In: Blood (ASH) 2022; 140 (Supplement 1): 1512-13. 8. Akin C, et al. J Allergy Clin Immunol, 2022, 149(6):1912-1918. Systemic Mastocytosis (SM) is a Rare and Debilitating Disease Characterized by Neoplastic Mast Cell Infiltration of Extracutaneous Tissues and Symptoms of Mast Cell Activation1
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SUMMIT Part 2: Double-Blind, Placebo-Controlled Randomized Clinical Study Evaluating Bezuclastinib in Non-Advanced Systemic Mastocytosis Patients 7 Data cut-off as of 22May25 QD: Once daily, BSC: Best supportive care, TSS: Total Symptom Score, OLE: Open-label Extension * For key secondary endpoints, reductions in TSS and objective measures of mast cell burden represent proportion of patients with ≥30% and ≥50% reductions in each parameter at Week 24. Patient Eligibility • Age ≥ 18 years • NonAdvSM confirmed by central pathology review • Receiving BSC, defined as ≥ 2 anti-mediator therapies • Moderate-to-severe symptoms of NonAdvSM • Prior therapy with approved treatments allowed Bezuclastinib 100mg QD + Best Supportive Care n=119 Placebo QD + Best Supportive Care n=60 Patients 2:1 Randomized Bezuclastinib 100 mg QD + Best Supportive Care C Open Label Extension Primary Endpoint • Mean change in TSS at Week 24 Key Secondary Endpoints* • ≥ 50% Reduction in Serum Tryptase • ≥ 50% Reduction in KIT D816V VAF • ≥ 50% Reduction in TSS • ≥ 50% Reduction in Bone Marrow MC • ≥ 30% Reduction in TSS 24 weeks Treatment
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SUMMIT Part 2 Population Had Significant Disease Burden Representative of Moderate-to-Severe NonAdvSM Patients 8 Clinical Characteristics Bezuclastinib Placebo Overall NonAdv Subtype, n (%) Indolent SM (ISM) 97 (81.5) 50 (83.3) 147 (82.1) Smoldering SM (SSM) 8 (6.7) 4 (6.7) 12 (6.7) Bone Marrow Mastocytosis (BMM) 14 (11.8) 6 (10.0) 20 (11.2) Baseline Mast Cell Burden Bezuclastinib Placebo Overall Median KIT D816V in Whole Blood, % (range) Below limit of detection (BLD), n (%) 0.22 (0-32) 28 (23.5) 0.30 (0-34) 12 (20.0) 0.25 (0-34) 40 (22.3) Median BM MC Burden, % (range) 10 (1-75) 10 (1-75) 10 (1-75) Median Serum Tryptase at baseline, ng/mL (range) Serum Tryptase < 20 ng/mL, n(%) 40 (6-448) 22 (18.5) 41 (7-692) 10 (16.7) 40 (6-692) 32 (17.9) Baseline QoL Measures Bezuclastinib Placebo Overall Mean MS2D2 TSS, (range) 57.1 (18-105) 52.6 (13-91) 55.6 (13-105) Mean MCQoL, (range)2 59.5 (23-96) 55.5 (18-89) 58.2 (18-96) Mean MAS, (range) 50.4 (26-94) 47.0 (27-86) 49.3 (26-94) Region Bezuclastinib Placebo Overall North America, n (%) 53 (44.5) 28 (46.7) 81 (45.3) Europe, n (%) 64 (53.8) 30 (50.0) 94 (52.5) Asia-Pacific, n (%) 2 (1.7) 2 (3.3) 4 (2.2) Systemic Mastocytosis Therapy Bezuclastinib Placebo Overall Prior KIT Inhibitor1 17 (14.3) 5 (8.3) 22 (12.3) Prior Avapritinib, n (%) 11 (9.2) 3 (5.0) 14 (7.8) Prior Midostaurin, n (%) 6 (5.0) 0 6 (3.4) # of BSC Meds, median (range) 3 (0-6) 3 (1-7) 3 (0-7) Patient Demographics Bezuclastinib Placebo Overall # Patients 119 60 179 Female, n (%) 74 (62.2) 44 (73.3) 118 (65.9) Median Age in years, (range) 51 (24-73) 52 (23-78) 51 (23-78) ECOG PS at baseline, n (%) 0 58 (48.7) 30 (50.0) 88 (49.2) 1 50 (42.0) 26 (43.3) 76 (42.5) 2 11 (9.2) 4 (6.7) 15 (8.4) Data cut-off as of 22May25 1. KIT Inhibitors included: avapritinib, imatinib, midostaurin, dasatinib, masitinib 2. MC-QOL baseline collection n= Bezuclastinib: 111, Placebo: 52 Overall: 163
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9 Data cut-off as of 22May25 TSS: total symptom score, VAF: variant allele fraction, MC: mast cell 1. Two-sided p-values < 0.05 indicated statistical significance. 2. For secondary endpoints, reductions in TSS and objective measures of mast cell burden represent proportion of patients with >30% and >50% reductions in each parameter at Week 24. All endpoints are key secondary endpoints, except “Mean Change in Most Severe Symptom Score” which is an additional secondary endpoint. SUMMIT Results Demonstrate Clinically Meaningful and Statistically Significant Effects Across All Primary and Secondary Endpoints P-Value1 Primary Endpoint Mean Change in TSS at Week 24 0.0002 Secondary Endpoints2 ≥ 50% Reduction in Serum Tryptase <0.0001 ≥ 50% Reduction in KIT D816V VAF <0.0001 ≥ 50% Reduction in TSS 0.0142 ≥ 50% Reduction in Bone Marrow MC < 0.0001 ≥ 30% Reduction in TSS 0.0004 Mean Change in Most Severe Symptom Score 0.0001 Clinical Outcome Measures
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-30 -25 -20 -15 -10 -5 0 Treatment with Bezuclastinib Results in Clinically Meaningful Decreases in Patient-Reported Symptoms and Objective Measures of Disease Burden 10Data cut-off as of 22May25 TSS: Total Symptom Score LS Mean (SE) Change from Baseline 0 12 24 Time (weeks) 4 168 20 Bezuclastinib Placebo Mean Change in TSS at Week 24 [95 % CI] Bezuclastinib Placebo P-Value -24.32 (-27.56, -21.08) -15.41 (-19.58, -11.24) 0.0002-8.91 (-13.56, -4.26) ≥50% Reduction in Serum Tryptase at Week 24 Bezuclastinib Placebo P-Value 87.4% 0% <0.0001
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Bezuclastinib Demonstrated a Favorable and Manageable Safety Profile 11 *Pooled terms • Majority of TEAEs were of low grade (70% Gr1) and reversible • Variety of AEs occurred more often in placebo group: Dizziness (10% vs. 12%), Fatigue (7% vs. 12%), Arthralgia (6% vs. 15%), Diarrhea (13% vs. 18%) • The only hepatic AEs reported were transient and manageable lab abnormalities • Only 5.9% of patients experienced ≥Gr 3 ALT/AST elevations, and no patients with transaminase AEs required hospitalization or treatment intervention • All DCs due to treatment-related AEs were due to transaminase elevations and all subjects fully resolved Data cut-off as of 22May25 TEAE: Treatment Emergent Adverse Event Bezuclastinib 100mg QD (N=118) Placebo (N=60) TEAEs, n (%) 116 (98.3) 53 (88.3) SAEs, n (%) 5 (4.2) 3 (5.0) Reductions due to TRAEs, n (%) 13 (11.0) 0 DCs due to TRAEs, n (%) 7 (5.9) 0 TEAEs > 10% that occurred in greater frequency in bezuclastinib arm , n (%) Hair color changes 82 (69.5) 3 (5.0) Altered taste* 28 (23.7) 0 Nausea 26 (22.0) 8 (13.3) ALT/AST increased* 26 (22.0) 4 (6.6) Headache 21 (17.8) 7 (11.7) Alopecia 14 (11.9) 2 (3.3) ALP increased 12 (10.2) 2 (3.3)
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MS2D2 TSS Percent Change Over Time -80 -70 -60 -50 -40 -30 -20 -10 0 0 12 24 36 48 Time (weeks) MS2D2 TSS Percent Change (%) Case Study 1: 44 yo Woman with ISM Randomized to 100 mg Bezuclastinib 12 Treatment-Related AEs Dysgeusia / Grade 1 Hoarseness / Grade 1 Hair Color Changes / Grade 1 SM-Related Medical History Monomorphic Maculopapular Cutaneous Mastocytosis / Grade 3 Splenomegaly / Grade 1 Other Relevant Medical History Obesity / Grade 3 Asthma / Grade 2 Best Supportive Care (BSC) Medications Famotidine Loratadine Cromolyn BL Wk 12 Wk 24 Wk 48 % Decrease BL → Wk48 Tryptase (ng/mL) 39.4 3.5 2.7 3.4 91% KIT D816V VAF (%) 0.19 0.03 Not Detected 0.03 84% BM MC Burden (%) 10 1 90%1 CD25 Expression (%) 100 0 100%1 MS2D2 TSS (0 – 110) 67.9 29.4 27.8 22 68% Most Severe Domain: Neurocognitive (0-10) 7.8 3.4 2.7 2.8 65% • Discontinued all BSC Medications in OLE • Patient remains on study more than 1 year with continued benefit 4 16 28 428 20 32 44 BL WK 48 Data cut-off as of 22May25 1. BM not collected at week 48 for this patient, so % reduction is based on week 24.
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Case Study 2: 63 yo Man with Long History of SM and High-Risk Features Randomized to 100 mg Bezuclastinib 13 SM-Related Medical History Osteoporosis / Grade Unknown GERD / Grade 1 Maculo-papular rash / Grade 1 Flushing / Grade 1 Urticaria Pigmentosa / Grade 1 Treatment-Related AEs Hair Color Changes / Grade 1 BL Week 12 Week 24 % Decrease BL → Wk24 Tryptase (ng/mL) 95.5 8.7 7.9 92% KIT D816V VAF (%) 5.04 2.07 59% BM MC Burden (%) 10 3 70% CD25 Expression (%) 100 0 100% MS2D2 TSS (0 – 110) 75.9 23.6 19.5 74% Most Severe Domain: Skin (0-10) 8.1 3.9 3.3 60% MS2D2 TSS Percent Change (%) -80 -70 -60 -50 -40 -30 -20 -10 0 0 12 24 Time (weeks) MS2D2 TSS Percent Change Over Time • Discontinued 3 BSC medications in OLE: cetirizine, cromolyn and montelukast and cromolyn nasal • Patient remains on study for 32 weeks with continued benefit 4 168 20 Best Supportive Care (BSC) Medications Montelukast Famotidine Cromolyn Cetirizine Data cut-off as of 22May25
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-30 -25 -20 -15 -10 -5 0 Total Symptom Score MS2D2: 11 Items 0-110 Scale, Each Item 10 Points ISM-SAF: 11 Items 0-110 Scale, Each Item 10 Points Weeks on Active Treatment Data cut-off as of 22May25 SkinGICNSSystemic Itching Flushing Spots Skin Redness Itching Flushing Spots Abdominal Pain Nausea Abdominal Pain Nausea Diarrhea Headache Brain Fog Dizziness Headache Difficulty Remembering Difficulty Concentrating Bone Pain Fatigue Bone Pain Feeling of Tiredness MS2D2 is highly analogous to ISM-SAF, inclusion of specific items within composite TSS endpoint derived from NonAdvSM patient baseline data and FDA interaction 14 Mean (SE) Change from Baseline 0 12 244 168 20 ISM-SAF like Bezuclastinib ISM-SAF like Placebo MS2D2 TSS Bezuclastinib MS2D2 TSS Placebo Highly Consistent Results Using Composite Items Included in Either MS2D2 or ISM-SAF TSS
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Bezuclastinib Systemic Mastocytosis Expanded Access Program (NCT069157661) Provides No-Cost Access to Patients in Need 15 *Other protocol-defined criteria apply. Key inclusion criteria* Key exclusion criteria* Age ≥ 18 years Eligibility for and/or enrolled in an ongoing bezuclastinib clinical trial Diagnosis of any NonAdvSM or AdvSM subtypes according to WHO classification for SM Discontinuation of investigational bezuclastinib due to toxicity or withdrawal of consent Lack of adequate disease control on current therapies Pregnant or currently breastfeeding Designed to provide bezuclastinib outside of a clinical trial to real-world patients with AdvSM or NonAdvSM who meet specific criteria including, but not limited to, having no comparable or satisfactory alternative therapy to treat the disease. Patients will receive oral bezuclastinib 100mg QD (NonAdvSM) or 150mg QD (AdvSM). Treating physician to assess patients, report any SAEs, and determine treatment duration. SM EAP is currently open to requests for access from treating physicians in the United States. AIM METHODS 1. ClinicalTrials.gov. Expanded Access to Bezuclastinib for Patients With NonAdvanced Systemic Mastocytosis or Advanced Systemic Mastocytosis. Identifier: NCT06915766. Retrieved July 6, 2025 from: https://clinicaltrials.gov/study/NCT06915766.
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Topline Results from PEAK and APEX Pivotal Trials On Track 2H 2025 16 • Locally advanced, unresectable or metastatic GIST • Disease progression on or intolerance to imatinib • No other prior treatment (other than imatinib) KEY ENTRY CRITERIA n=413 Bezuclastinib 600 mg QD + Sunitinib 37.5 mg QD Sunitinib 37.5 mg QD R 1:1 Primary endpoint: Progression Free Survival • PEAK enrollment Q4 2022 – Q3 2024; Blinded events on track to deliver TLR by EOY 2025 • 2nd-line GIST: No new drugs approved since 2006 • No other investigational products have initiated pivotal trials • >$1 billion US TAM opportunity • Centrally Confirmed ASM, SM-AHN or MCL • Measurable disease per mIWG-MRT-ECNM • ECOG PS 0 to 3 KEY ENTRY CRITERIA Bezuclastinib 150 mg QD Primary endpoint: ORR using mIWG-MRT-ECNM n=58 • APEX enrollment complete Q1 2025; TLR on track for 2H 2025 • Positive SUMMIT results provide expected read-through to APEX • SOC associated with significant safety concerns; no other investigational products in clinical development • ~$300 million US TAM opportunity Single- arm
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SUMMIT Results are Transformative 17 - Bezuclastinib establishes new benchmarks for NonAdvSM symptomatic reduction - 24.3 point reduction from baseline at 24 weeks - 8.91 point placebo-adjusted effect size, representing 57% improvement over approved KIT therapy - Bezuclastinib associated with powerful improvement in objective measures of mast cell burden - 87.4% of patients demonstrating a ≥50% reduction in serum tryptase - Favorable tolerability profile, positioning bezuclastinib for long-term use in chronic disease population - Significant majority of TEAEs reported as Gr 1 - Only 5.9% patients discontinued, all due to higher grade ALT/AST; all resolved rapidly after D/C - Other than lab abnormalities, no hepatic events reported - SUMMIT TSS results with either MS2D2 or ISM-SAF composite items led to highly consistent results - On track for NDA submission by end of 2025 - Two additional near-term pivotal trial TLR: PEAK in 2nd-line GIST, APEX in AdvSM - Strong existing balance sheet with access to significant capital via recently announced debt facility
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Q&A