This is an open label, single arm, phase 2 trial investigating bezuclastinib plus sunitinib in patients with GIST who have previously progressed on sunitinib.

Start Date01 Jul 2024

Sponsor / Collaborator

Sarcoma Alliance for Research through Collaboration

[+3]

NCT05186753 / RecruitingPhase 2

A Multi-Part, Randomized, Double-Blind, Placebo-Controlled Phase 2 Clinical Study of The Safety and Efficacy of CGT9486 in Subjects With Nonadvanced Systemic Mastocytosis

This is a multi-part, randomized, double-blind, placebo-controlled Phase 2 clinical study comparing the safety and efficacy of bezuclastinib (CGT9486) plus best supportive care (BSC) with placebo plus BSC in patients with nonadvanced systemic mastocytosis (NonAdvSM), including indolent systemic mastocytosis and smoldering systemic mastocytosis, whose symptoms are not adequately controlled by BSC. This study will be conducted in three parts. Patients in Parts 1a, 1b and 2 will receive bezuclastinib or placebo, and may roll over onto Part 3 to receive treatment with bezuclastinib.

Start Date27 Jun 2022

Sponsor / Collaborator

Cogent Biosciences, Inc.

NCT05208047 / RecruitingPhase 3

A Phase 3 Randomized, Open-Label, Multicenter Clinical Study of CGT9486+Sunitinib Vs. Sunitinib in Subjects with Locally Advanced, Unresectable, or Metastatic Gastrointestinal Stromal Tumors

This is a Phase 3, open-label, international, multicenter study of CGT9486 in combination with sunitinib. This is a multi-part study that will enroll approximately 442 patients. Part 1 consists of two evaluations: 1) confirming the dose of an updated formulation of CGT9486 to be used in subsequent parts in approximately 20 patients who have received at least one prior line of therapy for GIST and 2) evaluating the potential for drug-drug interactions between CGT9486 and sunitinib in approximately 18 patients who have received at least two prior tyrosine kinase inhibitors (TKIs) for GISTs. The second part of the study will enroll approximately 388 patients who are intolerant to, or who failed prior treatment with imatinib only and will compare the efficacy of CGT9486 plus sunitinib to sunitinib alone with patients being randomized in a 1:1 manner. Additionally, a drug-drug interactions substudy will investigate the potential for CGT9486 to be a CYP3A4 inducer in approximately 16 patients who have received at least one prior line of therapy for GIST.

Start Date14 Apr 2022

Sponsor / Collaborator

Cogent Biosciences, Inc.

100 Clinical Results associated with Bezuclastinib

100 Translational Medicine associated with Bezuclastinib

100 Patents (Medical) associated with Bezuclastinib

Literatures (Medical) associated with Bezuclastinib

01 Dec 2023·Expert opinion on emerging drugs

Systemic mastocytosis: 2023 update on diagnosis and management in adults.

Review

Author: Costa, Alessandro ; Masucci, Chiara ; Carmosino, Ida ; Ielo, Claudia ; Capriata, Marcello ; Passucci, Mauro ; Scalzulli, Emilia ; Martelli, Maurizio ; Breccia, Massimo

INTRODUCTION:

Systemic mastocytosis (SM) is a complex and heterogeneous disease, characterized by the clonal accumulation of mast cells in one or more organs. In 2022 both the World Health Organization (WHO) and the International Consensus Classification (ICC) modified the diagnostic and classification criteria of SM. Moreover, the identification of new clinical and molecular variables has improved prognostic tools and led to increasingly individualized therapeutic strategies.

AREAS COVERED:

The aim of this review is to present the updates introduced by the International Consensus Classification in diagnostic criteria of SM. In addition, we report the latest data available from the most important clinical trials in patients both with non-advanced and advanced disease, including elenestinib and bezuclastinib.

EXPERT OPINION:

Diagnosis and classification of SM has evolved over years. The most recent WHO and ICC classification improved SM diagnostic work-up, providing clinicians with a clear and simplified diagnostic scheme. New approved targeted therapies such as midostaurin and avapritinib modified the treatment paradigm in patients in advanced stage, and next-generation inhibitors actually investigated in clinical trials are expected in the next future.

09 Dec 2022·Hematology. American Society of Hematology. Education Program

Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms

Review

Author: Gotlib, Jason

Abstract:

The historically poor prognosis of patients with advanced systemic mastocytosis (AdvSM) and primary eosinophilic neoplasms has shifted to increasingly favorable outcomes with the discovery of druggable targets. The multikinase/KIT inhibitor midostaurin and the highly selective KIT D816V inhibitor avapritinib can elicit marked improvements in measures of mast cell (MC) burden as well as reversion of MC-mediated organ damage (C-findings) and disease symptoms. With avapritinib, the achievement of molecular remission of KIT D816V and improved survival compared with historical therapy suggests a potential to affect disease natural history. BLU-263 and bezuclastinib are KIT D816V inhibitors currently being tested in trials of AdvSM. In the new World Health Organization and International Consensus Classifications, the category of “myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions” is inclusive of rearrangements involving PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ETV6::ABL1. While the successful outcomes with imatinib in FIP1L1::PDGFRA-positive cases and PDGFRB-rearranged neoplasms have become the “poster children” of these disorders, the responses of the other TK-driven neoplasms to small-molecule inhibitors are more variable. The selective FGFR inhibitor pemigatinib, approved in August 2022, is a promising therapy in aggressive FGFR1-driven diseases and highlights the role of such agents in bridging patients to allogeneic transplantation. This review summarizes the data for these approved and investigational agents and discusses open questions and future priorities regarding the management of these rare diseases.

01 Sep 2021·JAMA oncologyQ1 · MEDICINE

Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors

Q1 · MEDICINE

Article

Author: Sanftner, Laura ; Tinoco, Gabriel ; Tsang, Garson ; Habets, Gaston ; Shields, Anthony F. ; Alcantar, Oscar ; Shellooe, Rafe ; Zhang, Chao ; Wagner, Andrew J. ; Trent, Jonathan C. ; Tsai, James ; Tsiatis, Athanasios C. ; Carias, Heidi ; Zhang, Ying ; Spevak, Wayne ; Ewing, Todd ; Chan, Katrina ; Lin, Jack ; Inokuchi, Kerry ; Tap, William D. ; Burton, Elizabeth A. ; Bollag, Gideon ; Nespi, Marika ; Michelson, Glenn ; Ibrahim, Prabha N. ; Patnaik, Amita ; Severson, Paul L. ; Chugh, Rashmi ; Rezaei, Hamid ; Matusow, Bernice ; Marimuthu, Adhirai ; Wu, Guoxian

IMPORTANCE:

Many cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors.

OBJECTIVE:

To assess whether combining a type II KIT inhibitor with a conformation-complementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control.

DESIGN, SETTING, AND PARTICIPANTS:

A highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020.

INTERVENTIONS:

Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal.

MAIN OUTCOMES AND MEASURES:

Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA.

RESULTS:

A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively.

CONCLUSIONS AND RELEVANCE:

In this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile.

TRIAL REGISTRATION:

ClinicalTrials.gov Identifier: NCT02401815.

News (Medical) associated with Bezuclastinib

09 Dec 2024

·www.globenewswire.com

Cogent Biosciences Announces Updated Clinical Results from SUMMIT, Showcasing Powerful Symptomatic Improvement in NonAdvanced Systemic Mastocytosis Patients

56% mean improvement in Total Symptom Score (TSS) at 24 weeks with 76% of patients achieving at least a 50% reduction in TSS 89% of patients had >50% decrease in serum tryptase by four weeks of treatment and 95% of patients with elevated baseline tryptase achieved serum tryptase levels <20 ng/ml by week 24 SUMMIT Part 2 enrollment completed early; surpassing original enrollment target with 179 patients enrolled, top-line results now expected in July 2025 Cogent to host investor webcast today, Monday, December 9 at 8:00 a.m. ET WALTHAM, Mass. and BOULDER, Colo., Dec. 09, 2024 (GLOBE NEWSWIRE) -- Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, today announced updated clinical results from the Open Label Extension (OLE) portion of SUMMIT, a clinical trial evaluating bezuclastinib in patients with nonadvanced systemic mastocytosis (NonAdvSM). The OLE data are being presented at the 66th American Society of Hematology (ASH 2024) Annual Meeting & Exposition taking place December 7-10, 2024 in San Diego, CA. “The rapid, deep, and sustained symptomatic improvement reported by SUMMIT patients receiving bezuclastinib is very impressive,” said Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and Professor of Medicine, Harvard Medical School. “Coupled with its favorable tolerability profile, bezuclastinib has clear potential to establish itself as the best-in-class KIT inhibitor for systemic mastocytosis patients.” “The SUMMIT data reported today are encouraging to thousands of NonAdvSM patients around the world who are waiting for a novel treatment that can rapidly and meaningfully improve a wide variety of symptoms that impact their daily lives,” said Andrew Robbins, Cogent’s President and Chief Executive Officer. “We set out earlier this year to enroll our registration-directed SUMMIT Part 2 trial, and I’m excited to announce that based on the overwhelming demand from investigators and patients around the world, we’ve completed enrollment in the study with 179 patients more than six months ahead of schedule. Top-line results are now expected in July 2025, meaning we have dramatically accelerated our timeline as we aim to make bezuclastinib available to all NonAdvSM patients.” Patient DemographicsSUMMIT is a registration-directed, randomized, double-blind, placebo-controlled, global, multicenter, clinical trial of bezuclastinib in patients with NonAdvSM. In SUMMIT Part 1, patients received bezuclastinib or placebo for a 12-week period to determine the recommended dose for use in the pivotal portion of the trial, SUMMIT Part 2. Earlier this year, Cogent announced that the recommended go-forward dose was selected at once-daily 100 mg. After the initial 12-week period, all patients were given the opportunity to receive bezuclastinib in the SUMMIT Open Label Extension (OLE). The clinical results presented today focus on 27 patients in the OLE who were treated with the once-daily 100 mg dose of bezuclastinib. The median age of patients at study entry was 52 years (ranging from 36-76 years). One patient had received prior avapritinib. Patient Reported Outcomes (PRO) DataSUMMIT patients were evaluated for signs of clinical activity over 24 weeks using multiple PRO measures, including the Mastocytosis Symptom Severity Daily Diary (MS2D2) and the Mastocytosis Quality-of-Life (MC-QoL) scale. Updated clinical data presented today show: 56% mean improvement in Total Symptom Score (TSS) at 24 weeks76% of patients demonstrated >50% reduction from baseline in MS2D2 Total Symptom Score (TSS) with 88% of patients exceeding 30% reduction from baseline after 24 weeks49% mean improvement in MC-QoL Total Score at 24 weeks At 24 weeks of treatment, 31% of patients have already reduced or discontinued best supportive care (BSC) medications. Pharmacodynamic DataBezuclastinib showed rapid, deep, and sustained reductions in serum tryptase over the course of 24 weeks of treatment including: 89% of patients had >50% decrease in serum tryptase levels by four weeks of treatment95% of patients with baseline tryptase ≥20ng/mL achieved <20ng/mL by week 2484% of patients with baseline serum tryptase >11.4ng/ml achieved <11.4ng/mL by week 24 Safety DataAs of the data cutoff, August 29, 2024, the median duration of bezuclastinib treatment was 56 weeks for patients in the active arm and 40 weeks for placebo patients who crossed over to the OLE. The majority of treatment emergent adverse events were low grade and reversible with no treatment-related bleeding or cognitive impairment events reported. The most common treatment related adverse events were hair discoloration and transaminase elevations. All patients experiencing elevated transaminases were asymptomatic and reversible: five patients resolved without any dose modifications and remain on study; two patients resolved with dose reduction and remain on study, one of whom re-escalated to original dose; and two patients resolved following discontinuation, one of whom was presented previously at ASH 2023. There were no other discontinuations due to adverse events. SUMMIT Enrollment UpdateCogent also announced today that enrollment in the registration-directed SUMMIT Part 2 study is now complete. In the nine months between February and October 2024, 265 NonAdvSM patients were screened for SUMMIT Part 2 at 70 clinical sites, concentrated predominantly in the U.S. and Western Europe. More than 90% of these patients were naïve to KIT inhibitor therapy. A total of 179 patients were enrolled and top-line results from the trial are expected in July 2025. Webcast Information and ASH PosterCogent will host a webcast today, Monday, December 9, 2024, at 8:00 a.m. ET to discuss these updated SUMMIT clinical results. The live event will be available on the Investors & Media page of Cogent’s website at investors.cogentbio.com. A replay of the webcast will be available approximately two hours after the completion of the event and will be archived for up to 30 days. The ASH poster is available to registered conference attendees and is also in the Posters and Publications section of Cogent’s website at www.cogentbio.com/research. About Cogent Biosciences, Inc. Cogent Biosciences is a biotechnology company focused on developing precision therapies for genetically defined diseases. The most advanced clinical program, bezuclastinib, is a selective tyrosine kinase inhibitor that is designed to potently inhibit the KIT D816V mutation as well as other mutations in KIT exon 17. KIT D816V is responsible for driving systemic mastocytosis, a serious disease caused by unchecked proliferation of mast cells. Exon 17 mutations are also found in patients with advanced gastrointestinal stromal tumors (GIST), a type of cancer with strong dependence on oncogenic KIT signaling. In addition to bezuclastinib, the Cogent Research Team is developing a portfolio of novel targeted therapies to help patients fighting serious, genetically driven diseases initially targeting mutations in FGFR2, ErbB2, PI3Kα and KRAS. Cogent Biosciences is based in Waltham, MA and Boulder, CO. Visit our website for more information at www.cogentbio.com. Follow Cogent Biosciences on social media: X (formerly known as Twitter) and LinkedIn. Information that may be important to investors will be routinely posted on our website and X. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding: the company’s expectation to present top-line results from SUMMIT Part 2 in July 2025; the potential for bezuclastinib to establish itself as the best-in-class KIT inhibitor for systemic mastocytosis patients; and the company’s goal of making bezuclastinib available to all NonAdvSM patients. The use of words such as, but not limited to, "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "might," "plan," "potential," "predict," "project," "should," "target," "will," or "would" and similar words expressions are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our clinical results, the rate of enrollment in our clinical trials and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. We may not actually achieve the forecasts or milestones disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to those set forth under the caption "Risk Factors" in Cogent's most recent Quarterly Report on Form 10-Q filed with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither we, nor our affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date hereof. Contact:Christi WaarichSenior Director, Investor Relationschristi.waarich@cogentbio.com617-830-1653

Clinical ResultClinical StudyASH

08 Dec 2024

·www.globenewswire.com

Cogent Biosciences Announces Positive Updated Data from Ongoing Phase 2 APEX Trial Evaluating Bezuclastinib in Patients with Advanced Systemic Mastocytosis (AdvSM)

52% ORR per mIWG criteria, including 83% ORR for patients receiving 100 mg BID 88% ORR per PPR criteria, including 100% ORR for patients receiving 100 mg BID Median time to response 2.2 months with median duration of response and median PFS not yet reached Top-line data from APEX Part 2 on-track for mid-2025 Cogent to host investor webcast on Monday, December 9 at 8:00 a.m. ET WALTHAM, Mass. and BOULDER, Colo., Dec. 08, 2024 (GLOBE NEWSWIRE) -- Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, today reported positive updated data from Part 1 of the Company’s ongoing Phase 2 APEX clinical trial evaluating bezuclastinib in patients with advanced systemic mastocytosis (AdvSM) at the 66th American Society of Hematology (ASH 2024) Annual Meeting & Exposition taking place December 7-10, 2024 in San Diego, CA. “Bezuclastinib has the potential to transform the treatment landscape for people living with advanced systemic mastocytosis,” said Daniel J. DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at the Dana-Farber Cancer Institute and Professor of Medicine, Harvard Medical School. “The impressive clinical data presented today from APEX Part 1 demonstrates a combination of rapid and deep clinical responses, with a safety profile that avoids several of the most concerning side effects for AdvSM patients today.” “We are excited to share today the updated clinical data from APEX Part 1 studying bezuclastinib in patients with advanced systemic mastocytosis,” said Andrew Robbins, Cogent’s President and Chief Executive Officer. “These results show the enormous promise that a highly potent, highly selective, non-brain penetrant KIT inhibitor may provide to this patient population. We look forward to completing enrollment in APEX Part 2 and sharing the results from that study in mid-2025.” Patient DemographicsAPEX is a global, open-label, multi-center, two-part Phase 2 clinical trial in patients with AdvSM evaluating the safety, efficacy, pharmacokinetic, and pharmacodynamic profiles of bezuclastinib. Thirty-two patients were treated in Part 1 at one of four dose levels (50 mg BID, 100 mg BID, 200 mg BID or 400 mg QD). Earlier this year, Cogent announced APEX Part 2 would be conducted at the optimized 150mg QD dose, which closely matches the exposure from 100 mg BID dose in APEX Part 1. The median age of patients at study entry was 68 years (ranging from 33-87 years). Patients were enrolled with the following sub-types: seven patients with aggressive systemic mastocytosis (ASM), 23 patients with systemic mastocytosis with associated hematologic neoplasm (SM-AHN), and two patients with mast cell leukemia (MCL). Five patients had received prior avapritinib and 10 patients had received prior midostaurin treatment. Clinical Activity DataAs of the data cutoff date of October 11, 2024, 32 patients enrolled were evaluated for signs of clinical activity, 27 of whom were mIWG-MRT-ECNM evaluable. Clinical activity analyzed across dose levels and focused on 100 mg BID cohort showed: 52% ORR (CR+CRh+PR+CI) per mIWG-MRT-ECNM criteria, including 61% ORR for TKI-treatment-naïve patients 83% ORR for patients treated at 100 mg BID dose cohort 88% ORR (CR+PR) per pure pathological response (PPR) criteria 100% ORR for patients treated at 100 mg BID dose cohort Median time to achieve response was 2.2 months and median duration of response has not yet been reached Median PFS was not yet reached at median follow-up of 20 months; PFS rate at 24 months was 82% Pharmacodynamic DataNearly all patients demonstrated a significant improvement in biomarkers associated with disease burden. Patients without post baseline biomarker data were excluded from relevant analyses. 94% of patients achieved ≥50% reduction in serum tryptase levels 100% of patients receiving ≥2 cycles achieved ≥50% reduction66% of patients achieved reduction of serum tryptase below 20 ng/mL 93% of KITD816V-positive patients achieved ≥50% reduction in KIT D816V variant allele fraction (VAF)100% of evaluable patients achieved a ≥50% reduction in bone marrow mast cell burden 83% achieved complete clearance of mast cell aggregates by central review Safety DataAs of the data cutoff date of October 11, 2024, bezuclastinib continues to demonstrate a differentiated safety and tolerability profile across doses. The majority of hematological adverse events were low grade and reversible. There have been no new treatment related serious adverse events or discontinuations reported since ASH 2023. Due to confounding medical issues, one patient previously reported with DILI has been reassessed and reported as a Grade 4 gamma-glutamyl transferase (GGT) elevation case. Twelve patients required dose reduction, eight of whom were treated at a 400 mg daily dose. Bezuclastinib in Systemic Mastocytosis Cogent is actively enrolling patients into APEX Part 2 which is anticipated to complete enrollment in Q1 2025 with top-line results expected in mid-2025. Cogent will present 24-week follow-up data from patients who participated in the Open Label Extension portion of the ongoing SUMMIT trial on Monday, December 9, 2024 at ASH. SUMMIT is a randomized, double-blind, placebo-controlled, global, multicenter Phase 2 trial evaluating bezuclastinib in patients with Nonadvanced Systemic Mastocytosis (NonAdvSM). Webcast Information and ASH PostersCogent will host a webcast on Monday, December 9, 2024 at 8:00 a.m. ET to discuss updated clinical results from both the APEX and SUMMIT ASH presentations. The live event will be available on the Investors & Media page of Cogent’s website at investors.cogentbio.com. A replay of the webcast will be available approximately two hours after the completion of the event and will be archived for up to 30 days. The ASH posters will be available to registered conference attendees and will also be in the Posters and Publications section of Cogent’s website at www.cogentbio.com/research. About Cogent Biosciences, Inc. Cogent Biosciences is a biotechnology company focused on developing precision therapies for genetically defined diseases. The most advanced clinical program, bezuclastinib, is a selective tyrosine kinase inhibitor that is designed to potently inhibit the KIT D816V mutation as well as other mutations in KIT exon 17. KIT D816V is responsible for driving systemic mastocytosis, a serious disease caused by unchecked proliferation of mast cells. Exon 17 mutations are also found in patients with advanced gastrointestinal stromal tumors (GIST), a type of cancer with strong dependence on oncogenic KIT signaling. In addition to bezuclastinib, the Cogent Research Team is developing a portfolio of novel targeted therapies to help patients fighting serious, genetically driven diseases initially targeting mutations in FGFR2, ErbB2, PI3Kα and KRAS. Cogent Biosciences is based in Waltham, MA and Boulder, CO. Visit our website for more information at www.cogentbio.com. Follow Cogent Biosciences on social media: X (formerly known as Twitter) and LinkedIn. Information that may be important to investors will be routinely posted on our website and X. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding: the expectation for the company to complete enrollment for APEX Part 2 in Q1 2025 and to have top-line data in mid-2025; the potential for bezuclastinib to transform the treatment landscape for people living with AdvSM; and the potential benefit that a highly potent, highly selective, non-brain penetrant KIT inhibitor may provide to patients with AdvSM. The use of words such as, but not limited to, "anticipate," "believe," "continue," "could," "estimate," "expect," "intend," "may," "might," "plan," "potential," "predict," "project," "should," "target," "will," or "would" and similar words expressions are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our clinical results, the rate of enrollment in our clinical trials and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. We may not actually achieve the forecasts or milestones disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to those set forth under the caption "Risk Factors" in Cogent's most recent Quarterly Report on Form 10-Q filed with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither we, nor our affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date hereof. Contact:Christi WaarichSenior Director, Investor Relationschristi.waarich@cogentbio.com617-830-1653

Clinical ResultPhase 2ASH

12 Nov 2024

·www.globenewswire.com

Cogent Biosciences Reports Recent Business Highlights and Third Quarter 2024 Financial Results

Top-line results from registration-directed SUMMIT, PEAK and APEX trials expected in 2025 Phase 1 trial initiated for CGT-4859, a reversible, potent, selective, FGFR2 inhibitor SUMMIT and APEX clinical presentations at upcoming ASH annual meeting Strong cash position of $346 million sufficient to fund operations into late 2026 WALTHAM, Mass. and BOULDER, Colo., Nov. 12, 2024 (GLOBE NEWSWIRE) -- Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, today reported recent business highlights and financial results for the third quarter ended September 30, 2024. “We made significant progress across our pipeline over the last quarter, including completing enrollment in our Phase 3 PEAK trial in Gastrointestinal Stromal Tumor (GIST) patients, accelerating enrollment in SUMMIT, our registration-directed trial with bezuclastinib in Nonadvanced Systemic Mastocytosis (NonAdvSM) and initiating our first Phase 1 trial with our FGFR2 inhibitor,” said Andrew Robbins, Cogent’s President and Chief Executive Officer. “Additionally, we recently presented new preclinical data from our research pipeline that demonstrated potential best-in-class attributes of our pan-KRAS inhibitor and our H1047R PI3Kα inhibitor. As we head into 2025, we are well positioned as we prepare to deliver top-line data from three registrational clinical trials.” Business Highlights & Milestones Completed enrollment in PEAK, a randomized, open-label, global Phase 3 trial evaluating bezuclastinib in combination with sunitinib vs sunitinib alone in patients with imatinib-resistant gastrointestinal stromal tumors (GIST). Based on strong global patient interest, a total of 413 patients were enrolled in the trial. The primary endpoint is median progression free survival (mPFS). In addition, Cogent completed a pre-planned interim futility analysis and the Independent Data Monitoring Committee (IDMC) recommended continuing the PEAK study without modification. This pre-specified analysis was based on an assessment of progression-free survival (PFS) as determined by independent central review and did not include the option for early stopping due to efficacy. Cogent will present updated clinical data from both SUMMIT and APEX clinical trials at the upcoming ASH annual meeting in December. There will be an investor webcast on December 9 at 8:00 a.m. ET to review the SUMMIT and APEX data. To register and listen please visit: https://investors.cogentbio.com/events Poster presentation highlighting long term follow-up from patients who participated in the Open Label Extension (OLE) portion of SUMMIT at the ASH annual meeting on Monday, December 9, 2024. SUMMIT is a randomized, global, multicenter, double-blind, placebo-controlled, multi-part Phase 2 trial evaluating bezuclastinib in patients with NonAdvSM.Oral presentation of long term follow-up from patients in Part 1 of the ongoing APEX study to be presented at the 2024 ASH annual meeting on Sunday, December 8, 2024. APEX is a global, multi-part Phase 2 trial evaluating bezuclastinib in patients with Advanced Systemic Mastocytosis (AdvSM). During the quarter, Cogent initiated a Phase 1 study of CGT4859, a reversible, selective FGFR2 inhibitor in patients with FGFR2 mutations, including advanced cholangiocarcinoma. The trial will explore the safety, tolerability and clinical activity of escalating doses of CGT4859 with a goal of selecting an active and well tolerated dose for further clinical investigation. Preliminary results from this trial are expected in 2025. Announced the addition of a potent and selective KRAS inhibitor to the pipeline. Preclinical data from this program as well as the Company’s H1047R mutant-selective PI3Kα clinical candidate were presented at the 2024 EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics. Mutations in KRAS are among the most prevalent mutations found in cancer, occurring most often in colorectal cancer, non-small cell lung cancer and pancreatic cancer. The first poster presented described Cogent’s internally-developed pan KRAS(ON) inhibitor with selectivity over HRAS and NRAS and picomolar (pM) activity across KRAS mutations without the potential liabilities of molecules in the class. Following oral administration, CGT6737 demonstrated robust PK/PD and tumor growth inhibition with 90% PD inhibition in mouse xenograft models. Lead optimization of CGT6737 is ongoing.The second poster highlighted Cogent’s clinical candidate CGT6297, a potent allosteric inhibitor of PI3K, with 25-fold selectivity over PI3Kα WT. CGT6297 has high oral bioavailability and low clearance across species, providing robust inhibition of downstream signaling and efficacy in animal models. Importantly, when compared to a clinically relevant dose of a currently approved therapy in a mouse tumor model, CGT6297 demonstrated superior efficacy with no increase in insulin. IND-enabling studies are expected to be initiated in 2025. Anticipated Upcoming Milestones Complete enrollment in SUMMIT Part 2 in the first quarter of 2025 and deliver top-line results in the second half of 2025. Deliver top-line results from APEX in mid-2025. Deliver top-line results from PEAK by the end of 2025. Upcoming Investor ConferencesA live webcast of the following events can be accessed on the Investors & Media page of Cogent’s website at investors.cogentbio.com/events. A replay will be available approximately two hours after completion of the events and will be archived for up to 30 days. Guggenheim Healthcare Innovation Conference, today, Tuesday, November 12, 2024 at 10:30 a.m. ET. Jefferies London Healthcare Conference on Wednesday, November 20, 2024 at 12:30 p.m. GMT (7:30 a.m. ET). Piper Sandler 35th Annual Healthcare Conference on Tuesday, December 4, 2024 at 9:30 a.m. ET. Third Quarter 2024 Financial Results Cash Position: As of September 30, 2024, cash, cash equivalents and marketable securities were $345.5 million, as compared to $389.9 million as of June 30, 2024. The company believes that its cash, cash equivalents and marketable securities will be sufficient to fund its operating expenses and capital expenditure requirements well past top-line results from SUMMIT, PEAK, and APEX registration-directed trials and into late 2026. R&D Expenses: Research and development expenses were $63.6 million for the third quarter of 2024 as compared to $50.1 million for the third quarter of 2023. R&D expenses include non-cash stock compensation expense of $4.8 million for the third quarter of 2024 compared to $4.0 million for the third quarter of 2023. Increases resulted from costs associated with the acceleration of enrollment in PEAK, SUMMIT and the continued development of our research pipeline. G&A Expenses: General and administrative expenses were $11.8 million for the third quarter of 2024 as compared to $9.5 million for the third quarter of 2023. The increase was primarily due to the growth of the organization. G&A expenses include non-cash stock compensation expense of $5.6 million for the third quarter of 2024 compared to $4.8 million for the third quarter of 2023. Net Loss: Net loss was $70.6 million for the third quarter of 2024 as compared to a net loss of $55.4 million for the same period of 2023. Inducement Grants Under Nasdaq Listing Rule 5635(c)(4) Cogent also announced today that, on November 6, 2024, the Compensation Committee of Cogent’s Board of Directors, made up entirely of independent directors, approved the grant of “inducement” equity awards to three new employees under the company’s 2020 Inducement Plan with grant dates of November 6, 2024 and November 11, 2024. The awards were approved in accordance with Listing Rule 5635(c)(4) of the corporate governance rules of the Nasdaq Stock Market. The employees received, in the aggregate, nonqualified options to purchase 132,350 shares of Cogent common stock. Each option has a 10-year term, an exercise price equal to the closing price of Cogent’s common stock on the grant date, and a 4-year vesting schedule with 25% vesting on the 1-year anniversary of the grant date and the remainder vesting in equal monthly installments over the subsequent 36 months, provided such employee remains employed through each such vesting date. About Cogent Biosciences, Inc. Cogent Biosciences is a biotechnology company focused on developing precision therapies for genetically defined diseases. The most advanced clinical program, bezuclastinib, is a selective tyrosine kinase inhibitor that is designed to potently inhibit the KIT D816V mutation as well as other mutations in KIT exon 17. KIT D816V is responsible for driving systemic mastocytosis, a serious disease caused by unchecked proliferation of mast cells. Exon 17 mutations are also found in patients with advanced gastrointestinal stromal tumors (GIST), a type of cancer with strong dependence on oncogenic KIT signaling. In addition to bezuclastinib, the Cogent Research Team is developing a portfolio of novel targeted therapies to help patients fighting serious, genetically driven diseases initially targeting mutations in FGFR2, ErbB2, PI3Kα and KRAS. Cogent Biosciences is based in Waltham, MA and Boulder, CO. Visit our website for more information at www.cogentbio.com. Follow Cogent Biosciences on social media: X (formerly known as Twitter) and LinkedIn. Information that may be important to investors will be routinely posted on our website and X. Forward Looking StatementsThis press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding: the potential for the company’s pipeline programs targeting KRAS and PI3Kα to produce best-in-class assets; the expectation to deliver preliminary results from the company’s Phase 1 study of CGT4859 in 2025; the expectation to initiate IND-enabling studies for CGT6297 in 2025; the expectation to complete enrollment in SUMMIT Part 2 in the first quarter of 2025 and deliver top-line results in the second half of 2025; the expectation to deliver top-line results from APEX in mid-2025; the expectation to deliver top-line results from PEAK by the end of 2025; the company’s anticipated cash runway into late 2026 and planned presentations at upcoming scientific and investor conferences. The use of words such as, but not limited to, “anticipate,” “believe,” “continue,” “could,” “estimate,” “expect,” “intend,” “may,” “might,” “plan,” “potential,” “predict,” “project," “should,” “target,” “will,” or “would” and similar words expressions are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on our current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our clinical results, the rate of enrollment in our clinical trials and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. We may not actually achieve the forecasts or milestones disclosed in our forward-looking statements, and you should not place undue reliance on our forward-looking statements. Such forward-looking statements are subject to a number of material risks and uncertainties including but not limited to those set forth under the caption “Risk Factors” in Cogent's most recent Quarterly Report on Form 10-Q filed with the SEC. Any forward-looking statement speaks only as of the date on which it was made. Neither we, nor our affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law. These forward-looking statements should not be relied upon as representing our views as of any date subsequent to the date hereof. COGENT BIOSCIENCES, INC.CONDENSED CONSOLIDATED STATEMENTS OF OPERATIONS(in thousands, except share and per share amounts)(unaudited) Three Months Ended September 30, Nine Months Ended September 30, 2024 2023 2024 2023 Operating expenses: Research and development$63,614 $50,127 $170,613 $125,036 General and administrative 11,800 9,453 31,592 24,866 Total operating expenses 75,414 59,580 202,205 149,902 Loss from operations (75,414) (59,580) (202,205) (149,902) Other income: Interest income 4,779 4,198 14,229 9,207 Other income, net 1 — 44 950 Change in fair value of CVR liability — — — 1,700 Total other income, net 4,780 4,198 14,273 11,857 Net loss$(70,634) $(55,382) $(187,932) $(138,045) Net loss per share attributable to common stockholders, basic and diluted$(0.64) $(0.64) $(1.85) $(1.79) Weighted average common shares outstanding, basic and diluted 110,165,580 86,165,951 101,435,402 77,274,580 COGENT BIOSCIENCES, INC.SELECTED CONDENSED CONSOLIDATEDBALANCE SHEET DATA(in thousands)(unaudited) September 30, 2024 December 31, 2023 Cash, cash equivalents and marketable securities$345,548 $273,170 Working capital$288,480 $232,603 Total assets$384,016 $313,437 Total liabilities$69,357 $55,635 Total stockholders’ equity$314,659 $257,802 Contact: Christi WaarichSenior Director, Investor Relationschristi.waarich@cogentbio.com617-830-1653

Phase 1Phase 2Clinical ResultFinancial StatementPhase 3

100 Deals associated with Bezuclastinib

R&D Status

10 top R&D records.

to view more data

Indication	Highest Phase	Country/Location	Organization	Date
Metastatic Gastrointestinal Stromal Tumor	Phase 3	US	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	AR	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	AU	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	BR	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	CA	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	CL	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	CZ	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	DK	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	FR	Cogent Biosciences, Inc.	14 Apr 2022
Metastatic Gastrointestinal Stromal Tumor	Phase 3	DE	Cogent Biosciences, Inc.	14 Apr 2022

Clinical Result

Indication

Phase

Evaluation

View All Results

Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04996875 (Apex, ASH2024) Manual	Phase 2	Systemic Mastocytosis	32	Bezuclastinib	eelvttvyhf(hgodcardhq) = ovofbtkjlg uphyknfvdm (axhyvvavto ) View more	Positive	08 Dec 2024
NCT05186753 (Summit, SOHO2024)	Phase 2	Aggressive Systemic Mastocytosis Serum tryptase \| KIT D816V positive	-	Bezuclastinib low dose	gtjcsfvmwe(gdeyhcrjar) = uybogwwfzw tgpilhqudf (oybyaucomo ) View more	Positive	04 Sep 2024
				Bezuclastinib high dose	gtjcsfvmwe(gdeyhcrjar) = qyejggnudf tgpilhqudf (oybyaucomo ) View more
NCT05208047 (Peak, ASCO2024) Manual	Phase 3	Gastrointestinal Stromal Tumors KIT Mutation	42	Bezuclastinib	pyqltfekks(gqqtwwqcxa) = The majority of TEAEs were low grade and reversible with low rate (38%) of Grade 3+ events mwvkwqfpxl (bmhgihvwfo )	Positive	24 May 2024
NCT05186753 (Summit, AAAAI2024) Manual	Phase 2	Systemic Mastocytosis KIT D816V positive	50	Bezuclastinib low dose	jkxxztsfur(inzqidauww) = jbylvhzpfa qmiathjoti (txjulzpxyk ) View more	Positive	23 Feb 2024
				Bezuclastinib high dose	jkxxztsfur(inzqidauww) = jxfowwzomo qmiathjoti (txjulzpxyk ) View more
NCT05186753 (SUMMIT, GlobeNewswire) Manual	Phase 2	Systemic Mastocytosis	34	Bezuclastinib	zryxuvmsrx(ylblxdnobx) = tsuxomoogt izbfwmaapq (izkdrcssfg ) View more	Positive	22 Feb 2024
APEX (Biospace) Manual	Phase 2	Systemic Mastocytosis KIT D816V	32	Bezuclastinib	ltwrpdrfrl(kqfkgzqtqj) = niiyuxxcea hahjbzlxgv (eoeahbnxlr ) View more	Positive	11 Dec 2023
				Bezuclastinib (50mg BID)	-
SUMMIT (GlobeNewswire) Manual	Phase 2	Systemic Mastocytosis KIT D816V	20	bezuclastinib	rumhuyoeno(ishgtyjluh) = ojwydggkxx jqtaqrdasv (knyfsyqxpx ) View more	Positive	09 Dec 2023
				placebo	rumhuyoeno(ishgtyjluh) = szbzvahipa jqtaqrdasv (knyfsyqxpx ) View more
NCT05186753 (Summit, ASH2023)	Phase 2	Systemic Mastocytosis	48	Bezuclastinib 100 mg	pkuyqdqmgs(hiajqlaaxb) = sgdhwbssmh ufkkgmmjrn (vxaipawugt )	-	09 Dec 2023
				Bezuclastinib 200 mg	pkuyqdqmgs(hiajqlaaxb) = kjfypghppp ufkkgmmjrn (vxaipawugt )
NCT05208047 (Peak, ASCO2023) Manual	Phase 3	Gastrointestinal Stromal Tumors	19	Bezuclastinib+sunitinib	aiilimoaqz(tnohrojuam) = dlhxybtfue xvhacrircl (wugxhxczcc ) View more	Positive	31 May 2023
NCT04996875 (APEX, Corporate Publications) Manual	Phase 2	Systemic Mastocytosis	16	bezuclastinib (TKI therapy naïve patients)	siwnkzkqex(olcapsngoj) = twrnocncvw idvnhdjsfv (bumpjngeuc )	Positive	11 Dec 2022
				bezuclastinib (all patients)	siwnkzkqex(olcapsngoj) = ifjsbvzotq idvnhdjsfv (bumpjngeuc )

Translational Medicine

Boost your research with our translational medicine data.

view full example data

Deal

Boost your decision using our deal data.

view full example data

Core Patent

Boost your research with our Core Patent data.

view full example data

Clinical Trial

Identify the latest clinical trials across global registries.

view full example data

Approval

Accelerate your research with the latest regulatory approval information.

view full example data

Regulation

Understand key drug designations in just a few clicks with Synapse.

view full example data

Chat with Hiro

Get started for free today!

Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.

Start your data trial now!

Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.

Bio

Bio Sequences Search & Analysis

Chemical

Chemical Structures Search & Analysis

Bezuclastinib

Overview

Basic Info

Structure

Related

R&D Status

Clinical Result

Translational Medicine

Deal

Core Patent

Clinical Trial

Approval

Regulation