On April 17, 2023 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported updated preclinical data from the Company’s pipeline programs, including its novel EGFR-sparing brain-penetrant ErbB2 inhibitor and its next-generation selective fibroblast growth factor receptor 2 (FGFR2) program (Press release, Cogent Biosciences, APR 17, 2023, View Source [SID1234630146]). The data are being presented today in poster sessions at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2023 Annual Meeting. Cogent also announced the initiation of Part 2 of the Company’s ongoing APEX trial with bezuclastinib in Advanced Systemic Mastocytosis (AdvSM).
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"We are pleased to share our progress highlighting the Cogent Research Team in their ongoing effort to discover and advance potential best-in-class novel therapies for rare disease populations with high unmet medical need," said Andrew Robbins, Cogent’s President and Chief Executive Officer. "Separately, based on bezuclastinib’s impressive and consistent clinical activity, safety and tolerability, we are also excited to announce the initiation of Part 2 of the APEX trial in AdvSM at a once-daily dose of 150 mg. We remain on track to provide clinical updates in the second half of 2023 from both APEX and SUMMIT, our trial of bezuclastinib in NonAdvSM patients, as well as updated clinical results from the PEAK lead-in trial in GIST patients this quarter."
AACR Poster Details
Title: Identification of a novel EGFR sparing brain penetrant ErbB2 inhibitor with activity against oncogenic ErbB2 mutations
Session Category: Molecular/Cellular Biology and Genetics
Session Title: Cell Cycle Progression, Checkpoint, and Telomeres
Session Date and Time: Monday Apr 17, 2023 9:00 AM – 12:30 PM ET
Location: Poster Section 10
Poster Board Number: 21
Published Abstract Number: 1440
Cogent is developing a potential best-in-class EGFR-sparing, brain-penetrant ErbB2 inhibitor that includes coverage of key mutations (YVMA, S310F, V842I, L755S) inadequately addressed by currently approved therapies. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification. The poster presented today describes a series of novel compounds which potently inhibit several key ErbB2 mutations, including YVMA insertions, while sparing inhibition of EGFR. An exemplar compound from these series demonstrates advantages versus tucatinib, an approved benchmark compound, on tumor growth inhibition in a peripheral ErbB2 L755S driven mutant model, as well as in an ErbB2 driven intracranial model. Recent program advances with a novel chemotype have further improved ErbB2 mutational potency and selectivity, increased estimated brain penetrance to 40% and improved human whole blood stability to nearly 24 hours, suggesting a favorable profile for optimal clinical efficacy.
Title: In vivo characterization of a selective FGFR2 inhibitor with potency against gatekeeper and molecular brake mutations
Session Category: Molecular/Cellular Biology and Genetics
Session Title: Cell Cycle Progression, Checkpoint, and Telomeres
Session Date and Time: Monday Apr 17, 2023, 9:00 AM – 12:30 PM ET
Location: Poster Section 10
Poster Board Number: 20
Published Abstract Number: 1439
FGFR inhibitors are well-established oncogenic drivers in multiple diseases, but approved medicines fail to capture the full landscape of FGFR altered tumor types, with FGFR1-mediated hyperphosphatemia serving as the most common dose-limiting toxicity for pan-FGFR inhibitors. The poster presented today provides the first published evidence of a reversible, selective FGFR2 inhibitor with coverage of activating and emerging resistance mutations that spares inhibition of FGFR1. Preclinical data demonstrate a profile that delivers equipotent coverage across both key gatekeeper and molecular brake mutations (V564X, N549X) in FGFR2, while avoiding any evidence of FGFR1-linked hyperphosphatemia at efficacious plasma concentrations. In addition, as a reversible inhibitor, the Cogent program retains enzymatic potency against potential cysteine 491 mutations which are known to emerge as key resistance mutations in patients treated with covalent inhibitors.
APEX Part 2 Design Highlights
APEX is an ongoing Phase 2 trial evaluating bezuclastinib in patients with AdvSM. Part 2 will enroll approximately 65 patients treated at a once-daily 150 mg optimized dose and if successful, is designed to support regulatory submission. Enrollment is expected to be complete by the end of 2024. Several additional patient cohorts are anticipated during Part 2 of the APEX trial designed to demonstrate the breadth of AdvSM patients who may benefit from bezuclastinib, including:
Up to 20 patients with systemic mastocytosis with an associated hematologic neoplasm (SM-AHN) treated concomitantly with bezuclastinib and AHN directed therapies, including azacitidine.
Up to 15 patients with inevaluable mIWG disease without C-findings.
Approximately 10 patients at a dose of 300 mg once-daily to explore the effect of exceeding IC90 KIT D816V engagement in AdvSM patients.
The predicted clinical exposure of the optimized 150 mg formulation of bezuclastinib is expected to surpass that of the previous formulation of bezuclastinib dosed at 100 mg twice-daily in APEX Part 1. Clinical data from approximately 30 patients from APEX Part 1 will be included in a presentation at a scientific meeting in the second half of 2023. Currently, clinical activity, safety and tolerability of patients dosed in APEX Part 1 remains consistent with results presented at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) meeting in December 2022.