On April 11, 2022 Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, reported two poster presentations at the American Association of Cancer Research (AACR) (Free AACR Whitepaper) annual meeting taking place April 8-13, 2022 (Press release, Cogent Biosciences, APR 11, 2022, View Source [SID1234611970]). The first included updated nonclinical bezuclastinib data reinforcing its potential to be a differentiated, best-in-class KIT mutant inhibitor. The second focused on nonclinical data from Cogent’s next-generation fibroblast growth factor receptor 2 (FGFR2) research program, designed to spare FGFR1 while potently covering all gatekeeper and molecular brake mutations. Finally, the company shared additional details at an R&D Investor Event, on its portfolio expansion plans by highlighting its early efforts to develop an ErbB2 mutant selective inhibitor for patients with non-exon 20 mutations.
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"We continue to make significant progress establishing Cogent as an emerging leader in precision medicines for genetically defined diseases," said Andrew Robbins, President and Chief Executive Officer of Cogent Biosciences. "This weekend we presented updated nonclinical data adding to a growing body of evidence supporting bezuclastinib as a potential best-in-class KIT mutant inhibitor for systemic mastocytosis and gastrointestinal stromal tumor (GIST) patients. Separately, we introduced two novel programs from the Cogent Research Team which highlighted our growing portfolio of novel, small-molecule targeted therapies for patients fighting genetically driven diseases. We continue to enroll patients into our APEX, SUMMIT and PEAK trials and look forward to sharing initial clinical results from the APEX study later this quarter."
Bezuclastinib Nonclinical Data
Bezuclastinib is a tyrosine kinase inhibitor that is active against KIT mutations relevant to both systemic mastocytosis (SM) and gastrointestinal stromal tumors (GIST). New nonclinical data, presented at AACR (Free AACR Whitepaper), demonstrates that bezuclastinib potently inhibits A loop-mutations exquisitely selective against other closely related kinases, and differentiates bezuclastinib by its lack of brain penetration. These data support that bezuclastinib inhibits KIT downstream signaling and is able to drive tumor regressions at clinically achievable doses.
"Currently approved KIT inhibitors are limited by off-target toxicities related to broad-spectrum kinase inhibition, secondary activation loop mutations, CNS-related adverse events, and sub-optimal clinical dosing," said Jessica Sachs, MD, Cogent’s Chief Medical Officer. "With KIT mutations serving as driver mutations in up to 80% of GIST and over 90% of systemic mastocytosis, we’re excited with the growing validation of bezuclastinib as a highly potent and selective inhibitor of KIT D816V and remain focused on advancing our ongoing clinical trials."
Growing Pipeline of Small Molecule Inhibitors
Cogent’s research team is also building a pipeline of small molecule inhibitors. 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. Based on preclinical data presented, the Company’s FGFR program has the potential to both spare FGFR1 inhibition, avoiding related toxicity, as well as potently cover the relevant molecular brake and gatekeeper mutations associated with this target. Cogent is advancing a potent, selective FGFR2 inhibitor program toward candidate selection later this year and expects to file this first internally developed Investigational New Drug application (IND) in the second half of 2023.
The Company also shared an early look at a novel, non-exon 20 ErbB2 mutant program. ErbB2 is a tyrosine kinase receptor that belongs to a family of four receptors, which are also known as HER1, HER2, HER3 and HER4, respectively. A significant unmet need remains for patients with non-exon 20 ErbB2 mutations. Activating mutations in the ErbB2 gene have been identified in multiple cancers and demonstrate a tumorigenic role similar to that of ErbB2 amplification.
"We’ve made tremendous progress moving our programs from early discovery into lead generation," said John Robinson, PhD, Cogent’s Chief Scientific Officer. "We are pleased to share the latest developments which highlight the ability of our team to discover new treatment candidates in genetically defined diseases with high unmet need, and we look forward to discussing additional programs in the future, including potential first-to-market opportunities."