On January 3, 2024 BridgeBio Pharma, Inc. (Nasdaq: BBIO) ("BridgeBio" or the "Company"), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported that the United States Food and Drug Administration (FDA) has cleared the investigational new drug (IND) application for BBO-8520, a first-in-class orally bioavailable and highly potent small molecule direct inhibitor of KRASG12C (ON) state (Press release, BridgeBio, JAN 3, 2024, View Source [SID1234638904]). BBO-8520 binds covalently to the Switch II pocket in both the GTP-bound (ON) and GDP-bound (OFF) state conformations of KRASG12C, leading to rapid and robust inhibition of KRASG12C activity.

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BBO-8520’s ability to inhibit the (ON) state should provide optimal target coverage and address KRASG12C amplification and receptor tyrosine kinase activation – the two key mechanisms of adaptive resistance to current (OFF) state inhibitors. BBO-8520 drives substantial tumor growth inhibition in multiple preclinical models, even after emergence of resistance to sotorasib, an FDA approved (OFF) state inhibitor of KRASG12C.

"Clinical results from the first generation of KRASG12C inhibitors suggest that compounds with better potency and the ability to target the ON state are likely to lead to better outcomes," said Frank McCormick, Ph.D., Chairman of Oncology at BridgeBio, David A. Wood Distinguished Professor of Tumor Biology and Cancer Research at UCSF and advisor to the National Cancer Institute’s RAS Initiative at Frederick National Laboratory for Cancer Research (FNL). "BBO-8520 is the most potent G12C inhibitor with an IND, and the only compound that directly binds and targets the ON state. We hope that this drug will bring significantly improved benefit for patients suffering from KRASG12C cancers."

BBO-8520’s discovery was the result of a collaboration between the RAS Initiative FNL, Lawrence Livermore National Laboratory and BridgeBio. It is specifically designed to provide patients afflicted with KRASG12C mutant cancers with a best-in-class, oral small molecule therapy that directly targets the tumor at its source – oncogenic KRASG12C GTP-bound (ON) signaling. Enrollment of patients with KRASG12C mutant non-small cell lung cancer into the ONKORAS-101 trial is expected to begin in H1 of this year.