On October 17, 2022 BridgeBio Pharma, Inc. (Nasdaq: BBIO) ("BridgeBio" or the "Company"), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, reported that preclinical data for its two lead RAS programs – a next-generation KRASG12C dual inhibitor program and a novel PI3Kα:RAS breaker program – in an oral presentation at the Fourth RAS Initiative Symposium in Frederick, MD (Press release, BridgeBio, OCT 17, 2022, View Source [SID1234622062]). BridgeBio will also be hosting an investor call at 1:30 ET today to discuss the data.

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KRAS G12C dual inhibitor:
BridgeBio has selected a next-generation KRASG12C dual inhibitor development candidate, BBO-8520, and plans to enter the clinic in 2023. BBO-8520 is the first-known small molecule that directly binds and inhibits KRASG12C in both its active (GTP bound) and inactive (GDP bound) conformations. BridgeBio believes this could lead to differentiated activity in cancer patients with KRASG12C driven disease, as all other known clinical stage direct KRASG12C inhibitors do not inhibit the active oncogenic form of the protein (GTP-bound KRASG12C).

Presentation highlights:
The KRASG12C GTP/GDP dual inhibitor development candidate

Using mass spectrometry, BBO-8520 was shown to completely modify both GTP (active) and GDP (inactive) forms of KRASG12C
BBO-8520 shows exceptional potency and selectivity – significantly greater potency than first-generation KRASG12C GDP-only inhibitors across multiple in vitro and in vivo assays including KRASG12C:RAF1 effector binding
Targeting KRASG12C GTP allows BBO-8520 to overcome growth factor override that is an important source of resistance for 1st-generation KRASG12C GDP-only inhibitors
BBO-8520 shows strong efficacy in KRASG12C models, including deep regressions in an NSCLC model and differentiated activity vs a first-generation KRASG12C GDP-only inhibitor in a patient-derived xenograft model
PI3Kα:RAS breaker:
BridgeBio is also pursuing PI3Kα:RAS breakers, small molecules that block RAS driven PI3Kα activation. Inhibiting PI3Kα activity by preventing its interaction with RAS can provide a "tumor selective" mechanism that spares glucose metabolism. This novel approach could, if successful, potentially have broad utility against oncogene-driven tumors (including RAS mutant tumors, PI3Kα mutant tumors, and tumors driven by RTK activation of RAS signaling) as both a monotherapy and in combination with other agents.

Presentation highlights:
PI3Kα:RAS breakers

Exhibited potent inhibition of AKT activation in KRAS G12X, PIK3CA helical mutation and HER family driven populations
Showed potent efficacy in multiple models without hyperglycemia, a common dose-limiting adverse reaction among PI3Kα kinase inhibitors
"We are excited about our next-generation KRASG12C GTP/GDP dual inhibitor development candidate and are hopeful that it has the opportunity to deliver improved outcomes for patients given the considerable unmet need remaining in the KRAS-driven cancer space," said Eli Wallace, Chief Scientific Officer, Oncology at BridgeBio. "We also think that the progress of our novel PI3Kα:RAS breaker program is very compelling, especially its in vivo demonstration of efficacy without hyperglycemia, which has proven a challenge for standard PI3Ka inhibitor treatments. We look forward to developing both programs further and hope to be able to serve the patients impacted by these two common oncogenes who are in need of innovative treatments."

Webcast Information
BridgeBio will host an investor call and simultaneous webcast to discuss preclinical data from both lead RAS programs and the selection of the KRASG12C dual inhibitor development candidate today, October 17, 2022, at 1:30 pm ET. To access this call via phone, participants will need to register using the following link where they will be provided a phone number and access code: (https://register.vevent.com/register/BIbd4d7a752dcc4ade970571556d4060e5). The webcast and presentation slides can be viewed during the time of the call via a link on the event calendar page of BridgeBio’s website at View Source A replay of the conference call and webcast will be archived on the Company’s website and will be available for at least 30 days following the event.