BridgeBio Pharma Highlights its RAS Precision Oncology Portfolio and Shares Compelling Data from Next-generation G12C Inhibitor and Novel PI3Kα:RAS Breaker Mechanism at the Fourth RAS Initiative Symposium
– BridgeBio to host investor call today (October 17, 2022) at 1:30 pm ET to discuss its two most advanced RAS precision oncology programs – KRASG12C GTP/GDP dual inhibitor development candidate BBO-8520, and its novel PI3Kα:RAS breaker mechanism which is in late lead optimization
– KRASG12C GTP/GDP dual inhibitor BBO-8520 has shown significantly greater potency in KRAS models than first-generation KRAS G12C GDP-only inhibitors as measured by its ability to bind and covalently modify KRASG12C, block KRASG12C binding to effector proteins such as RAF, and inhibit downstream signaling
– BBO-8520 was shown to retain potency in the context of receptor tyrosine kinase drive, which renders KRAS G12C GDP-only inhibitors inactive and is thought to be a major mechanism of non-response and resistance to these first-generation agents
– BBO-8520 showed strong activity in KRASG12C in vivo models including deep regressions and differentiated efficacy compared to a first-generation KRASG12C GDP-only inhibitor
– BridgeBio scientists highlighted rationale and design of compounds targeting PI3Kα:RAS binding, which is a novel and potentially broad MoA to target PI3Kα mutant tumors, RAS mutant tumors and potentially other tumors driven by RTK activation of RAS signaling
– Targeting PI3Kα activity in tumors through its interaction with RAS may spare glucose metabolism, potentially allowing for potent target coverage without displaying the dose-limiting hyperglycemia common to PI3Kα kinase inhibitors
– RAS is the most common oncogenic driver with approximately 30% of all human cancers being driven by RAS mutations, including large proportions of lung, colorectal and pancreatic tumors. PIK3CA is the second most common oncogene in human tumors, being present in more than 30% of breast and endometrial carcinomas
PALO ALTO, Calif., Oct. 17, 2022 (GLOBE NEWSWIRE) — BridgeBio Pharma, Inc. (Nasdaq: BBIO) (“BridgeBio” or the “Company”), a commercial-stage biopharmaceutical company focused on genetic diseases and cancers, today presented 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. BridgeBio will also be hosting an investor call at 1:30 ET today to discuss the data.
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).
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
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.
- 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.”
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 https://investor.bridgebio.com/news-and-events/event-calendar. 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.
About BridgeBio Pharma, Inc.
BridgeBio Pharma, Inc. (BridgeBio) is a commercial-stage biopharmaceutical company founded to discover, create, test and deliver transformative medicines to treat patients who suffer from genetic diseases and cancers with clear genetic drivers. BridgeBio’s pipeline of development programs ranges from early science to advanced clinical trials. BridgeBio was founded in 2015 and its team of experienced drug discoverers, developers and innovators are committed to applying advances in genetic medicine to help patients as quickly as possible. For more information visit bridgebio.com and follow us on LinkedIn and Twitter.
BridgeBio Pharma, Inc. Forward-Looking Statements
This press release contains forward-looking statements. Statements we make in this press release may include statements that are not historical facts and are considered forward-looking within the meaning of Section 27A of the Securities Act of 1933, as amended (the Securities Act), and Section 21E of the Securities Exchange Act of 1934, as amended (the Exchange Act), which are usually identified by the use of words such as “anticipates,” “believes,” “estimates,” “expects,” “intends,” “may,” “plans,” “projects,” “seeks,” “should,” “will,” and variations of such words or similar expressions. We intend these forward-looking statements to be covered by the safe harbor provisions for forward-looking statements contained in Section 27A of the Securities Act and Section 21E of the Exchange Act and are making this statement for purposes of complying with those safe harbor provisions. These forward-looking statements, including statements relating to expectations, plans and prospects regarding the preclinical and clinical development plans, clinical trial designs, clinical and therapeutic potential, safety profile, and strategy of our product candidates, including, but not limited to: the timing and success of our RAS program, including our KRAS G12C/GDP dual inhibitor development candidate BBO-8520 and plans to be in the clinic in 2023; the potential for our next-generation G12C dual inhibitors to be the first known compounds designed to directly bind and inhibit KRAS in both its active (GTP bound) and inactive (GDP bound) conformations driven by insights from its molecular dynamics platform; the potential for BBO-8520 to lead to differentiated activity in cancer patients with KRASG12C driven disease; our pursuit of PI3Kα:RAS breakers, if successfully developed, for potential 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; and the timing of these events, reflect our current views about our plans, intentions, expectations, strategies and prospects, which are based on the information currently available to us and on assumptions we have made. Although we believe that our plans, intentions, expectations, strategies and prospects as reflected in or suggested by those forward-looking statements are reasonable, we can give no assurance that the plans, intentions, expectations or strategies will be attained or achieved. Furthermore, actual results may differ materially from those described in the forward-looking statements and will be affected by a number of risks, uncertainties and assumptions, including, but not limited to: if the development program is not successful or if competing therapy options are approved; the design and success of planned clinical trials, future regulatory filings, approvals and/or sales; the FDA or such other regulatory agencies may not agree with our regulatory approval strategies, components of our filings, such as clinical trial designs, conduct and methodologies, or the sufficiency of data submitted; potential adverse impacts due to the global COVID-19 pandemic such as delays in regulatory review, manufacturing and supply chain interruptions, adverse effects on healthcare systems and disruption of the global economy; and those risks set forth in the Risk Factors section of our most recent annual report on Form 10-K filed with the U.S. Securities and Exchange Commission (SEC) and our other SEC filings. Moreover, BridgeBio operates in a very competitive and rapidly changing environment in which new risks emerge from time to time. These forward-looking statements are based upon the current expectations and beliefs of BridgeBio’s management as of the date of this release and are subject to certain risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements. Except as required by applicable law, we assume no obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.