BBO-10203 / BridgeBio, BridgeBio Oncology Therapeutics - LARVOL DELTA

Trial in Progress Poster (GlobeNewswire) - "The data is being presented today at the San Antonio Breast Cancer Symposium (SABCS)....BREAKER-101 (NCT06625775) is a first-in-human, multicenter, open-label, Phase 1a/1b study evaluating the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of BBO-10203....Key endpoints include safety and tolerability, anti-tumor activity, and pharmacokinetics. Intracranial activity of BBO-10203 will also be evaluated as an exploratory endpoint. The study is currently enrolling patients in the United States and Australia, and initial Phase 1 clinical data are expected in the first half of 2026."

First-in-human • P1 data • Trial status • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer

BBOT Announces Late-Breaking Preclinical Data on BBO-10203, a First-in-Class RAS:PI3Kα Breaker, at the San Antonio Breast Cancer Symposium (SABCS) (GlobeNewswire) - "Preclinical data demonstrate BBO-10203 blocks RAS-mediated activation of PI3Kα, strongly inhibits pAKT signaling in tumor cells without inducing hyperglycemia, and shows robust anti-tumor activity both as monotherapy and in combination with standard of care therapies in mutant or wild-type PIK3CA breast cancer models."

Late-breaking abstract • Preclinical • Breast Cancer

BREAKER-101: a phase 1a/1b open-label study evaluating the safety, tolerability, pharmacokinetics, and efficacy of BBO-10203 in patients with advanced solid tumors (SABCS 2025) - P1 | "At recommended dose(s) for expansion, additional safety, PK, and antitumor activity will be evaluated for BBO-10203 monotherapy and in combination with trastuzumab in HER2+ aBC, as well as in combination with fulvestrant ± ribociclib in HR+/HER2- aBC, and with FOLFOX + bevacizumab in aCRC...BBO-10203 will be taken orally, once daily, in a 21-day or 28-day treatment cycle depending on the cohort. This study is currently open for enrollment."

Clinical • Metastases • P1 data • PK/PD data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Oncology • Solid Tumor • CDK4 • KRAS • PIK3CA

BBO-10203, a first-in-class breaker of the RAS:PI3Kα interaction, inhibits tumor growth alone and in combination with fulvestrant or ribociclib in breast cancer models without inducing hyperglycemia (SABCS 2025) - P1 | "In the EFM-19 CDX model, which harbors a kinase domain PIK3CA mutation, the combination of BBO-10203 and fulvestrant show the same activity as the combination of STX-478 and fulvestrant. In conclusion, BBO-10203 blocks RAS-mediated activation of PI3Kα, strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism, and shows robust tumor activity alone or in combination with standard of care therapies in mutant or wild-type PIK3CA breast cancer models. BBO-10203 has entered phase 1 clinical trials (NCT06625775) and may provide clinical benefit without the limiting toxicities that have restricted the use of PI3Kα inhibitors."

Combination therapy • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HRAS • KRAS • NRAS • PIK3CA

BBO-10203, a first-in-class, orally bioavailable, selective breaker of the RAS:PI3Kα interaction inhibits tumor growth alone and in combination with KRAS inhibitors in KRAS mutant models without inducing hyperglycemia (AACR-NCI-EORTC 2025) - P1 | "In vitro cellular studies and in vivo CDX, PDX, and GEM model studies show that BBO-10203 significantly enhances the anti-tumor activity of the dual GTP-bound (ON) and GDP-bound (OFF) KRASG12C and pan-KRAS inhibitors BBO-8520 (NCT06343402) and BBO-11818 (NCT06917079), respectively...In conclusion, BBO-10203 blocks RAS-mediated activation of PI3Kα and strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism. BBO-10203 has entered phase 1 clinical trials (NCT06625775) and is being evaluated in KRAS mutant CRC and NSCLC, both as a monotherapy and in combination with KRAS inhibitors."

Combination therapy • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • HRAS • KRAS • NRAS • PIK3CA

BridgeBio Oncology Therapeutics…announced two poster presentations featuring BBO-10203, a first-in-class, orally bioavailable, selective breaker of the RAS:PI3Kα interaction, at the San Antonio Breast Cancer Symposium (SABCS)… (GlobeNewswire)

Late-breaking abstract • Preclinical • Trial status • Breast Cancer

Preclinical Data Presented at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics Support Potential of BBO-10203, a First-in-Class RAS:PI3Kα Breaker That Inhibits KRAS-Mutant Tumor Growth without Inducing Hyperglycemia (GlobeNewswire) - "Data demonstrate BBO-10203 blocks RAS-mediated activation of PI3Kα and strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism. Robust monotherapy activity, as well as combination activity with BBOT’s KRASG12C ON/OFF inhibitor, BBO-8520, and panKRAS inhibitor, BBO-11818, was observed at well-tolerated dose levels in a panel of KRAS-mutant models."

Preclinical • Solid Tumor

BBO-11818: an orally bioavailable, highly potent and selective non-covalent pan-KRAS(ON) and (OFF) inhibitor with robust anti-tumor activity in KRAS-mutant preclinical models (AACR-NCI-EORTC 2025) - P1 | "Combination treatment with BBO-10203, a selective RAS:PI3Kα breaker that blocks RAS-mediated activation of the PI3K-AKT pathway (NCT06625775), results in decreased cellular proliferation, increased apoptosis, and enhanced efficacy in CDX and PDX models harboring KRASG12D or KRASG12V mutations. Similarly, combination treatment with BBO-11818 and cetuximab, an approved anti-EGFR monoclonal antibody, results in enhanced anti-tumor activity in a KRASG12D CDX model...BBO-11818 is a potent pan-KRAS inhibitor with activity against both the GTP- and GDP-bound states of KRAS, presenting the opportunity to address, as monotherapy or combination, a large fraction of KRAS mutant tumors currently lacking targeted therapeutic options. BBO-11818 has entered Phase 1 clinical trials for patients with various KRAS mutations in colorectal, pancreatic, and lung cancers (NCT06917079)."

IO biomarker • Preclinical • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BRAF • KRAS • NRAS • PIK3CA

BBOT-10203 is currently being evaluated in the Phase 1 BREAKER-101 trial for patients with HER2+ amplified or HR+/HER2- breast cancer, and KRAS mutant colorectal or non-small cell lung cancer with initial Phase 1 clinical data expected in the first half of 2026 (GlobeNewswire)

P1 data • Colorectal Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Non Small Cell Lung Cancer

BBOT Presents Preclinical Data Demonstrating Potential of BBO-11818 as a Potent panKRAS Inhibitor at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire) - "Data demonstrate potent suppression of MAPK signaling and viability in KRAS mutant cell lines, as well as anti-tumor activity across multiple KRASG12D and KRASG12V cell-derived xenograft (CDX) models....Efficacy of the combination with BBOT’s RAS:PI3K⍺ breaker, BBO-10203, is driven by a robust decrease in tumor cell proliferation and increase in apoptosis..."

Preclinical • Colorectal Cancer • Non Small Cell Lung Cancer • Pancreatic Cancer

BBOT Announces Poster Presentations at the 2025 AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics (GlobeNewswire)

Preclinical • Solid Tumor

Precise regulation of RAS-Mediated PI3Kα activation: therapeutic potential of BBO-10203 in cancer treatment. (PubMed, Exp Hematol Oncol) - "Although conventional PI3Kα inhibitors (e.g., Alpelisib) have shown efficacy in extending progression-free survival in patients with PI3Kα-mutant breast cancer, their clinical application remains constrained by off-target toxicities, particularly hyperglycemia, which limits dosing and therapeutic feasibility. The compound is rationally designed to selectively and covalently bind to Cysteine 242 (Cys242) within the Rat Sarcoma (RAS)-Binding Domain (RBD) of PI3Kα, thereby effectively disrupting RAS-mediated PI3Kα activation. This unique mechanism confers potent in vivo antitumor activity while preserving insulin-regulated glucose metabolism, thereby mitigating metabolic adverse effects."

Journal • Breast Cancer • Diabetes • Oncology • Sarcoma • Solid Tumor • PIK3CA

BBOT Debuts as a Publicly Traded Company Focused on RAS-Pathway Malignances with a Potential to Realize the Full Promise of KRAS and PI3K Inhibition (GlobeNewswire) - "BridgeBio Oncology Therapeutics...announced the closing of its previously announced business combination with Helix Acquisition Corp. I....The combined business is expected to have approximately $490 million in cash....BBOT will use the net proceeds to accelerate the development of its pipeline of RAS-targeted oncology drug candidates, including: BBO-8520..., BBO-10203..., BBO-11818...."

Commercial • Breast Cancer • Colorectal Cancer • Non Small Cell Lung Cancer

BREAKER-101: Open-Label Study of BBO-10203 in Subjects With Advanced Solid Tumors (clinicaltrials.gov) - P1 | N=392 | Recruiting | Sponsor: TheRas, Inc., d/b/a BBOT (BridgeBio Oncology Therapeutics) | N=153 ➔ 392

Enrollment change • Breast Cancer • Colorectal Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Hormone Receptor Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • KRAS

BBOT Announces Publication in Science Highlighting Preclinical Data that Supports the Potential for RAS:PI3Kα Breaker BBO-10203 to Provide Therapeutic Benefit across Multiple Tumor Types (Businesswire) - "These data describe the discovery and preclinical evaluation of BBO-10203, a first-in-class, orally available inhibitor that selectively blocks the interaction between RAS proteins and PI3Kα without impairing insulin signaling....The compound showed broad antitumor activity in vitro and in vivo and demonstrated enhanced efficacy when combined with targeted therapies such as CDK4/6 inhibitors, ER antagonists, HER2 inhibitors, and KRASG12C inhibitors. These findings support the potential of BBO-10203 as a well-tolerated, mechanistically distinct therapeutic for PI3Kα- and RAS-driven cancers."

Preclinical • Oncology

BBO-10203 inhibits tumor growth without inducing hyperglycemia by blocking RAS-PI3Kα interaction. (PubMed, Science) - "In preclinical models, BBO-10203 caused significant tumor growth inhibition across multiple tumor types and showed enhanced efficacy in combination with inhibitors of cyclin-dependent kinase 4/6 (CDK4/6), estrogen receptor (ER), HER2 and KRAS-G12C mutant, including in tumors harboring mutations in Kelch-like ECH-associated protein 1 (KEAP1) and Serine/Threonine Kinase 11 (STK11). Notably, these antitumor effects occurred without inducing hyperglycemia, as insulin signaling does not depend on RAS-mediated PI3Kα activation to promote glucose uptake."

Journal • Diabetes • Oncology • CDK4 • ER • HER-2 • HRAS • KEAP1 • KRAS • NRAS • PIK3CA • STK11

BBO-8520, a first-in-class direct dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C, exhibits robust efficacy in non-small cell lung cancer preclinical models (AACR 2025) - P1 | "Sotorasib and adagrasib, allele-specific KRASG12C covalent inhibitors that only target KRASG12C in the inactive GDP-bound (OFF) state, have been approved for patients with KRASG12C locally advanced or metastatic non-small cell lung cancer (NSCLC)...BBO-8520 also exhibits strong combination benefit in vivo in the KRASG12 CDX model NCI-H2122 when combined with either BBO-10203, a selective RAS:PI3Kα breaker that blocks RAS-mediated activation of AKT in clinical development (NCT06625775), or the anti-EGFR antibody cetuximab. In summary, BBO-8520 is a first in class, potent and selective KRASG12C dual GTP-bound (ON) and GDP-bound (OFF) inhibitor that exhibits robust efficacy and may improve upon approved, KRASG12C GDP-bound (OFF)-only inhibitors in NSCLC. BBO-8520 has entered phase 1 clinical trials in patients with KRASG12C NSCLC that are either naïve or have experienced first-generation KRASG12C (OFF) inhibitors (NCT06343402)."

Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PIK3CA

BBO-11818, an orally bioavailable, highly potent and non-covalent pan-KRAS inhibitor demonstrates robust anti-tumor activity in KRAS-mutant preclinical models (AACR 2025) - "In combination with either BBO-10203, a selective RAS:PI3Kα breaker that blocks RAS-mediated activation of AKT; or cetuximab, an anti-EGFR monoclonal antibody, BBO-11818 shows significantly enhanced efficacy in models harboring KRASG12D or KRASG12V mutations. BBO-11818 also shows a combination benefit with anti-PD-1 treatment, resulting in complete tumor regressions in the CT-26 syngeneic tumor mouse model. BBO-11818 is a potent pan-KRAS inhibitor with activity against both GTP and GDP forms of KRAS, presenting the opportunity to address, as monotherapy or combination, a large fraction of KRAS mutant tumors currently lacking targeted therapeutic options."

IO biomarker • Preclinical • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Pancreatic Cancer • Solid Tumor • BRAF • KRAS • NRAS • PIK3CA

BridgeBio Oncology Therapeutics (BBOT) and Helix Acquisition Corp. II Announce Business Combination Agreement to Create Publicly Listed Biotechnology Company Advancing a Pipeline of RAS and PI3Kα-Targeting Medicines (Businesswire) - "TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics...and Helix Acquisition Corp...announced that they have entered into a definitive business combination agreement. Upon closing of the transaction, the combined company will be renamed 'BridgeBio Oncology Therapeutics, Inc.'...In addition to approximately $196 million held in Helix Acquisition Corp. II’s trust account (assumed as of the closing and assuming no redemptions by Helix’s public shareholders), the transaction also includes commitments for an approximately $260 million PIPE from a group of premier institutional investors...Net proceeds from the transaction are expected to provide BBOT with the capital needed to accelerate the development of three lead programs: BBO-8520, BBO-10203, and BBO-11818....BBOT expects to dose the first patient with BBO-11818 in the first half of 2025."

M&A • New trial • Colorectal Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Non Small Cell Lung Cancer • Solid Tumor

BBO-10203, a first-in-class, orally bioavailable, selective blocker of the PI3Kα:RAS interaction inhibits tumor growth alone and in combination with standard of care therapies in breast cancer models without inducing hyperglycemia. (SABCS 2024) - "In vitro and in vivo studies show that BBO-10203 significantly enhances the anti-tumor activity of the HER2-targeted antibody trastuzumab in the BT-474 (ER+, HER2amp, and PIK3CAK111N) and MDA-MB-453 (ER-, HER2+, and PIK3CAH1047R) breast cancer models. In addition, BBO-10203 also significantly enhances the anti-tumor activity of the SERD fulvestrant or the CDK4/6 inhibitor palbociclib in the MCF7 (ER+, HER2-, and PIK3CAE545K) breast cancer model...In conclusion, BBO-10203 blocks RAS-mediated activation of PI3Kα and strongly inhibits pAKT signaling in tumor cells without affecting glucose metabolism. BBO-10203 has entered phase 1 clinical trials and may provide clinical benefit without the limiting toxicities that have restricted the use of PI3Kα inhibitors."

Combination therapy • Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Oncology • Solid Tumor • ER • HRAS • IR • KRAS • NRAS • PIK3CA

BridgeBio Oncology Therapeutics (BBOT) Announces First Patient Dosed with First-in-Class BBO-10203, a RAS:PI3Kα Breaker, in the Phase 1 BREAKER-101 Trial for Advanced Solid Tumors (Businesswire) - "TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics...has announced that the first patient has been dosed with BBO-10203 in the BREAKER-101 trial. BBO-10203 is a first-in-class orally bioavailable RAS:PI3Ka breaker that blocks the interaction between RAS and PI3Kα to inhibit PI3Kα-AKT signaling in tumors, without directly inhibiting the catalytic activity of PI3Kα....The BREAKER-101 trial will enroll patients globally with locally advanced or metastatic HER2-positive breast cancer, HR-positive/HER2-negative breast cancer, KRAS mutant advanced colorectal cancer, and KRAS mutant advanced non-small cell lung cancer."

Trial status • Colorectal Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Non Small Cell Lung Cancer

BBO-10203, an orally bioavailable small molecule that disrupts the RAS-PI3K interaction leading to pAKT and tumor growth inhibition in models of breast, lung and colorectal cancer (EORTC-NCI-AACR 2024) - "Even though BBO-10203 does not inhibit the kinase activity of PI3Ka, its effects on cancer cell signaling inhibition and transcriptional regulation highly resemble those of alpelisib...Combinations with trastuzumab, fulvestrant, palbociclib, KRASG12C inhibitor, and irinotecan results in significantly better efficacy than either agent alone in HER2amp, ER+ Breast, KRASG12C mutant NSCLC and KRAS mutant CRC, respectively... We have identified a novel pharmacological approach to inhibit the PI3Ka signaling pathway by blocking its interaction with, and activation by RAS proteins. This approach can achieve strong pAKT inhibition in tumor cells without changes in glucose metabolism. Clinical investigation of BBO-10203 alone and in combination with multiple standard of care therapeutics is warranted."

Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • Hormone Receptor Breast Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • EGFR • IR • KRAS

Dose Escalation and Expansion of BBO-10203 in Advanced Solid Tumors (BREAKER-101) (clinicaltrials.gov) - P1 | N=153 | Recruiting | Sponsor: TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics | Not yet recruiting ➔ Recruiting

Enrollment open • Metastases • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • KRAS

Dose Escalation and Expansion of BBO-10203 in Advanced Solid Tumors (BREAKER-101) (clinicaltrials.gov) - P1 | N=153 | Not yet recruiting | Sponsor: TheRas, Inc., d/b/a BridgeBio Oncology Therapeutics

New P1 trial • Breast Cancer • Colorectal Cancer • Gastrointestinal Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Lung Cancer • Oncology • Solid Tumor • KRAS

BridgeBio launches BridgeBio Oncology Therapeutics (BBOT) with $200M of private external capital to accelerate the development of its novel precision oncology pipeline (GlobeNewswire) - "BridgeBio Pharma, Inc...has announced the completion of a $200M private financing of its former subsidiary, TheRas, Inc. d/b/a BridgeBio Oncology Therapeutics (BBOT), to accelerate the development of its oncology portfolio....BBOT will be advancing three initial programs: BBO-8520, a direct inhibitor of KRASG12C that binds to both the ON and OFF states of the protein....BBOT expects to file an Investigational New Drug application (IND) for BBO-10203 in Q2 2024 and, subject to clearance of the IND, will begin enrolling patients later this year. BBO-11818, a pan-KRAS inhibitor that targets both the ON and OFF states of KRASG12X for which BBOT expects to file an IND in early 2025."

Financing • IND • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor