Business Description

Overview OnKure Therapeutics, Inc. (“OnKure”, “we”, “us” or the “Company”) is a clinical-stage biopharmaceutical company focused on the discovery and development of precision medicines that target biologically validated drivers of cancers and other diseases that are underserved by available therapies. Using a structure-based drug design platform, we are committed to improving clinical outcomes for patients by building a pipeline of small molecule drugs designed to achieve optimal efficacy and tolerability by selectively targeting specific mutations shown to be key drivers of cancer and other diseases. By selectively sparing the wild-type enzyme and preferentially targeting the mutated form of the protein, which is oncogenic and drives disease processes in both cancer and vascular overgrowth syndromes, we aim to discover and develop drugs with improved safety and efficacy by sparing toxicity that arises from non-selective inhibition of the non-mutated (or wild-type) version of the protein. We work under the principle that inhibiting target proteins with specific mutations instead of wild-type variants should enable precise patient selection that will, in turn, improve the probability of clinical success. We designed our current product candidates utilizing disciplined medicinal chemistry, x-ray crystallography and computational chemistry to inhibit specified mutated versions of phosphoinositide 3-kinase alpha (“PI3Kα”), a key disease creating gene. Our lead product candidate, OKI-219, is a highly selective inhibitor of PI3K α harboring the H1047R mutation (“PI3Kα H1047R ”) that has a much smaller impact on wild-type PI3Kα (“PI3Kα WT ”). By minimizing the targeting of PI3Kα WT (approximately 80-fold selectivity for PI3Kα H1047R over PI3Kα WT ), we believe OKI-219 can achieve exposures required for activity in PI3Kα-mutated cancers with minimal effect on wild-type PI3Kα signaling, thus potentially limiting on-target toxicities, such as hyperglycemia, gastrointestinal (“GI”) effects, fatigue, and rash. We plan to initially focus on the development of OKI-219 in patients with advanced breast cancer of genetic subtypes that are (a) both hormone receptor positive (“HR+”) and human epidermal growth factor receptor 2 negative (“HER2-”); and (b) human epidermal growth factor receptor 2 positive (“HER2+”). We believe we can potentially expand the application of OKI-219 by conducting appropriate clinical trials in earlier lines of treatment within breast cancer, other subtypes of breast cancer, and potentially in other solid tumors. We aim to render OKI-219 as a preferred backbone therapy to which other medicines are added in the context of PI3Kα H1047R -driven disease. OKI-219 is currently being investigated in a first-in-human Phase 1 open-label multi-arm clinical trial evaluating OKI-219 in patients with solid tumors, including breast cancer harboring a PI3Kα H1047R mutation (“PIKture-01”). In the first arm, OKI-219 is being investigated as a monotherapy in patients with solid tumors, including breast cancer, harboring a PI3K a H1047R mutation. Data reported from this arm supported the initiation of the first combination arm investigating OKI-219 as part of a doublet therapy in combination with fulvestrant in patients with HR+/HER2- breast cancer harboring a PI3Kα H1047R mutation (“Part B)”. In the second half of 2025, we expanded PIKture-01 to investigate OKI-219 as part of triplet regimens in two breast cancer subtypes, HR+HER2- (HR+) and HER2+. In September 2025, we initiated the first triplet expansion arm of PIKture-01 evaluating OKI-219 in combination with fulvestrant and ribociclib in patients with PI3K a H1047R mutated, HR+ metastatic breast cancer (“Part E”). In October 2025, we initiated a triplet expansion arm of PIKture-01 evaluating OKI-219 in combination with trastuzumab and tucatinib in patients with PI3Kα H1047R mutated, HER2+ metastatic breast cancer (“Part C”). In December 2024, we announced preliminary safety, tolerability, and pharmacokinetic (“PK”) data from Part A of PIKture-01 with a cut off date of October 28, 2024. These data showed that OKI-219 was well tolerated across all dose levels with no hyperglycemia, stomatitis, or rash observed at any dose, and all reported treatment-related adverse events (“TRAEs”) have been grade 1. No dose interruptions, delays, reductions, or discontinuations were reported for TRAEs.…