OKI-219 / OnKure - LARVOL DELTA

OnKure Therapeutics Reports Fourth Quarter and Full Year 2024 Financial Results and Recent Business Highlights (GlobeNewswire) - "...Upcoming Anticipated Milestones:... (i) PIKture-01 trial Part A Monotherapy:...OnKure is currently enrolling the last cohort with a top dose of 1500 mg BID and enrollment in Part A is almost complete. OnKure expects to provide a clinical update in the second half of 2025; (ii) PIKture-01 Part B Fulvestrant Combination - In the fourth quarter of 2024, OnKure initiated patient dosing in Part B of the PIKture-01 trial, evaluating OKI-219 in combination with fulvestrant in patients with PI3KαH1047R mutated HR+/HER2- metastatic breast cancer. To date, OnKure has enrolled patients in the Part B fulvestrant combination arm of PIKTure-01 through the 900 mg BID cohort with no dose limiting toxicities observed for all completed cohorts through 600 mg BID and enrollment in the dose escalation portion of Part B is almost complete. OnKure expects to report initial combination data with fulvestrant in the second half of 2025."

P1 data • Trial status • HER2 Negative Breast Cancer • Hormone Receptor Positive Breast Cancer

OKI-219 enhances activity of SOC therapies in double and triple combinations in pre-clinical PI3Kα H1047R mutant breast cancer models (SABCS 2024) - P1 | "In vitro, in the T47D ER+, PI3KαH1047R model, the combination activity of OKI-219 + fulvestrant + ribociclib or palbociclib was assessed in proliferation assays and evaluated for synergy using the Loewe additivity model...Importantly, in tumors that had progressed on alpelisib or alpelisib + fulvestrant, the replacement of alpelisib with OKI-219 drove tumor regression...These preclinical studies provide compelling evidence of synergistic antitumor effects and lay the groundwork for ongoing clinical trials. OKI-219 is being investigated clinically in the PIKture-01 study, a First-in-Human Study of OKI-219 in Advanced Solid Tumors and Advanced Breast Cancer (NCT06239467)."

Preclinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

Preliminary results from PIKture-01, a First-in-Human Study of OKI-219, a mutant selective inhibitor of PI3Kα-H1047R, in mutant selected solid tumors including breast cancer. (SABCS 2024) - "The currently approved PI3Kα inhibitors such as alpelisib target both wild-type and mutant forms, leading to significant on-target toxicities, including hyperglycemia, rash, and diarrhea [4,5]...The study also includes a dose optimization phase to evaluate the optimal combination doses of OKI-219 with fulvestrant or trastuzumab... OKI-219 has been very well tolerated with a favorable safety profile, and only Grade 1 TRAEs observed at exposures that are consistent with preclinical activity, even at the lowest dose level. As a single agent, OKI-219 has shown favorable PK that support pharmacologically relevant exposures, even at the lowest assessed dose levels, with a safety profile that suggests little or no inhibition of WT PI3Kα. We anticipate near completion of enrollment of the single agent portion of the study as well as the initiation of combination expansion of OKI-219 with fulvestrant by the end of the year."

P1 data • Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

OnKure Announces Encouraging Preliminary Safety, Tolerability, and Pharmacokinetic (PK) Data from its First-In-Human PIKture-01 Trial of OKI-219 (GlobeNewswire) - P1 | N=150 | PIKture-01 (NCT06239467) | Sponsor: OnKure, Inc. | "Patients have been treated with OKI-219 at three dose levels as a single agent: 300 mg BID, 600 mg BID, and 900 mg BID....OKI-219 has been generally well tolerated, with no dose-limiting toxicities, dose interruptions, or dose reductions required. The most common TRAEs were Grade 1 diarrhea (N=4), Grade 1 nausea (N=2) and Grade 1 pruritus (N=2). OKI-219 has shown favorable PK data that support pharmacologically relevant exposures, even at the lowest assessed dose levels, with a safety profile that suggests little or no inhibition of wild-type PI3Kα....Data support the initiation of Part 1b of PIKture-01 evaluating OKI-219 in combination with fulvestrant; first patients dosed, and initial data are expected in 2H-2025."

P1 data • PK/PD data • Colorectal Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Positive Breast Cancer • Squamous Cell Carcinoma • Triple Negative Breast Cancer

Pre-Clinical Data (GlobeNewswire) - "Preclinical in vivo data show that OKI-219 used in combination with standard-of-care therapies for mutant-selected solid tumors, including breast cancers, showed potent anti-tumor activity with excellent tolerability at doses well above those needed for tumor regressions in those models. Specifically, OKI-219 shows strong combination activity in doublet with SERDs and in triplet with SERD + CDK4/6 inhibitors. Additional preclinical combination studies are ongoing. The Company believes OKI-219’s selectivity could provide increased safety both as a single agent and in combination."

Preclinical • Breast Cancer • Solid Tumor

OnKure to Present Clinical and Preclinical Data for OKI-219 at the 2024 San Antonio Breast Cancer Symposium (GlobeNewswire) - "OnKure plans to include additional data in the posters being presented at SABCS...OnKure will host a conference call and live webcast Friday, December 13, 2024 at 7:00 a.m. CT (8:00 a.m. ET) to discuss the preliminary data from its first-in-human PIKture-01 trial of OKI-219..."

P1 data • Preclinical • Breast Cancer

Reneo Pharmaceuticals Announces Stockholder Approval of Merger with OnKure (GlobeNewswire) - "Reneo Pharmaceuticals...announced the results of the special meeting of its stockholders held on September 26, 2024. At the special meeting, Reneo’s stockholders voted in favor of all proposals, including the proposals required to complete the proposed merger of Reneo and OnKure....The closing of the merger is anticipated to take place on or around Friday, October 4, 2024. Following the closing of the merger, the combined company plans to change its name from 'Reneo Pharmaceuticals, Inc.' to 'OnKure Therapeutics, Inc'....The combined company will focus on advancing OnKure’s pipeline candidates targeting oncogenic mutations in phosphoinositide 3-kinase alpha (PI3Kα), including its lead program OKI-219, which is currently in a Phase 1 clinical trial for the treatment of solid tumors."

M&A • Solid Tumor

OnKure Announces Closing of Merger with Reneo Pharmaceuticals and Concurrent Private Placement of $65 Million (GlobeNewswire) - "OnKure Therapeutics...announced the completion of its previously announced merger of OnKure, Inc. and Reneo Pharmaceuticals, Inc. ('Reneo'). The combined company will operate under the name OnKure Therapeutics....Concurrent with the closing of the merger, the company completed a $65 million private placement with a group of new and existing investors, including Acorn Bioventures, Cormorant Asset Management, Deep Track Capital, Perceptive Advisors, Samsara BioCapital, Surveyor Capital (a Citadel company), Vestal Point Capital, and other undisclosed investors....'With the PIKture-01 trial of OKI-219 well underway, we look forward to releasing early clinical data in the fourth quarter of 2024'..."

M&A • P1 data • Breast Cancer

Reneo Pharmaceuticals and OnKure Announce Proposed Merger (GlobeNewswire) - "Reneo Pharmaceuticals, Inc...announced that they have entered into a definitive merger agreement to combine the companies in an all-stock transaction. The combined company will focus on advancing OnKure’s pipeline candidates targeting oncogenic mutations in phosphoinositide 3-kinase alpha (PI3Kα), including its lead program OKI-219, which is currently in a Phase 1 clinical trial for the treatment of solid tumors. Upon completion of the transaction, the combined company is expected to operate under the name OnKure Therapeutics, Inc., and trade on the Nasdaq Global Market under the ticker symbol 'OKUR'.... The merger and concurrent PIPE financing are expected to close in 2024."

M&A • Breast Cancer • Oncology • Solid Tumor

OKI-219 is an inhibitor of PI3Kα H1047R that has brain penetrance and anti-tumor activity in a preclinical intracranial model of metastatic breast cancer (AACR 2024) - "The FDA-approved PI3K inhibitor alpelisib lacks CNS activity, and brain-penetrant alternatives such as buparlisib and paxalasib were not approved due to toxicity associated with a lack of mutant selectivity. Here we show that OKI-219 had consistently good brain penetrance across multiple species by multiple methods of measuring free drug levels in the brain. We further demonstrated that OKI-219 had anti-tumor activity against xxT47D-luc tumors in an intracranial mouse model that is similar to activity in the same tumor when implanted subcutaneously, demonstrating that the brain levels achieved were pharmacologically active. These data indicate the potential for activity of OKI-219 in CNS disease settings, including metastatic brain cancer, which are not currently addressed with existing PI3K pathway inhibitors."

Late-breaking abstract • Metastases • Preclinical • Brain Cancer • Breast Cancer • HER2 Breast Cancer • Lung Cancer • Oncology • Solid Tumor • HER-2 • PIK3CA

PIKture-01: First-in-Human Study of OKI-219 in Advanced Solid Tumors and Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=150 | Recruiting | Sponsor: OnKure, Inc. | Not yet recruiting ➔ Recruiting

Combination therapy • Enrollment open • Metastases • Monotherapy • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor

PIKture-01: First-in-Human Study of OKI-219 in Advanced Solid Tumors and Advanced Breast Cancer (clinicaltrials.gov) - P1 | N=150 | Not yet recruiting | Sponsor: OnKure, Inc.

New P1 trial • Breast Cancer • HER2 Breast Cancer • Oncology • Solid Tumor

OnKure Announces IND Clearance by U.S. FDA Enabling Phase 1 Initiation for its Mutant Selective PI3Kα inhibitor, OKI-219 (GlobeNewswire) - "OnKure...announced that the U.S. Food and Drug Administration (FDA) has cleared the Investigational New Drug (IND) application of OKI-219, a potential best-in-class, mutant selective PI3Kα H1047R inhibitor, for clinical evaluation....OnKure plans to initiate a first-in-human clinical trial, OKI-219-101 (PIKture-01), in the first quarter of 2024 that will include a dose escalation in patients with advanced solid tumors harboring the PI3Kα H1047R mutation. Subsequent evaluation of OKI-219 in combination with the SERD fulvestrant in ER+/ PI3Kα H1047R advanced breast cancer, and with the HER2-monoclonal antibody trastuzumab in HER2+/ PI3Kα H1047R advanced breast cancers will follow."

IND • New P1 trial • HER2 Positive Breast Cancer

OKI-219, a PI3KαH1047R-mutant-selective inhibitor demonstrates efficacy as a single agent and drives combination responses with standard of care therapies in pre-clinical PI3KαH1047R mutant breast cancer models. (SABCS 2023) - "Although targeting PI3Kα in cancer is a therapeutically proven strategy, with the currently approved drug alpelisib showing clinical efficacy alone or in combination with other therapies, treatment with non-mutant selective PI3Kα inhibitors such as alpelisib is associated with significant toxicities such as hyperglycemia, due to on-target inhibition of the wild-type enzyme...Moreover, OKI-219 dosed in combination with the selective estrogen receptor degraders (SERDs) fulvestrant, elacestrant or camizestrant showed significant combination benefit leading to tumor regressions of up to 100% in the ER+ H1047R mutant breast cancer model xxT47D, at doses where no regressions were observed with single agent treatment. Dosing OKI-219 in combination with HER2-inhibitors, such as tucatinib, led to tumor regressions in the ER-HER2+ and H1047R mutant breast cancer CDX model HCC1954, also at doses where no regressions were observed with single agent treatment. These data indicate..."

Preclinical • Breast Cancer • HER2 Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • ER • PIK3CA

Discovery and characterization of OKI-219, an orally bioavailable H1047R-mutant-selective inhibitor of PI3Kα. (AACR-NCI-EORTC 2023) - No abstract available

Oncology • PIK3CA

OnKure Therapeutics Announces $54 Million Series C Financing (GlobeNewswire) - “OnKure, Inc...announced that it has successfully closed a $54 million Series C financing. The financing was led by Surveyor Capital...with participation from new investor Deep Track Capital...Acorn Bioventures, Cormorant Asset Management, Perceptive Advisors, Samsara BioCapital, funds and accounts managed by BlackRock, and other undisclosed investors. Proceeds from the financing will be used to support the continued development of OnKure’s differentiated pipeline of next generation precision medicines, including the advancement of its lead discovery program OKI-219, a selective PI3K alpha H1047R inhibitor, into the clinic....'We look forward to filing our second IND in 2023 and advancing OKI-219 into clinical development early next year'."

Financing • IND • New trial • Oncology