OKI-179 was generally well-tolerated with a manageable toxicity profile
Achieves circulating plasma exposure that is consistent with efficacious exposure in preclinical models
Demonstrated robust target engagement and dose proportionate effects on histone acetylation
Data support initiation of Phase 1b/2 trial of OKI-179 in combination with MEK inhibitor, binimetinib, in NRAS melanoma
BOULDER, Colorado—December 14, 2021 — OnKure, Inc., a clinical-stage biopharmaceutical company discovering and developing the next generation of oncology precision medicines, today announced positive topline results from the first-in-human Phase 1 trial of OKI-179, the Company’s oral Class 1 histone deacetylase (HDAC) inhibitor.
The first-in-human Phase 1 dose-finding study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of escalating oral doses of OKI-179 in cancer patients. OKI-179 was shown to be safe and generally well-tolerated as a single agent using intermittent dosing schedules of either 4 days on/3 days off or 5 days on/2 days off for 21 days. The most common adverse events were nausea, fatigue and anemia. Nausea was manageable with antiemetics.
At doses of 120 mg and above, PK/PD data demonstrated robust target engagement, with exposures that were above the pharmacologically active concentrations observed in multiple preclinical, solid tumor models of RAS pathway mutated cancers. Results from this study indicate that 450 mg and 300 mg are the maximum tolerated doses for the 4 days on/3 days off and 5 days on/2 days off schedules, respectively.
“HDAC inhibitors have shown great promise, however they have little success treating solid tumors due to poor tolerability. We are extremely encouraged by these Phase 1 results and we believe OKI-179 can overcome the historic limitations, having demonstrated high levels of target engagement at two well-tolerated dosing schedules,” said Tony Piscopio, Ph.D., Co-Founder, President and Chief Executive Officer of OnKure. “We look forward to investigating our promising selective HDAC inhibitor as a potential treatment for a wide range of solid malignancies.”
“We are excited by the results of our first-in-human trial of OKI-179 that demonstrate a best-in-class selectivity and tolerability profile in an oral HDAC inhibitor,” said Jennifer Diamond, M.D., Chief Medical Officer of OnKure. “Class 1 HDAC inhibitors have shown chemical synthetic lethality with RAS pathway inhibitors in cell-line and patient-derived tumor models that harbor mutations in the RAS pathway, driving increased cell death and tumor regressions.”
Dr. Diamond continued: “With approximately 25-35% of all cancers having mutations in the RAS pathway, OKI-179 has the potential to change the treatment paradigm for many tumor types, potentially becoming a backbone therapy for all RAS mutated cancers in combination with a RAS-pathway inhibitor.”
Based on these favorable results, the Company expects to initiate a Phase 1b/2 trial of OKI-179 in combination with binimetinib in patients with NRAS mutant melanoma where checkpoint inhibitor therapy has failed in the first half of 2022. This trial will initially evaluate safety, PK and PD of the combination and establish a recommended Phase 2 dose before initiating the open-label Phase 2 portion of the study.
OKI-179 is a novel, oral Class 1 histone deacetylase (HDAC) inhibitor for the potential treatment of a wide range of solid and hematological malignancies. HDAC inhibitors have shown great promise in preclinical models, however they have had little success treating solid tumors, often due to poor tolerability, inappropriate dosing regimens, poorly conceived combinations, and a lack of stratifying biomarkers. OKI-179 is designed to have improved potency, selectivity, tolerability, as well as easy combinability to overcome the historic limitations of other HDAC inhibitors. OnKure is currently planning to conduct a Phase 1b/2 trial of OKI-179 in combination with binimetinib in patients with NRAS mutant melanoma in 2022.
About OnKure Therapeutics
OnKure, Inc. is a clinical-stage biopharmaceutical company focused on the discovery and development of best-in-class precision medicines that target biologically validated drivers of cancer. Using its proven structure-based drug design approach, the Company is building a robust pipeline of tumor-agnostic candidates that are designed to achieve optimal tolerability and efficacy. OnKure is currently developing its lead clinical candidate, OKI-179, an oral, selective Class 1 HDAC inhibitor, for the treatment of both hematological and solid tumors, with plans to initiate a Phase 1b/2 combination trial with binimetinib in NRAS mutant melanoma in 2022.