On January 4, 2024 OnKure, Inc. reported 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 PI3Ka H1047R inhibitor, for clinical evaluation (Press release, OnKure, JAN 4, 2024, View Source [SID1234638979]). H1047R is the most common mutation in PI3Ka, being found in 15% of breast cancer and 4% of cancers overall.
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There is a significant need for improved therapies targeting PI3Kα with safer and more effective drugs. OKI-219 is a highly selective inhibitor of PI3Ka H1047R, with over 100-fold selectivity for the wild-type enzyme, potentially sparing on-target toxicities that arise from inhibition of the wild-type form of the protein in normal tissues. OKI-219 shows strong, single-agent activity, including regressions at low doses in multiple PI3Ka H1047R xenograft models that are heterozygous for PI3Ka H1047R, the most common profile seen clinically for this mutation, and supporting the potential activity of highly mutant-selective inhibitors. Notably, in preclinical models, OKI-219 shows no evidence of toxicities related to PI3Ka wild-type inhibition as measured by markers of hyperglycemia, even at doses that are >15x higher than minimally active doses for antitumor activity.
Mutational activation of PI3Kα is associated with lower activity of both estrogen receptor (ER)-targeted and HER2-targeted agents in breast cancer. OKI-219 shows synergistic activity in combination with selective estrogen receptor degraders (SERDs), overcoming SERD resistance and driving strong regressions. Similarly, the combination of OKI-219 + tucatinib drives strong regressions in models of HER2+/ PI3Ka H1047R breast cancer that are resistant to HER2- inhibitors.
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 PI3Ka H1047R mutation. Subsequent evaluation of OKI-219 in combination with the SERD fulvestrant in ER+/ PI3Ka H1047R advanced breast cancer, and with the HER2-monoclonal antibody trastuzumab in HER2+/ PI3Ka H1047R advanced breast cancers will follow.
About PI3Ka and OKI-219
PI3Ka is the most frequently mutated oncogene in cancers, and PI3Ka H1047R is the most common mutation in this gene, being found in 15% of breast cancer and 4% of cancers overall. While novel drugs targeting PI3Ka have been approved, the lack of mutant selectivity of these therapeutics drives considerable on-target toxicity by inhibiting the normal version of this protein in various tissues. To address this challenge, OnKure is discovering and developing a platform of highly mutant-selective PI3Ka inhibitors with the goal of improving efficacy and safety with molecules that fully inhibit the mutant oncogene while sparing the wild-type enzyme in normal tissues. OKI-219 is a potential best-in-class, orally bioavailable, highly selective inhibitor of PI3Ka H1047R with over 100-fold selectivity for the mutated form of the enzyme compared to wild-type. OnKure believes that the wild-type sparing properties of OKI-219 should significantly improve the activity and safety relative to currently approved agents. OKI-219 is currently in Phase 1 of clinical development in solid tumor patients with PI3Ka H1047R mutations.