FDA Approves OnKure's Phase 1 Trial for PI3Kα Inhibitor OKI-219

OnKure, a biopharmaceutical firm, has received approval from the FDA to commence clinical trials for a novel drug, OKI-219. This drug is designed to target a specific mutation in the PI3Kα gene, which is prevalent in a significant portion of breast and other cancers. The PI3Kα mutation, H1047R, is found in approximately 15% of breast cancers and 4% of all cancers, making it a crucial target for new therapies.

OKI-219 is a highly selective inhibitor, with over 100 times more affinity for the mutated PI3Kα H1047R than the normal enzyme. This selectivity is intended to minimize toxic side effects that can occur when the normal protein is inhibited. In preclinical studies, OKI-219 has demonstrated strong single-agent activity, causing tumor regressions at low doses in models that mimic the most common clinical profile of the mutation.

Furthermore, the drug has shown no signs of toxicities typically associated with inhibiting the normal form of PI3Kα, such as hyperglycemia, even at high doses. The mutational activation of PI3Kα is linked to reduced effectiveness of estrogen receptor and HER2-targeted therapies in breast cancer. However, OKI-219 has exhibited synergistic effects when combined with selective estrogen receptor degraders (SERDs) and with tucatinib, a drug used in HER2+ breast cancer, indicating its potential to overcome resistance to these therapies.

OnKure is planning to initiate a first-in-human clinical trial, named OKI-219-101 (PIKture-01), in early 2024. This trial will involve dose escalation in patients with advanced solid tumors that carry the PI3Kα H1047R mutation. Following this, the company intends to evaluate the drug in combination with fulvestrant, a SERD, for ER+/PI3Kα H1047R advanced breast cancer, and with trastuzumab, a HER2-monoclonal antibody, for HER2+/PI3Kα H1047R advanced breast cancers.

OKI-219 is a potential best-in-class oral inhibitor of the mutated form of PI3Kα H1047R, with a significant selectivity advantage over the wild-type enzyme. OnKure is committed to developing a series of highly mutant-selective PI3Kα inhibitors, aiming to enhance the efficacy and safety of cancer treatments by targeting the mutant oncogene while preserving the normal enzyme in healthy tissues.

OnKure is a clinical-stage company dedicated to discovering and developing precision medicines for cancers that lack effective therapies. Utilizing a structure-based drug design platform, the company is developing a pipeline of candidates that are designed to be both tumor-agnostic and highly effective. The lead program is OKI-219, which is currently in Phase 1 clinical development for patients with PI3Kα H1047R mutations.