OnKure Therapeutics (OKUR) Guggenheim Securities 2nd Annual Healthcare Innovation Conference summary

Company overview and scientific focus

• Focuses on developing highly mutant-selective PI3K alpha inhibitors, with OKI-219 as the lead clinical candidate.

• OKI-219 targets the H1047R mutation, representing about two-thirds of PI3K alpha mutations in cancer.

• Emphasizes selectivity to avoid wild type PI3K alpha inhibition and associated side effects.

• Portfolio includes a pan-mutant PI3K alpha inhibitor with >10x selectivity across all hotspot mutations.

Clinical development and trial design

• OKI-219 is being evaluated in three clinical studies: monotherapy, doublet (with fulvestrant), and triplet combinations (with ribociclib/fulvestrant and trastuzumab/tucatinib).

• Progression from monotherapy to doublet and triplet studies was informed by learnings from each prior phase.

• Dose selection for triplet studies is ongoing, with expansion doses identified from earlier cohorts.

• Data from these studies, including efficacy and tolerability, will be reported in Q1 2026.

Differentiation and competitive landscape

• OKI-219 demonstrates >80x selectivity for mutant over wild type, surpassing other approved and investigational PI3K inhibitors.

• No observed increases in insulin or dose-limiting side effects due to minimal wild type inhibition.

• CNS penetration is a key differentiator, with a brain-to-plasma ratio (Kp,uu) of 0.6, supporting use in HER2-positive breast cancer with CNS metastases.

• Plans to compete in front-line settings, especially in HER2-positive and ER-positive breast cancer, where combinability and tolerability are critical.