PI3Kα is the most commonly mutated oncogene in cancer, with 14% of patients having mutations in this gene. PI3KαH1047R is the most common mutation, found in approximately 4% of all cancers and 15% of breast cancers, where it is associated with poor outcome and resistance to approved therapy.

PI3Kα is a clinically proven target in metastatic breast cancer patients harboring mutations in this oncogene.  First-generation PI3Kα inhibitors are only 1-5X selective for the mutant enzyme compared to the wild type, which results in on-target toxicity (including hyperglycemia, rash, stomatitis, and diarrhea) that limits the potential to dose to higher and potentially more active exposures.  This safety profile may also impede advancement into the adjuvant setting.

OnKure believes that a high degree of mutation-selectivity is required to drive optimal efficacy without burdening patients with the toxic side effects of targeting the wild-type enzyme.  A highly selective mutant PI3Kα may achieve much greater activity and tolerability by sparing on-target inhibition of the wild-type enzyme and enabling greater and longer target coverage by being able to dose to exposures above those that can be achieved by less-selective molecules.

OKI-219 has been designed to solve this problem.  OKI-219 is an allosteric, direct-mutation inhibitor that targets the PI3KαH1047R mutation. OKI-219 has best-in-class attributes that may position it for development in both the metastatic and adjuvant settings in breast and other cancer types. In preclinical models, OKI-219 has shown:

  • Strong activity at low doses as a single-agent and in combination with SERDs and HER2-targeted agents in models of metastatic breast cancer.
  • Superior activity as compared to the current approved drug at doses that are very well tolerated.
  • No observed toxicity at exposures well above the optimally efficacious doses.
  • CNS penetration and activity in models of CNS disease.

OKI-219 is being investigated in the ongoing PIKture-01 clinical trial.

Program/Target Prog/Tgt
Indication Ind
Discovery Discov
Preclinical Preclin
Phase 1 Ph 1
Phase 2 Ph 2
Current Status Status
OKI-219
Breast cancer
OKI-219
PI3KαH1047R
selected inhibitor
Breast cancer
PIKture-01 Trial
OKI-219
PIKture-01 Trial
OKI-219 is being investigated in the PIKture-01 clinical trial. PIKture-01 is a First-in-Human Study of the PI3KαH1047R Mutant-Selective Inhibitor OKI-219 as Monotherapy in Participants with Advanced Solid Tumors and in Combination with Endocrine Therapy or HER2-Targeted Therapy in Participants with Advanced Breast Cancer. Additional information about PIKture-01 may be found at www.ClinicalTrials.gov, using Identifier NCT06239467
OKI-TBD
Breast cancer
OKI-TBD
PI3KαH1047X (next gen)
selected inhibitor
Breast cancer
OKI-TBD
OKI-TBD
Breast cancer
OKI-TBD
PI3Kα E542K, E545K
selected inhibitor
Breast cancer
OKI-TBD

Our Targets

OnKure has selected and is exploring several oncology targets to expand its growing pipeline, with the goal of filing two or more INDs in the next three years. These biologically validated drivers of cancer have been chosen based on the following criteria:

Cell Cycle Biology icon

Ability to leverage our team’s expertise in kinase inhibition, cell cycle biology, signal transduction, epigenetics, and oncogenic pathway destabilization

target icon

Target structure can be determined (structural enablement)

biological validation icon

Compelling biological validation

shield icon

Potential for best-in-class drug candidate

clinical proof of concept path icon

Focused clinical proof of concept path identified

synergy icon

Opportunity for portfolio synergy