PI3Kα is one of the most commonly mutated oncogene in cancer. PI3Kα can be activated by oncogenic point mutations in PI3Kα gene. The three most common mutations of PI3Kα are H1047R, E542K and E545K. Mutation of PI3KαH1047R in a mouse model has induced breast cancer tumorigenesis and is also associated with drug resistance to HER2-targeting agents in breast cancer. PI3Kα is mutated in up to 36% of breast cancer cases. Notably, the PI3KαH1047R mutation is also found in approximately 13% of breast cancer cases, making this an attractive target for novel therapeutics in metastatic breast cancer.
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 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 |
|---|
|
| Breast cancer |
PI3KαH1047R
selective inhibitor | Breast cancer | | Phase 1
enrolling |
|---|
OKI-219 is being investigated in the PIKture-01 clinical trial. PIKture-01 is a First-in-Human Study of the PI3Kα H1047R 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 | |
|
| Breast cancer |
OKI-TBD PI3KαH1047X (next gen)
selective inhibitor | Breast cancer | | Candidate
selection |
|---|
|
| Breast cancer |
OKI-TBD PI3Kα E542K, E545K
selective inhibitor | Breast cancer | | Active
discovery |
|---|
