A first test of OnKure’s mutant-specific gamble

Nearly two years ago investors took a $65m punt on a very specific way to target the elusive PI3K pathway in breast cancer, and they will soon find out whether this was a wise gamble. OnKure, the subject of their enthusiasm, is set to report the first substantial human data with its lead project, OKI-219, in the current quarter.

OKI-219 is a PI3Kα inhibitor specific for the H1047R mutation in this protein, a strategy that could avoid the toxicities commonly associated with broader targeting of PI3Kα. There’s a separate dimension here, too: Lilly is a major competitor in PI3Kα inhibition, but its approach features an important difference versus that of OnKure.

It’s important to understand how this field has evolved, from the industry’s first attempts to avoid the toxicities of broad PI3K inhibition by looking to molecules that spare PI3Kδ, to those targeting the α subunit specifically. That gave rise to two approved PI3Kα-selective inhibitors, Novartis’s Piqray and Roche’s Itovebi, but both carry toxicity warnings.

This has driven some to look at even more finely tuned inhibitors, including OnKure’s H1047R-specific OKI-219. Lilly, an important force in breast cancer, also tried to develop such an inhibitor with a molecule coded LOXO-783/LY3849524, but this was discontinued after showing a 3% response rate in the phase 1 Pikasso-01 study.

As if to underline its lack of faith in PI3Kα mutant-specific inhibition, Lilly then bought Scorpion Therapeutics for Scorpion’s lead asset, tersolisib. That molecule is a PI3Kα mutant-selective inhibitor, sparing wild-type PI3Kα, but not having specificity for any one mutation; tersolisib is now vying with Relay’s similarly acting zovegalisib to be first to market.

Last one standing?

Lilly’s approach doesn’t of course mean that OKI-219 won’t work, but the fact remains that OnKure’s is one of the last H1047R-specific PI3Kα inhibitors left in clinical development, with another player, Cogent, yet to advance CGT4824 from preclinical trials.

With the market now valuing OnKure at just $38m what does OKI-219 have to show in its phase 1 Pikture-01 study to restore investors’ faith? Most important is a clean safety profile, something that an October 2024 cutoff in Pikture-01 already suggested last year, though at the time it was too early to say anything meaningful about efficacy.

Pikture-01 comprises four breast cancer cohorts: OKI-219 monotherapy, a Faslodex doublet, a Faslodex plus atirmocicolib triplet in HER2-negative patients, a Faslodex plus Kisqali triplet (also HER2-negative), and a Herceptin plus Tukysa triplet in HER2-positives. The fact these started enrolling at different times will complicate the data presentation. 

Evercore ISI analysts reckon the doublet needs to hit a mid-30% ORR with clean safety. In comparison zovegalisib plus Faslodex has reported 39% ORR, while tersolisib at ESMO 2025 yielded 18% as monotherapy and 28% as part of a Faslodex doublet.

“OnKure doesn’t necessarily need to beat Relay or Lilly on combo ORR – but safety must stay rigorously clean, especially on GI and hyperglycaemia, where Lilly still has liability,” wrote Evercore’s Jonathan Miller in a note to clients on 23 January.

There’s also a benchmark of sorts for OnKure’s Kisqali triplet, in that 24% of 17 patients responded to tersolisib plus Faslodex and a CDK4/6 inhibitor. However, here Miller wants to see OKI-219 ORR approaching 40%, and says combinability with CDK4/6 inhibition is critical as it could open up the first-line breast cancer opportunity, and could trigger a licensing deal.

OnKure gained a Nasdaq listing when it reversed into the shell of Reneo Pharmaceuticals in 2024 and closed a concurrent $65m financing. That was a straight gamble on OKI-219, and since then the company has spread its bets in PI3K inhibition, adding a pan-PI3Kα inhibitor and a molecule specific for two other PI3Kα mutations, E542K and E545K, to its pipeline.

Lilly has already taken tersolisib into a front-line pivotal study, but Relay’s phase 3 effort with zovegalisib for now targets the second line with a different combo.

Benchmarks for OnKure’s Pikture-01 study of OKI-219

Source: OncologyPipeline, ESMO & prescribing information.