Ideaya’s first pivotal catalyst looms

With the required disease progressions having now been reached in a registrational uveal melanoma trial of Ideaya’s darovasertib, investors have a hard deadline by which to expect this catalyst to read out. Topline results are expected by approximately the last week of March, Ideaya said this week.

That’s a slight delay for this study, Dar-UM-2, which was once expected to support an accelerated approval by the end of 2025. This probably doesn’t matter too much, especially given last September’s buy-in from Servier, which licensed ex-US darovasertib rights for $210m up front. In the past 12 months Ideaya stock has risen more than 50%, suggesting that expectations are high.

Ideaya’s ownership of darovasertib, a pan-PKC inhibitor, dates back to deal with Novartis signed in 2018, a year before Ideaya listed on Nasdaq. At that point the compound was known as LXS196, and was in phase 1; Ideaya’s listing document subsequently disclosed that the up-front fee involved was just $2.5m in cash plus $3.5m in Ideaya series B preferred stock.

A positive outcome in Dar-UM-2, a trial Ideaya begun in 2023, would therefore come as an embarrassment for Novartis given the Swiss firm’s decision to let the molecule go for such a paltry amount.

HLA-A2 negatives

Dar-UM-2 concerns first-line metastatic uveal melanoma in patients who do not carry the HLA-A2 serotype. That’s relevant because these patients have no formally approved treatments; Immunocore’s HLA-directed T-cell engager Kimmtrak is available for uveal melanoma, but only in patients who are HLA-A*02:01-positive; these make up nearly 50% of the Caucasian population.

In the study darovasertib is being combined with Pfizer’s Xalkori, and compared against investigator’s choice of Keytruda, Opdivo plus Yervoy, or dacarbazine chemo. Formally Dar-UM-2 is a phase 2/3 trial, with phase 2 primarily testing PFS (as well as determining the optimal darovasertib dose), and phase 3 focused on the gold standard of overall survival.

It’s hoped that PFS readout could support an accelerated approval filing, and Ideaya has already set the benchmarks, outlining a median of three months for Opdivo plus Yervoy. Meanwhile, in the separate phase 1/2 Optimum-01 trial darovasertib plus Xalkori scored mPFS of 7.1 months, a number that would logically be expected to wane in the larger setting of a registrational study.

OS next

In an ideal scenario Dar-UM-2 would produce mPFS not too far off 7 months, resulting in a healthy increase over control. The same trial could then be used for full approval, once its overall survival data mature sufficiently.

As for the slight delay to Dar-UM-2’s readout, that’s probably a minor irritation. Ideaya had once planned to enrol 400 patients into this study, but later upped this to 520, a move that pushed out the timeline but probably raised the chances of a statistically significant result. The company confirmed this week that the 130 required progression events needed to trigger PFS analysis had been hit, setting the stage for readout at the end of March.

Ideaya has bigger plans beyond HLA-A2-negative uveal melanoma, recently starting the phase 3 Optimum-10 trial in the neoadjuvant setting irrespective of patients’ HLA status. Optimum-11, a pivotal study in adjuvant uveal melanoma also irrespective of HLA status, is planned in collaboration with Servier to begin in the second quarter.