Relay pulls ahead of Lilly

Developing a wild-type sparing PI3Kα inhibitor has become a David versus Goliath battle, with the small-cap biotech Relay Therapeutics going up against Lilly – but in terms of timing Relay has pulled ahead. A phase 3 trial of Relay's RLY-2608 just went live on clinicaltrials.gov.Lilly hasn’t disclosed pivotal plans yet for its lead contender, STX-478, which it gained via the January acquisition of Scorpion Therapeutics. Presumably Relay will need to stay in front of its bigger rival if it wants to make a mark here. Relay raceAs promised last year, Relay’s pivotal study, called ReDiscover-2, will enrol patients with PIK3CA-mutated breast cancer refractory to one line of CDK4/6 therapy, and test RLY-2608 plus Faslodex versus AstraZeneca’s AKT inhibitor Truqap plus Faslodex. The primary endpoint is centrally assessed progression-free survival, with overall survival a secondary endpoint. RLY-2608 will be dosed at 400mg twice-daily in the fed state. Truqap is in the comparator cohort because it's approved for breast cancer with mutations including PIK3CA alteration.In the phase 1 ReDiscover trial, a RLY-2608/Faslodex combo produced a confirmed overall response rate of 39% among 31 second-line PIK3CA-mutated ER-positive, HER2-negative breast cancer patients. That was with a 600mg twice-daily dose of RLY-2608, although Relay has said that the 400mg fed dose has shown equivalent exposure to 600mg fasted.That trial is ongoing, and will also test triplets of RLY-2608 plus Faslodex plus a CDK4/6 inhibitor like Ibrance or Kisqali; and RLY-2608 plus Faslodex plus Pfizer’s CDK4 inhibitor atirmociclib.A couple of PI3Kα inhibitors are approved in the US, namely Novartis’s Piqray and Roche’s Itovebi, though both hit wild-type as well as mutant forms of the protein, and come with warnings on their US labels.It’s hoped that wild-type sparing projects could be less toxic. Others are developing even more selective molecules, targeting specific mutations; however, Lilly recently pulled back from the latter approach when it discontinued the H1047R mutant-specific LOXO-783 last August.Third shotAt that time, Lilly shifted to a next-generation asset that, it later emerged, was the wild-type sparing LY4045004.STX-478, which is also wild-type sparing, is therefore Lilly’s third shot at PI3Kα inhibition. It’s unclear whether, since agreeing to buy Scorpion in January for up to $2.5bn, Lilly is still developing LY4045004. That project had been due to enter the clinic in the first half of 2025, but a clinicaltrials.gov listing hasn’t yet emerged.STX-478 has produced an ORR of 23% in breast cancer – but this was as monotherapy, making a cross-trial comparison against the RLY-2608/Faslodex combo tricky. STK-478’s phase 1/2 trial is also testing a triplet including Faslodex and CDK4/6 inhibition, while an atirmociclib-containing triplet is slated to begin in the second half.With Lilly on its tail Relay will need to make the most of its head start. Battle of the PI3Kα wild-type sparing inhibitorsProjectCompanyTrialSettingRegimenNoteRLY-2608RelayPh3 ReDiscover-2PIK3CA-mutated breast cancer, after CDK4/6i+ Faslodex, vs Truqap + FaslodexTo start Jul 2025; ph1 ReDiscover found 39% ORR (n=31) with Faslodex comboSTX-478Lilly (via Scorpion)Ph1/2 STX-478-101PIK3CA-mutated solid tumours+/- Faslodex, +/- CDK4/6i, +/- atirmociclib23% ORR (n=22) as monotherapy in breast cancerSource: OncologyPipeline.