Lilly buys in another PI3Kα inhibitor

Keith Flaherty has done it again. The co-founder of Loxo Oncology, sold to Lilly for $8bn six years ago, has just seen his subsequent oncology company, Scorpion Therapeutics, taken over by Lilly in deal focused on a single small molecule, the wild-type sparing PI3Kα inhibitor STX-478.

The move, whose terms remain vague, is an unexpected outcome for Lilly's work in PI3Kα. The company spent years trying to develop a potent molecule, and recently discontinued the phase 1 asset LOXO-783 in favour of the preclinical project LY4045004. Now it seems to be saying that the best approach is not to persevere with what it has in house, but simply to buy in a more advanced asset.

Flaherty is director of clinical research at the Massachusetts General Hospital Cancer Center, and professor of medicine at Harvard Medical School. He co-founded Loxo, and after Lilly bought that company in 2019 he teamed up with Gary Glick to set up Scorpion, which raised first $102m and then $162m from venture financiers.

The two deals have another thing in common: they were both announced to coincide with the JP Morgan healthcare conference. The Lilly/Scorpion transaction was rumoured in the FT over the weekend, and has been confirmed as biotech's annual San Francisco curtain raiser is set to get under way today.

Takeover?

While to all intents and purposes the latest deal is a takeover of Scorpion, it's obvious that Lilly is interested only in STX-478.

Lilly is paying an undisclosed amount for Scorpion, but will take forward only the PI3Kα inhibitor work. All non-PI3Kα assets are to be spun into a new entity, in which Lilly will have only a majority stake, with the remainder being owned by current Scorpion holders. These assets include the mutant-selective EGFR exon 20 inhibitor STX-721, and EGFR exon 19/exon 21 inhibitor STX-241.

The deal is said to be worth up to $2.5bn, but Lilly isn't disclosing how much of this it has to pay immediately. The FT story cited a $1bn up-front fee, followed by up to $1.5bn in performance-based milestones.

That Lilly, a big pharma group with a breast cancer presence, should now get behind STX-478 could be a blow for Relay Therapeutics. Both STX-478 and Relay's PI3Kα inhibitor RLY-2608 put up impressive data at last year's ESMO conference, though Relay's was combined with Faslodex, and STX-478 came with liver enzyme elevations. RLY-2608 is unpartnered.

Precision... up to a point

The data showed the growing interest in precise PI3K targeting, which had gone from α-selective molecules through those sparing the protein's wild-type, to those hitting a single, specific PI3Kα mutation. However, Lilly's discontinuation of LOXO-783, a molecule specific for H1047R, suggested that this focus narrowing had its limits.

LOXO-783 likely stemmed from work that was already ongoing at Loxo when that company was acquired, while LY4045004, the preclinical wild-type sparing molecule Lilly presented at SABCS, came from the private entity Petra Pharma, which Lilly acquired in May 2020 before putting on the back burner while it worked on LOXO-783.

Scorpion therefore seems to be the third time Lilly has turned to an acquisition in its attempts to develop a PI3Kα inhibitor.

Take three: Lilly's work in PI3Kα inhibition

Source: OncologyPipeline.