Like Lilly, Novartis bets against mutation specificity

The value of next-generation PI3Kα inhibitors just went up, with Novartis paying $2bn for Synnovation’s SNV4818, a molecule yet to generate any clinical data. This seems a remarkable amount to pay for an asset that went into its first human trial only a year ago; Synnovation had raised little more than the $102m series A round it closed in January 2024. 

The deal is analogous to Lilly’s acquisition of Scorpion's tersolisib in January 2025; but that was worth a reported $1.5bn up front, and tersolisib already had an impressive, early clinical dataset under its belt. There’s a more subtle trend here, too: tersolisib and SNV4818 are both mutant-selective inhibitors, and that could be bad news for OnKure and Cogent, which have put their money on mutation-specific PI3Kα inhibition.

SNV4818 is said to spare wild-type PI3Kα, meaning that it hits only mutated forms of this protein, though it’s not specific for any single mutation type. Many companies have been refining the PI3Kα approach, knowing that the protein can drive some breast cancers, but also conscious of the fact that broad targeting of PI3Kα is associated with significant toxicity.

The trend has seen the approvals of two PI3Kα-selective inhibitors, Novartis’s Piqray and Roche’s Itovebi, though both hit wild-type as well as mutant PI3Kα, and carry toxicity warnings. Accordingly, work has seen some companies developing wild-type-sparing molecules, and others going further, working on those specific for a single PI3Kα mutation, typically H1047R.

Moving away from specificity

That’s all very well up to a point, and it’s notable that Lilly rowed back from the last approach, discontinuing the H1047R mutation-specific inhibitor LY3849524 after it showed very limited activity, and instead buying in Scorpion’s mutant-selective inhibitor. In effect, therefore, Novartis is continuing the move away from H1047R mutation specificity.

Friday’s acquisition is focused on SNV4818, with Novartis paying $2bn, plus agreeing to a further $1bn contingent on milestones, for Synnovation’s Pikavation subsidiary, into which ownership of a portfolio of pan-mutant selective PI3Kα inhibitors including SNV4818 had been spun.

That shows another similarity with the Lilly deal, which involved tersolisib being carved out into a separate entity that Lilly acquired, and Scorpion continuing with a portfolio of non-PI3Kα assets. For its part, Synnovation’s lead asset is the PARP1 inhibitor SNV1521, so presumably the private company will continue working on this, despite the limited promise it has shown so far.

So what about the competition in PI3Kα inhibition? If the mechanistic logic of the Lilly and Novartis deals is anything to go by then that’s good news for Relay Therapeutics, which is the other major player in mutation-selective PI3Kα inhibition; its molecule, zovegalisib, has produced efficacy in line with tersolisib, albeit in combination with Faslodex.

Conversely, OnKure and Cogent might today seem a little less attractive than they once were. OnKure is especially exposed, since OKI-219 – an H1047R mutation-specific inhibitor – is its lead asset, and faces a looming clinical catalyst. OnKure is also developing mutation-selective molecules, but that project is still at the preclinical stage.

And just last month Cogent took the H1047R mutation-specific inhibitor CGT6297 into phase 1. However, this is more of a sideline for Cogent, which is primarily focused on the KIT inhibitor bezuclastinib in gastrointestinal stromal tumours.

Selected PI3Kα inhibitors in breast cancer

Source: OncologyPipeline.