GSK raises more questions about synthetic lethality

After Astra canned its Wee1 inhibitor, and Prelude Therapeutics posted disappointing data with a PRMT5-directed asset, Ideaya has discovered that synthetic lethality might not be all it was cracked up to be.

Ideaya has a broad, early-stage collaboration with GSK, but yesterday slipped out news that the UK big pharma was not taking up an option on its Mat2A inhibitor IDE397. GSK claims that synthetic lethality is one of its four core oncology research areas, but this marks the second time in six months that its work here has misfired.

GSK and Ideaya had struck a deal in 2020 focusing on the latter’s Mat2A, Pol Theta and Werner helicase projects; that was worth $100m up front and $20m in equity, and GSK deciding to opt in to develop IDE397 would have triggered another $50m for the biotech.

Ideaya claims that the strategic rationale for GSK developing IDE397 “became less compelling” after GSK discontinued internal projects targeting PRMT5 and PRMT1, related synthetic lethality mechanisms that GSK had licensed from Epizyme. That separate deal was canned in February, and Epizyme was subsequently bought by Ipsen.

No compelling data

But the fact remains that IDE397 itself has failed to yield compelling data. In the package Ideaya submitted to GSK last month were phase 1 findings backing the mechanistic rationale, but citing in support only molecular responses rather than actual clinical remissions.

As such there is still little to suggest that Mat2A is a relevant target in solid tumours with an MTAP deletion, where a phase 1 trial is ongoing.

The GSK deal remains in play for Ideaya’s Pol Theta and Werner helicase assets, but these are still preclinical. All these mechanisms involve synthetic lethality, broadly meaning that the projects interfere with a tumour’s DNA repair mechanisms, a concept whose main success has been Parp inhibition.

Ideaya also has the prospect of a separate tie-up, courtesy of a planned clinical trial combining IDE397 with Amgen’s own PRMT5 inhibitor, AMG 193. However, given GSK’s experience with the now discontinued GSK3326595, the prospects here do not look great.

And GSK is not the only group to run into difficulties with synthetic lethality. Last October Prelude revealed early clinical data at the Triple meeting that left much to be desired as regards its two PRMT5-directed projects, PRT543 and PRT811: across two trials of the two projects, in a combined 45 evaluable subjects, there was only one remission.

Also investigating synthetic lethality via PRMT5 inhibition is Tango Therapeutics, which like Prelude floated in September 2020. Tango’s lead asset, TNG908, is not due to yield initial clinical data until the first half of next year, however.

Investors in Tango, not to mention the private owners of Insilico, Angex and Argonaut, other players in this approach, might be eyeing developments nervously.