Revolution adds to its KRAS ambitions

Revolution Medicines is adding to its pan-RAS and subtype-selective KRAS inhibitor work with a new molecule targeting KRAS G12V, RMC-5127, having just begun its first-in-human trial. The study was disclosed on the clinicaltrials.gov registry two weeks ago, and on Thursday Revolution announced the dosing of the first patient.

A separate newly listed first-in-human study, that of AbelZeta’s A-CAR032, could draw further parallels with AstraZeneca, after the recent tidying up of those two firms’ licensing arrangement. But most attention will likely fall on RMC-5127, given Revolution’s recent links with takeover activity – something that appears now to have come to an end.

Revolution was first rumoured to have been in talks to be acquired by AbbVie, before that company denied having any interest. Then Merck & Co entered the rumour mill, before the Wall Street Journal reported a few days ago that Merck was “no longer in talks to buy Revolution”.

If there has been interest in Revolution that was likely driven by the company’s lead asset, the pan-RAS inhibitor daraxonrasib. The company’s clinical pipeline also includes the KRAS G12C-specific elironrasib, and the anti-G12D molecule zoldonrasib, and now RMC-5127, targeting the G12V mutation variant, joins these efofrts.

Like Revolution's other projects, RMC-5127 is a RAS(on) inhibitor, meaning that it hits only the active, GTP-bound form of the mutated protein. Curiously, Revolution’s trials of elironrasib and zoldonrasib include combinations of these molecules with daraxonrasib; similarly, the new RMC-5127 trial includes a cohort testing such a combo.

Revolution’s preclinical pipeline includes the RAS(on) inhibitors RMC-0708 (Q61H) and RMC-8839 (G13C).

Recently disclosed first-in-human studies*

Note: *these projects were first listed on the clinicaltrials.gov database between 8 and 22 Jan 2026.

AstraZeneca and China’s AbelZeta have worked together, formally and informally, for a number of years, and their parallel work on a Car-T project against GPC3 was recently focused on one asset, AZD7003, to which the UK company recently locked in full rights.

Now comes a first-in-human trial of another AbelZeta Car-T therapy, A-CAR032, which targets Steap2. This also appears to be the result of joint work with Astra, which has another Car-T hope in the dnTGFbRII-armoured anti-Steap2 Car AZD0754. It’s not clear if AZD0754 and A-CAR032 use the same Car construct, but based on the precedent of the GPC3 work this seems likely.

And those following any resurgence in biotech flotations will note the planned start this year of a phase 1 trial of Chengdu Zenitar’s PARP1 inhibitor ZL-85FA. That’s because Eikon Therapeutics, a biotech led by the former Merck & Co executive Roger Perlmutter that has attracted $804m in private investment and is targeting a monster IPO, counts a PARP1 inhibitor as a key pipeline project.

That Eikon asset is EIK1003, and is in a phase 1/2 solid tumour study. Still, PARP1 inhibition is becoming crowded, and Astra’s phase 3 asset saruparib looks like the most advanced competitor.