Another pan-KRAS project enters the clinic

Revolution Medicines is the leader in pan-KRAS inhibition, but other groups are aiming to muscle in on this space, and Quanta therapeutics now has a second shot on goal here. The group will start a phase 1 trial of its “G12V-preferring” multi-KRAS inhibitor QTX3544 in January, according to the latest listings on clinicaltrials.gov.

Other new entrants include a Werner helicase inhibitor from Ideaya and GSK, an EphA2 peptide drug conjugate from ConjuStar, and a CD73 x Lag3 bispecific from Akeso.

QTX3544 will become privately held Quanta’s third project to hit the clinic, following its “G12D-preferring” pan-KRAS project QTX3034, and G12D-selective inhibitor QTX3046. The company has claimed that its assets have favourable preclinical properties; now it must show that these make a difference in the clinic.

Plenty of others are vying for a piece of the pan-KRAS space, notably Pfizer, which started a first-in-human trial of PF-07934040 in June. Revolution is well ahead of the pack, though, with a phase 3 trial of its contender, RMC-6236, already begun in pancreatic cancer, and pivotal plans in NSCLC.

Werner helicase

Werner helicase, meanwhile, is a synthetic lethality target that’s also drawn big pharma interest. GSK and Ideaya’s GSK4418959, being co-developed under a 2020 deal, is the third asset in this class to go into the clinic, following Novartis’s HRO761 and Roche’s RO7589831, licensed from Vividion. With no clinical data yet available from any of these projects, this mechanism still has much to prove.

EphA2 also has some convincing to do, but for different reasons: over a decade ago AstraZeneca’s ADC MEDI-547 was linked with bleeding and coagulation toxicity, and discontinued. Bicycle is still pressing ahead here with its toxin conjugate BT5528, which produced a 12% ORR across various tumour types, including 34% in urothelial carcinoma; importantly, no treatment-related haemorrhages were seen.

The latest entrant into this race is ConjuStar Biologics’ SC-102, a peptide drug conjugate. Other projects in the EphA2 pipeline include Bristol Myers Squibb’s preclinical actinium-based radioconjugate RAYZ-6114, gained through last year’s purchase of RayzeBio.

CD73 interest

CD73 is more crowded, with the likes of AstraZeneca and Sanofi seeing promise with monoclonal antibodies, and Otsuka licensing Arcus’s small molecule.

Akeso, which is riding high on the success of its PD-1 x VEGF bispecific ivonescimab, is taking a different approach with the CD73 x Lag3 project AK137, which will soon go into a Chinese phase 1 study. This the only asset in development said to hit both targets, according to OncologyPipeline.

Other Lag3-targeting antibodies and bispecifics haven't lived up to early promise, so Akeso could have its work cut out. The group also has a straight anti-CD73 MAb, drebuxelimab, and a PD-1 x Lag3, AK129, both in phase 1/2 trials in China.

A separate project that’s set to enter the clinic soon is Olema’s KAT6 inhibitor OP-3136. The company announced IND clearance for the project earlier this month, and said phase 1 should start early next year; this has yet to appear on clinicaltrials.gov.

The company will be going up against Pfizer, whose PF-07248144 had promising early data at ASCO this year, and an update this week at SABCS, showing a confirmed ORR of 37% among 43 patients. Pfizer plans to start a phase 3 study in mid-2025.

Recently disclosed first-in-human studies*

Note: *projects newly listed on the clinicaltrials.gov database between 15 Nov and 5 Dec 2024.