A new menin challenger

When Hutchmed’s menin inhibitor HMPL-506 enters phase 1 this week, as its new clinicaltrials.gov listing reveals, it will join just a handful of clinical-stage players that share this mechanism of action, of which Syndax’s revumenib and Kura’s ziftomenib are the most advanced.

Other first-in-human initiations include yet more entrants into the crowded fields of KRAS inhibition and radiopharmaceuticals, as well as Genmab/BioNTech’s contender in the cautiously resurgent space of Ox40 agonism. But a spotlight will fall on Hutchmed’s HMPL-506 given Johnson & Johnson’s recent challenge in menin inhibition with its molecule, JNJ-75276617.

It was at last year’s ASH conference that first data emerged with JNJ-75276617, and while these looked decent they didn’t suggest meaningful improvements over the two more advanced contenders. Revumenib has been filed, and has a 26 September PDUFA date, while ziftomenib is a little further behind.

Hutchmed’s HMPL-506 will be tested in MLL-rearranged and/or NPM1-mutant AML and ALL, and any data in these subgroups will be scrutinised given revumenib’s and ziftomenib’s emerging efficacy and toxicity profiles. OncologyPipeline reveals just five other menin inhibitors in clinical trials.

Ox40 resurgence?

Ox40 agonism was largely abandoned by big pharma, but Inhibrx recently made a renewed push into this mechanism, taking INBRX-106 into phase 2/3.

Now Genmab and BioNTech, under a longstanding 50/50 research partnership, are taking GEN1055 into a phase 1 trial that will include monotherapy and Keytruda combo cohorts. Rather than being a straight Ox40 agonist, GEN1055 is an Fcγ receptor crosslinking-independent Ox40-targeting project that uses the “Hexabody” format.

Recently disclosed first-in-human studies*

Notes: *projects newly listed on the clinicaltrials.gov database between ; **likely a KRAS G12C inhibitor.

In KRAS inhibition the G12C and G12D spaces have both become extremely crowded, and after reporting NSCLC data with glecirasib Jacobio yesterday filed this G12C-selective asset for approval in China. Jiangsu HengRui is taking into phase 1 two projects with undisclosed mechanisms of action, one of which, HRS-7058, seems to be a KRAS G12C inhibitor, judging by enrolment criteria.

In the G12D subspace, where Jiangsu HengRui failed to impress last year, Tyligand Bioscience is starting a first-in-human study of TSN1611. 

For its part, Jacobio is starting a phase 1 trial of JAB-30355, a p53 Y220C reactivator – a field seen by many as a holy grail of cancer drug development, but one that has crushed the valuation of one of the most advanced players, PMV Pharmaceuticals.

Elsewhere Arvinas is starting clinical trials of another degrader project, ARV-393, this one targeting BCL6. This is a somewhat unusual mechanism, but already features Bristol Myers Squibb, which last year highlighted its contender, BMS-986458, shortly before taking this into phase 1.

And after Coherus last year told ApexOnco of the promise of ILT4 blockade a phase 1 study has been revealed testing its in-house asset CHS-1000 alone or in combination with toripalimab. Coherus recently cut its workforce and divested ophthalmology assets to Sandoz, and the CHS-1000 trial won’t start until October.