Third time lucky for Roche in MAGE-A4?

Another radioligand, and another multiple myeloma bispecific antibody targeting GPRC5D x BCMA, feature among the latest first-in-human study initiations, which also include what looks like Astellas’s latest attempt at target degradation in the KRAS space.

That said, perhaps the most intriguing newly listed study concerns Roche’s next shot at the MAGE-A4 antigen, at least going by the trial’s enrolment criteria. This is noteworthy given that the Swiss group has already tried and failed against this target with two earlier clinical-stage approaches, one of which concerned a tie-up with Immunocore.

The Immunocore project was a soluble anti-MAGE-A4 T-cell receptor coded IMC-C103C or RG6290, and dated back to a 2018 licensing deal. But after entering a phase 1/2 study in MAGE-A4-positive cancers this asset was terminated, and at the same time Roche scrapped an in-house CD3-based T-cell engager against MAGE-A4, coded RO7444973/RG6129, which had also entered phase 1.

At the time it had been speculated that Roche was giving up on MAGE-A4, but this now seems not to be the case. A phase 1 trial of RO7617991 has just been posted on the clinicaltrials.gov registry; though Roche hasn’t specifically disclosed RO7617991’s mechanism, the giveaway lies in the study being run in MAGE-A4-positive cancers, in people who have the HLA-A*02 haplotype.

HLA restriction suggests that RO7617991 resembles a T-cell receptor, but the clinical trial entry makes no mention of lymphodepletion or apheresis, suggesting this isn’t a cell therapy. Adaptimmune’s anti-MAGE-A4 engineered TCR afami-cel is awaiting a US approval verdict by 4 August, and interestingly Roche recently canned a collaboration with Adaptimmune, which in 2022 lost GSK as a partner.

Multiple myeloma

In multiple myeloma Beijing Mabworks this year took into the clinic MBS314, a T-cell engager against GPRC5D and BCMA, and now Simcere is following suit with the similarly acting bispecific SIM0500.

Phase 1 trials of MBS314 and SIM0500 alike will be run in China, however. In the west the focus is on pursuing these antigens with separately acting drugs, and Johnson & Johnson has started a phase 3 study combining its two approved T-cell engagers Talvey and Tecvayli. 

Meanwhile, interest in KRAS continues, and one of the clinical prospects here is Astellas’s KRAS G12D degrader ASP3082, in phase 1. The Japanese company separately has preclinical degrader assets including one that claims pan-KRAS activity, and had an IND filed last year.

Now clinicaltrials.gov reveals the start of phase 1 with ASP4396 in KRAS G12D-positive solid tumours. Given Astellas’s priorities this project could be the IND-ready pan-KRAS degrader, though the first-in-human trial’s restriction to G12D-positive patients means that it might merely be a back-up for ASP3082.

And ADC watchers will note the entry into phase 1 of Byondis’s BYON4413. This is the fourth CD123-targeting ADC in clinical trials, and each uses a different payload: BYON4413 uses a duocarmycin prodrug, Astra’s AZD9829 a topoisomerase 1 inhibitor, AbbVie’s pivekimab sunirine the cytotoxic DGN549, and Vincerx’s VIP943 the kinesin spindle protein inhibitor BAY-331.

Recently disclosed first-in-human studies*

Notes: *projects newly listed on the clinicaltrials.gov database between 10 and 19 Apr 2024; **possibly targets folate receptor alpha.