FDA knocks back Regeneron’s CD20 T-cell engager

Questions about toxicity have dogged Regeneron’s T-cell engagers, and these have come to the fore again with today’s FDA complete response letter for odronextamab. The agency didn’t specifically flag any tox issues for the CD20 x CD3 bispecific – but its decision shines a light on the fact that Regeneron is still trying to nail down the ideal dose for odronextamab, despite it being in phase 3.

The company says the FDA rejected odronextamab for third-line-plus follicular and diffuse large B-cell lymphomas because Regeneron’s confirmatory trials were still in their dose-finding stages. The group added that the agency wants confirmatory portions to have begun before Regeneron can resubmit; the FDA has previously said that, in general, phase 3 must be “well under way if not fully enrolled” at the time of accelerated approval.

Regeneron noted that its trials included dose-finding and confirmatory portions at the FDA’s request, citing the group’s paradigm-shifting approach, particularly with odronextamab combinations in early lines of therapy. A company spokesperson added: "The dose for the indication we were seeking has been defined. It’s these new settings, especially combinations, that require further dose-finding investigation."

She claimed that this was “new territory” for the industry, adding that there were currently no “rigid criteria” to assess whether progress on a confirmatory trial was adequate for accelerated approval. “To our knowledge this is the first time the FDA has issued a CRL for this reason,” she concluded.

Balancing act

However, the fact that Regeneron is still looking for a dose window for odronextamab highlights a problem that has been apparent for some time: the project looks efficacious, but has been linked with a high rate of infection-related deaths.

Regeneron has previously blamed this observation on underlying disease and the fact that the uncontrolled mid-stage trials were carried out at the height of the Covid pandemic.

That’s why it is particularly important for controlled studies to be carried out, to see whether this really is the case, or whether there is indeed an elevated risk of death with odronextamab. 

Five global phase 3 studies of odronextamab are under way. Three of these, Olympia-1, 2 and 5, could serve as the confirmatory trial in follicular lymphoma, while Olympia-3 is the confirmatory trial in DLBCL. Regeneron is promising an update on enrolment and regulatory timelines later this year.

Meanwhile, similar questions are hanging over Regeneron’s other key CD3-based T-cell engager, the anti-BCMA project linvoseltamab, which is due an FDA approval decision by 22 August in fourth-line-plus multiple myeloma. Only one phase 3 linvoseltamab trial, Linker-MM3, is currently recruiting, according to OncologyPipeline; this study doesn't have a dose-finding portion, the Regeneron spokesperson highlighted. The company has previously said that other trials are in the works.

Regeneron-sponsored phase 3 trials of odronextamab

Notes: DLBCL=diffuse large B-cell lymphoma; FL=follicular lymphoma; MZL=marginal zone lymphoma; NHL=non-Hodgkin lymphoma. Source: OncologyPipeline & clinicaltrials.gov.

This story has been updated to include further comments from Regeneron.