What does it mean for a confirmatory trial to be 'well underway'? Regeneron wants to know

Days after Regeneron received a complete response letter (CRL) for the blood cancer medicine odronextamab, hematology executive Andres Sirulnik, M.D., Ph.D., says the trial is enrolling just fine—it’s just that randomization hasn’t begun.

Which is to say, Regeneron has the patients needed to progress the study and clear up the issues at the FDA. Speaking to Fierce Biotech in an interview, Sirulnik, who serves as senior vice president, translational and clinical sciences for hematology, said the company is on the leading edge of the FDA’s new requirement that confirmatory trials be well underway by the time a company files for an accelerated approval.

The FDA declined to approve odronextamab under the accelerated review pathway on Monday, citing an issue with the enrollment status of the confirmatory trials. Regeneron is running five trials to support the approval of the bispecific antibody in relapsed/refractory (R/R) follicular lymphoma or R/R diffuse large B-cell lymphoma who have progressed after at least two prior systemic therapies. The request for a swift approval was supported by the phase 1 ELM-1 study and the phase 2 ELM-2 study.

Sirulnik stressed that the agency did not take issue with the safety or efficacy of the drug but balked at the one technical aspect. “This is not about the science, not about the kind of studies,” he said.

Specifically, because Regeneron is seeking to move odronextamab up in the line of treatment—from fifth line to first in some instances—the company was required to conduct a safety lead-in test before patients could be randomized.

“They wanted to see a small group of patients for each of these indications and studies where we look at safety first before we proceed into the randomized phase of the study,” Sirulnik explained.

That portion of the trials is underway, including tests in combination with chemotherapy. Meanwhile, the randomization portion is ongoing and accruing patients. Sirulnik declined to say how many total patients were enrolled in the program so far but was confident the company can fulfill the FDA’s request for a confirmatory trial.

“The agency made the point that we have not yet randomized patients. That all these patients are in the safety lead-in in all these studies,” Sirulnik said. “So we are waiting to clear that safety lead-in and enter the randomized phase. So that is what holds us back.”

When the CRL was announced, eyes immediately turned to Regeneron’s recent application for multiple myeloma bispecific linvoseltamab, which was filed for a priority review in February. Regeneron is similarly conducting confirmatory trials for the treatment, a phase 3 test for adult patients with R/R multiple myeloma. Would this application also receive a CRL?

While he can’t predict exactly what the FDA will do, Sirulnik says the safety lead-in issue does not apply here, so he believes the application will advance through the regulatory process without issue. The confirmatory study is underway and has reached the randomization portion already. It’s “way further along,” according to Sirulnik. Regeneron did not have to do a safety lead-in test because the population in the confirmatory trials matches earlier studies in the R/R setting. Regeneron was able to go straight to randomization of linvoseltamab alone versus standard of care.

“We're not having the same concern, and we think that we will be able to clear those regulatory hurdles,” Sirulnik said. “We feel confident that we are in a good place.”

But that brings Sirulnik to the regulatory uncertainty that the FDA’s new emphasis on confirmatory studies has brought up for companies like Regeneron.

Drugs can be approved on an accelerated basis based on a surrogate endpoint for conditions with an unmet need. Companies are required to conduct a confirmatory trial to secure a full approval later. But the FDA has recently cracked down on the confirmatory trial requirement, asking companies to have the studies “well underway” at the time of filing.

The agency has yet to truly define what it means by “well underway.” In absence of strict guidance—which the FDA is working on—companies like Regeneron are having to submit and hope for the best. Looking at his peers, Sirulnik said he’s seen multiple myeloma studies that were 25% along at the time of approval, and some that were at 50% or even 100%.

“I know that we are internally trying to understand what number that we look for in the future,” Sirulnik said. “I'm not sure that they have drawn a line in the sand on the exact number.”

Regeneron supports the confirmatory trial requirement, but Sirulnik said the industry just needs guidance to get it right.

“Eventually, it will be important for the industry and for the field to understand ... what does it mean, 'well underway'? They keep using that word … You can interpret it whatever way people want, but they need to provide a little bit more clarity around that very sticky point, I would say,” Sirulnik said.

Regeneron has not provided guidance on when the odronextamab application will be resubmitted. Sirulnik still expects the application to be reviewed under the accelerated pathway once it’s back in the agency’s hands. As for linvoseltamab, Regeneron will present more data on the program at the American Association for Cancer Research meeting in April.