The FDA’s rebuff of Replimune comes a day after the agency similarly called into question the Phase 3 trial for Capricor’s Duchenne muscular dystrophy cell therapy.
The FDA has deemed the single-arm mid-stage study submitted by Replimune to support the approval of an oncolytic immunotherapy “not interpretable,” setting up what should be a challenging advisory committee meeting for the biotech this week.
The drug, vusolimogene oderparepvec, or RP1, has been rejected by the FDA twice. The agency accepted another resubmission in June and committed to rendering a third verdict by August 2—but also announced a meeting of the Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) to discuss the therapy.
Two days ahead of that Thursday meeting, FDA briefing documents show that the agency still has significant concerns about the data package that Replimune has offered to support RP1’s accelerated approval in combination with Bristol Myers Squibb’s PD-1 inhibitor Opdivo for adults with unresectable advanced cutaneous melanoma who experience disease progression after a PD-1-blocking antibody-based therapy.
The response assessment used in the Phase 1/2 IGNYTE study “confounds interpretation of the reported efficacy results and limits FDA’s ability to verify the reported results,” the FDA reviewers said.
Moreover, the agency determined that the objective response data from the single-arm trial “are not of sufficient magnitude to overcome concerns” about the drug’s efficacy. Without a reliable historical control, the FDA stated “it cannot be determined whether RP1 contributes to any observed effect” when combined with Opdivo.
“The overall survival analysis from the single-arm IGNYTE study is not interpretable,” the FDA wrote.
Replimune was down as much as 20% to $6.98 in premarket trading Tuesday.
Replimune argued that experts have determined a randomized trial to be unethical in this population.
“It is not feasible or ethical to randomize this patient population to a comparator arm of anti-PD-1 monotherapy that offered no hope for response, therefore a study comparing RP1 in combination with nivolumab, to nivolumab monotherapy in patients whose disease progressed while on nivolumab or other anti-PD-1 was not conducted,” the company wrote in its own briefing document.
Replimune also addressed the FDA’s questions regarding historical data. When IGNYTE was performed, there were no treatments available for patients who had progressed after anti-PD-1 treatment, the company explained. And there is no evidence that continuing on an anti-PD-1 therapy poses any benefit to patients.
“Consequently, there is very little literature evaluating this specific scenario, as continuing a therapy that has definitively failed would generally not be considered appropriate clinical practice,” Replimune wrote, adding that the IGNYTE study had strict criteria to ensure patients were “truly anti-PD-1 resistant.”
Replimune also pointed out that the FDA has previously granted approval based on a single-arm study for melanoma patients. Iovance Biotherapeutics most recently received approval in 2024 for Amtagvi in this scenario. Merck’s Keytruda and Opdivo also got FDA nods for unresectable or metastatic melanoma following that of BMS’s Yervoy with single arm trials.
With Replimune, however, the FDA has been consistent in its disagreement with this study design. In its first complete response letter in July 2025, the FDA said it “did not consider IGNYTE an “adequate and well-controlled clinical investigation,” according to Replimune at the time. In a second CRL in April, trial design remained the sticking point for the regulator, which wrote that it “would not recommend” seeking approval based on results from a single-arm study.
On Thursday, the CTGTAC will vote on just one question: Are the efficacy results from IGNYTE evaluable and clinically meaningful?
Replimune’s turn before the CTGTAC will be the committee’s second event this week. On Monday, the FDA similarly released adcomm documents for Capricor’s Duchenne muscular dystrophy cell therapy deramiocel. The agency disagrees with the company’s claim that a Phase 3 trial submitted to support approval was successful. That hearing will take place Wednesday.
The meetings follow a nine-month drought of adcomms at the FDA under the Trump administration. After a leadership shakeup, the agency appears to be recommitting to these public meetings.
