The FDA in a complete response letter to Replimune maintained its original objection to the single-arm trial the biotech used to support the application for RP1.
Replimune’s stock fell nearly 20% Friday after the FDA rejected its advanced melanoma drug for the second time.
The FDA’s first rejection of RP1, an oncolytic immunotherapy also known as vusolimogene oderparepvec, in July 2025 sparked months of controversy, including an open letter from 22 researchers involved with the drug’s trials urging the agency to “re-review” its decision. Replimune resubmitted the application for the drug in October with new analyses on RP1’s mechanism of action and on how patients fared relative to prior treatment with an approved immunotherapy, a Replimune spokesperson told STAT News at the time.
The review team members for Friday’s decision were different from those who reviewed the company’s initial biologics license application, according to the FDA’s Complete Response Letter (CRL), which was published Friday. This was intended to “maintain objectivity and account for potential bias,” the agency said. Despite this, the team found the data presented was “insufficient to conclude substantial evidence of effectiveness” of RP1 in unresectable advanced cutaneous melanoma. RP1 was being proposed in combination with Bristol Myers Squibb’s Opdivo to treat the rare skin cancer.
Replimune’s use of a single-arm trial appears to be the sticking point for the FDA, which wrote in the rejection letter that it “would not recommend” seeking approval based on results from a single-arm study. The use of alternative trial designs, such as single-arm trials, has been a hot-button issue that drew many biotech onlookers to the FDA’s decision regarding RP1.
The FDA added in the letter to Replimune that its advice “has remained consistent as evidenced by our communications dating back to March 2021 and subsequent interactions.”
There appears to be a disconnect between the agency and Replimune, however, as CEO Sushil Patel expressed surprise with the initial rejection. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews,” Patel said in a statement at the time. “Additionally, we had also aligned on the design of the confirmatory study.”
Analysts had given RP1 a 50/50 chance of approval this time around.
Replimune had been seeking accelerated approval for RP1. The company is currently conducting a randomized Phase 3 trial of the immunotherapy in combination with Opdivo, with an estimated completion date of January 2029.
