Replimune gets second CRL

One cancer drug was rejected twice by the same regulator, and this time the company answered by publicly arguing with the Food and Drug Administration instead of quietly trying again. On April 10, 2026, Replimune said the agency had sent a second Complete Response Letter for RP1 with nivolumab in advanced melanoma. (fda.gov, markets.businessinsider.com) A Complete Response Letter is the Food and Drug Administration’s formal “not yet” for a drug application. It means the agency will not approve the filing in its current form, even if the drug may still be studied or resubmitted later. (fda.gov) RP1 is an oncolytic virus, which means a virus engineered to infect tumors the way a heat-seeking tool is aimed at one target instead of the whole room. Replimune says RP1 is built from herpes simplex virus type 1 and is designed to kill tumor cells and stir up a broader immune attack. (sec.gov) Nivolumab is the second half of the combo, and it is an immune checkpoint drug already sold as Opdivo. It works by blocking programmed death receptor 1, a brake cancer uses to slow down T cells. (opdivo.com, guidelinecentral.com) The melanoma Replimune targeted here is the hard case: adults with unresectable advanced cutaneous melanoma whose disease had already progressed after a programmed death receptor 1 blocker. That is the group named in the April 10, 2026 letter. (fda.gov) The company’s main evidence came from a single-arm Phase 2 study called IGNYTE, where everyone got RP1 plus nivolumab and there was no concurrent control group getting another treatment. In drug review, that is like trying to judge a new batter’s swing without seeing anyone else step up to the plate under the same conditions. (fda.gov, clinicaltrials.gov) Replimune’s argument is that the results were strong enough anyway. In updated IGNYTE data presented in 2025, the company reported a 32.9% objective response rate, a 15.0% complete response rate, and a median duration of response of 33.7 months in anti–programmed death receptor 1 failed melanoma. (jitc.bmj.com, biospace.com) The Food and Drug Administration’s answer was that the trial still could not prove what part RP1 itself played. In the new letter, the agency said the study did not isolate RP1’s contribution when it was given with nivolumab, used a heterogeneous patient population, and had uncertainty in response assessments because surgical procedures could confound the results. (fda.gov) The company had tried to patch that hole with early data from a larger confirmatory trial called IGNYTE-3. The regulator said that study had treated only about 10% of its planned 400 patients so far, relied on investigator-only response assessment, and did not yet have duration-of-response data mature enough to settle the case. (fda.gov, clinicaltrials.gov) One unusual detail is that the Food and Drug Administration said it changed the review team for the resubmission to maintain objectivity. The letter says the new primary clinical reviewers, supervisory leadership, and Oncology Center of Excellence experts unanimously agreed the evidence still fell short of “substantial evidence of effectiveness.” (fda.gov) That language matters because Replimune has spent months saying the agency had once signaled flexibility. After the first Complete Response Letter on July 22, 2025, the company said no safety issues were raised, said the late-cycle review had not flagged these exact problems, and said it believed it had aligned with the agency on the confirmatory study design. (sec.gov) Now the disagreement is out in the open. Replimune said on April 10, 2026 that it disagrees with the agency about whether the same data set that supported breakthrough therapy designation is enough to make RP1 available, and it warned the second rejection will force layoffs and a substantial scale-back of United States manufacturing. (markets.businessinsider.com, stocktitan.net) The fight is really about a basic approval question: when a drug is aimed at very sick patients with few options, how much uncertainty will the regulator tolerate up front and clean up later in a confirmatory trial. In Replimune’s case, the Food and Drug Administration answered twice that the evidence package is still too blurry. (fda.gov, clinicaltrials.gov)