Replimune receives second CRL from FDA for oncolytic virus melanoma treatment

Replimune Group, Inc. (Nasdaq: REPL) announced on April 10, 2026 that the FDA issued a Complete Response Letter (CRL) for the company’s Biologics License Application for vusolimogene oderparepvec (RP1) in combination with nivolumab for the treatment of advanced melanoma. The CRL represents the second such action against the Replimune BLA, following an initial CRL issued in July 2025. Replimune stated that it disagrees with the agency’s determination that the existing data package does not constitute adequate evidence of effectiveness to support approval under the accelerated approval pathway.

The FDA’s stated concerns in the current CRL centered on questions regarding adequate evidence of the contribution of RP1 to the combination regimen with nivolumab, tumor assessment methodology, and the sufficiency of single-arm trial data from the Phase II IGNYTE study to support accelerated approval.

Replimune contended that the agency’s positions in the CRL contradicted guidance expressed at a September 2025 Type A meeting, at which the FDA had not raised further concerns about patient population heterogeneity in IGNYTE and had acknowledged that randomizing patients to an anti-PD-1-only arm in a confirmatory study was not feasible. The company also noted that the FDA did not respond to a proposal Replimune submitted for a descriptive analysis from the ongoing Phase III IGNYTE-3 trial, yet subsequently accepted the BLA resubmission as a complete response to the July 2025 CRL.

Regarding tumor assessment, Replimune stated that responses in IGNYTE were assessed using RECIST 1.1 without modifications, as the FDA had requested, and that analyses showed no material difference in response rates between injected and non-injected lesions. The CRL requires Replimune to address these deficiencies before the BLA can be approved, and the company indicated that, without timely accelerated approval, continued development of RP1 will not be commercially viable.

The RP1 development context

RP1 is an engineered oncolytic herpes simplex virus type 1 expressing a fusogenic glycoprotein, GALV-GP R-, and GM-CSF. The construct is designed to selectively replicate within and lyse tumor cells, promote immunogenic cell death, and stimulate a systemic anti-tumor immune response. It forms the basis of Replimune’s proprietary RPx platform. The drug was being evaluated in combination with nivolumab, a PD-1 checkpoint inhibitor marketed by Bristol Myers Squibb.

In the IGNYTE trial, patients with advanced melanoma who had confirmed progression on a prior anti-PD-1-based regimen achieved a 34% objective response rate, with a median duration of response of 24.8 months. Median progression-free survival on RP1 plus nivolumab was 30.6 months, compared with 4.4 months on patients’ prior PD-1-based regimens. Advanced melanoma accounts for approximately 8,500 deaths annually in the United States, and no therapy is currently approved specifically for patients who have progressed on prior anti-PD-1 treatment, representing a defined area of unmet medical need.

RP1 originated from academic research at University College London (UCL), where Professor Robert Coffin and colleagues developed the foundational HSV-based oncolytic platform. Replimune was founded in 2015 as a spinout from that work, with Coffin as a co-founder.

The BLA for RP1 in advanced melanoma was accepted by the FDA with breakthrough therapy designation and granted priority review, reflecting the agency’s prior assessment that the program addressed an unmet need and showed early clinical activity.

In March 2021, FDA Type B meeting minutes indicated that a single-arm trial could be acceptable for consideration under accelerated approval if the data were sufficiently compelling. At a subsequent pre-BLA meeting, the FDA stated it did not object to a submission based primarily on data from 140 patients in the Phase 2 IGNYTE trial who had advanced melanoma and had progressed on prior anti-PD-1 therapy.

The first CRL was issued in July 2025. Following that action, Replimune engaged in a Type A meeting with the agency in September 2025 and resubmitted the BLA. The second CRL, issued April 10, 2026, reflects the agency’s continued determination that the data package does not meet the standard for approval. Replimune noted that a different review team was assigned for the resubmission, replacing the team that had previously interacted with the company, and that the new team did not meet with Replimune during the review period. A senior member of the prior review team stated publicly that the BLA clinical team had considered the evidence adequate to support contribution of effect, but that agency leadership did not agree. No approvals of RP1 in other jurisdictions have been reported.

Replimune’s chief executive officer Sushil Patel stated that the company has no choice but to eliminate jobs and substantially scale back its US-based manufacturing operations. The company indicated it does not consider continued development of RP1 viable without timely accelerated approval. No plans for an FDA meeting request, further resubmission, or alternative regulatory pathway were announced at the time of the disclosure.