FDA Issues CRL for RP1 and Nivolumab in Melanoma

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Today, the US FDA issued a Complete Response Letter (CRL) to Replimune Group regarding its Biologics License Application (BLA) for RP1 (vusolimogene oderparepvec) in combination with nivolumab. This decision follows the FDA’s earlier acceptance of the BLA under Priority Review in January 2025, based on promising results from the IGNYTE clinical trial.^1-2

RP1 is Replimune’s lead oncolytic immunotherapy candidate, developed from a genetically modified herpes simplex virus and engineered to induce direct tumor cell lysis, enhance immunogenicity, and activate systemic anti-tumor responses. In combination with the PD-1 checkpoint inhibitor nivolumab, Replimune stated RP1 had shown potential in patients with advanced melanoma who had progressed after prior checkpoint inhibitor therapy—an area with significant unmet medical need and limited therapeutic alternatives.

“We are surprised by this FDA decision and disappointed for advanced melanoma patients who have limited treatment options as highlighted by the granting of breakthrough status at the time we provided the IGNYTE primary data,” said Sushil Patel, PhD, chief executive officer, Replimune, in a news release. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews. Additionally, we had also aligned on the design of the confirmatory study. We strongly believe that RP1 in combination with nivolumab can bring substantial benefit to advanced melanoma patients.”

Initial Promise, Subsequent Setback

The BLA was supported by data from the IGNYTE trial, which evaluated RP1 plus nivolumab in patients with advanced melanoma who failed anti-PD-1 treatment. The FDA granted the submission Priority Review status and Breakthrough Therapy designation earlier this year, signaling that the therapy might offer meaningful improvements over existing treatments. At the time, the agency did not request an advisory committee meeting and had not cited major review concerns.²

However, in a CRL the FDA concluded that the IGNYTE study does not constitute an “adequate and well-controlled” trial sufficient to demonstrate substantial evidence of effectiveness. The agency expressed concerns about the heterogeneity of the patient population in IGNYTE, which complicated interpretation of the trial’s results. In addition, the CRL raised design issues with the confirmatory phase 3 trial, IGNYTE-3, particularly around evaluating the individual contribution of each treatment component in the combination therapy. No safety concerns were identified.

Replimune said it plans to request a Type A meeting with the FDA, expected within 30 days, to discuss a path forward. The company noted that many of the issues raised in the CRL were not previously flagged during mid- or late-cycle reviews, and that they had already aligned with the FDA on the design of the confirmatory trial.

FDA's Broader Transparency Initiative

This CRL comes as the FDA is undertaking a broad initiative to enhance transparency in its drug approval process. In a landmark move, the agency recently published over 200 previously confidential CRLs issued between 2020 and 2024. These documents, now available through openFDA, provide public insight into the common deficiencies that lead to non-approval—including safety and efficacy concerns, trial design flaws, and manufacturing issues.³

In a recent news release, FDA Commissioner Marty Makary, MD, MPH, stated, “For far too long, drug developers have been playing a guessing game when navigating the FDA… We’re one step closer to delivering predictability, with an ultimate goal of bringing cures and meaningful treatments to patients faster.”

Historically, sponsors have often declined to disclose key regulatory feedback, with 1 FDA analysis showing that 85% of the agency’s concerns were omitted from public announcements. The new transparency measures aim to reduce miscommunication, improve industry learning from past mistakes, and enhance the quality of future submissions.

Conclusion

The FDA’s decision to issue a CRL for RP1 and nivolumab underscores both the complexities of cancer drug development and the evolving regulatory environment. While the absence of safety issues offers a degree of reassurance, Replimune now faces the challenge of addressing efficacy concerns and refining its clinical development strategy. The outcome of upcoming FDA interactions will be critical in determining whether RP1 can ultimately fulfill its promise as a novel therapy for patients with advanced melanoma.

References

1. Replimune receives complete response letter from FDA for RP1 biologics license application for the treatment of advanced melanoma. News release. Global Newswire. Published July 22, 2025. Accessed July 22, 2025. https://www.globenewswire.com/news-release/2025/07/22/3119299/0/en/Replimune-Receives-Complete-Response-Letter-from-FDA-for-RP1-Biologics-License-Application-for-the-Treatment-of-Advanced-Melanoma.html
2. Replimune announces biologics license application acceptance and priority review for RP1 for the treatment of advanced melanoma. News release. Replimune. Published January 21, 2025. Accessed July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-biologics-license-application-acceptance-and
3. FDA embraces radical transparency by publishing complete response letters. News Release. US FDA. Published July 10, 2025. Accessed July 22, 2025. https://www.fda.gov/news-events/press-announcements/fda-embraces-radical-transparency-publishing-complete-response-letters?utm_medium=email&utm_source=govdelivery