In the wake of the FDA’s complete response letter (CRL) to Replimune’s Biologics License Application (BLA) for RP1 (vusolimogene oderparepvec), investigators from the confirmatory Phase I/II IGNYTE trial (NCT03767348) are urging the agency to reconsider the application.^1,2

FDA Cites IGNYTE Study Limitations in CRL for Replimune's RP1

The BLA was seeking accelerated approval for RP1 in combination with Opdivo (nivolumab) for the treatment of advanced melanoma. In issuing the CRL, the FDA stated that the trial was not “an adequate and well-controlled clinical investigation that provides substantial evidence of effectiveness.” The agency also stated that trial data cannot be adequately evaluated because of the heterogeneity of the patient population.¹

In a prepared statement, Replimune CEO Sushil Patel, PhD, said the issues cited in the CRL were not raised by the FDA during the mid- and late-cycle reviews. He added that Replimune and the agency had aligned on the confirmatory study's design.¹

Trial Investigators Defend Efficacy and Urge Reassessment

A letter sent to FDA Commissioner Marty Makary, MD, MPH, and posted to LinkedIn by IGNYTE trial investigator Kevin Harrington, MD, PhD, FRCP, FRCR, FRSB, is requesting the agency to reevaluate the BLA based on the strength of the trial data. The letter, authored by Harrington and IGNYTE co-investigators Mark Middleton, MD, PhD, FRCP, and Joseph Sacco, MBChB, MSc, MRCP, PhD, notes the importance of new therapies for patients with advanced melanoma whose disease progressed on anti-PD1 drugs.

“The trial was designed as a single-arm study in order to expedite assessment and lead to early access for patients if promising activity was confirmed,” the letter stated. “Indeed, breakthrough designation was ascribed by yourselves based on interim results of the study. We appreciate a single-arm study is inherently limited in certain aspects; however, we strongly believe that the strength of data supports approval of RP1/nivolumab (and thus access for patients) while the randomised study is completed. We, therefore, humbly request that you reconsider the application.”

Regulatory Uncertainty Grows Amid FDA Leadership Shakeup

The letter comes at a time in which the FDA has faced criticism from both sides of the political aisle. In addition to the rejection of the Replimune BLA, the FDA issued a CRL to Capricor Therapeutics, Inc. for its investigational Duchenne muscular dystrophy therapy. Controversy also surrounds the FDA’s decision to halt shipments of Sarepta’s gene therapy Elevidys and place clinical trials for the drug on hold while it investigated three deaths of patients taking the drug, one of which was not found to be related to Elevidys.

Sarepta announced on July 21 that it would voluntarily pause shipments of Elevidys within the United States. On July 28, Sarepta announced that the FDA had backtracked and removed the recommendation to stop shipments of Elevidys for ambulatory patients.

Following the turmoil regarding the FDA’s recent regulatory decisions, an HHS spokesperson confirmed to Endpoints News yesterday that Vinay Prasad, MD, MPH, head of the FDA's Center for Biologics Evaluation and Research, has departed the agency after a three-month stint. Jefferies analyst Roger Song told Reuters that Prasad’s tenure had “raised concerns that he was anti-patient choice,” noting that investors will see his ouster as a positive development for gene therapy and vaccine manufacturers.

The departure of Prasad may also be a positive development for Replimune’s application for RP1. The drug is based on a proprietary strain of herpes simplex virus that was designed to harness the immune system to produce a systemic anti-tumor immune response.

RP1 Shows Durable Survival in Hard-to-Treat Melanoma

The open label, dose escalation and expansion IGNYTE trial analyzed RP1 monotherapy and in combination with Opdivo in 140 adult patients with advanced and/or refractory solid tumors, to determine the preliminary efficacy, as well as the maximum tolerated dose and recommended Phase II dose.

Results from the trial show an objective response rate of 32.9% as per RECIST 1.1 criteria among patients administered RP1. The drug showed a complete response rate of 15.0% and overall survival (OS) rates of 75.3% at one year, 63.3% at two years, and 54.8% at three years. Median OS was not reached in the trial. Further, the drug also showed a favorable safety profile.³

“During both the initial dose-escalation phase and an initial melanoma expansion, we observed promising activity for RP1 combined with nivolumab. This included patients who had confirmed progression while on combined ipilimumab and nivolumab, including with visceral disease; many patients went on to have durable responses,” the IGNYTE trial investigators wrote in the letter to Makary. “The PD1-failed melanoma cohort was subsequently initiated and enrolled 140 patients. This confirmed the early promise with durable responses in around a third of patients; and with encouraging survival to date. Strikingly, responses occurred in both injected and uninjected lesions, demonstrating the ability of RP1 to promote a systemic immune response as well as local benefits.”

Next Steps: Replimune Seeks FDA Type A Meeting

Replimune has requested a Type A meeting with the FDA, which it expects to occur within the next 30 days. The manufacturer said it will urgently interact with the agency to facilitate the accelerated approval of RP1 for a patient population with limited treatment options.

“Survival from metastatic melanoma has improved immensely over the past 10-15 years, from a median survival of approximately 6-9 months with almost no longer-term survivors to the current situation where around 50% of patients can achieve durable response and likely cure,” the investigators wrote in the letter. “However, in those who do not respond to initial anti-PD1- based immunotherapy or who progress on or after treatment, there are few options, with dismal outcomes that largely mirror those that were the norm in the pre-immune checkpoint inhibitor era.”

References

1. Replimune Receives Complete Response Letter from FDA for RP1 Biologics License Application for the Treatment of Advanced Melanoma. News release. Replimune. July 22, 2025. Accessed July 30, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics

2. Study of RP1 Monotherapy and RP1 in Combination With Nivolumab (IGNYTE). ClinicalTrials.gov. Updated January 24, 2025. Accessed July 30, 2025. https://clinicaltrials.gov/study/NCT03767348

3. Replimune Presents New Analyses from the IGNYTE Study of RP1 plus Nivolumab in Anti-PD1 Failed Melanoma at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting. Replimune. News release. June 1, 2025. Accessed July 30, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-presents-new-analyses-ignyte-study-rp1-plus-nivolumab