Key Takeaways
- FDA cites trial design concerns in Complete Response Letter (CRL) to Replimune: The agency rejected the RP1 Biologics License Application (BLA) due to issues with the IGNYTE trial’s control and patient heterogeneity.
- Encouraging survival data from RP1-nivolumab combo: The combination therapy showed a 32.9% overall response rate (ORR) and strong three-year survival rates in anti–PD-1-failed melanoma.
- Replimune and Capricor both face regulatory hurdles: Recent CRLs for RP1 and Deramiocel highlight ongoing challenges in securing approval for novel biologics.
The FDA has issued a Complete Response Letter (CRL) to Replimune Group regarding its Biologics License Application (BLA) for RP1 (vusolimogene oderparepvec) in combination with nivolumab for the treatment of advanced melanoma. According to the company, the FDA determined that the application could not be approved in its current form, citing concerns that the Phase I/II IGNYTE trial (NCT03767348) did not constitute an adequate and well-controlled study, and that its heterogeneous patient population hindered interpretability. The agency also raised issues related to the confirmatory trial’s design—specifically the contribution of components—though no safety concerns were identified.1
Why Did the FDA Reject Replimune’s RP1 Application in Advanced Melanoma?
“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, CEO, Replimune, in the press release.
IGNYTE Trial Results Underscore RP1's Potential
- The open-label, dose-escalation, multicenter IGNYTE trial evaluated RP1 alone and in combination with nivolumab in an estimated 340 adults with advanced and/or refractory solid tumors.
- Primary endpoints included the percentage of adverse events (AEs), serious AEs, dose-limiting toxicities, overall response rate (ORR), maximum tolerated dose, and recommended Phase II dose.2
- Results showed that the ORR was 32.9% per RECIST 1.1, including a 15% complete response.
- Overall survival (OS) rates were encouraging, with 75.3% of patients alive at one year, 63.3% at two years, and 54.8% at three years.
- Deeper injections led to numerically higher ORRs—42.9% with deep/superficial combination and 40.9% with deep/visceral only—compared to 29.8% for superficial injection alone.
- Additionally, ≥30% lesion reduction was seen in 93.6% of injected lesions and 79% of non-injected lesions, with similar kinetics of response between the two.
- Among non-injected visceral lesions in responding patients, 96.2% showed tumor shrinkage, and 65.4% met the ≥30% reduction threshold.3
Phase III Trial Underway to Support Global Approval
Building on these findings, Replimune initiated the Phase III IGNYTE-3 trial in August 2024. The global study is enrolling approximately 400 patients with advanced melanoma who progressed on or are ineligible for checkpoint inhibitors. It aims to confirm the efficacy of RP1 plus nivolumab, with overall survival as the primary endpoint, to support global regulatory approval.4
Replimune’s CRL Follows a Similar Setback for Capricor
Replimune is not alone in navigating late-stage regulatory setbacks. Earlier this month, Capricor Therapeutics also received a CRL for Deramiocel, its cell therapy for cardiomyopathy associated with Duchenne muscular dystrophy. The FDA cited insufficient evidence of effectiveness and the need for additional clinical data, despite prior Priority Review status and supporting data from the HOPE-2 trial and its open-label extension.5
FDA Releases CRLs to Improve Transparency
On July 11, 2025, the FDA published more than 200 CRLs issued between 2020 and 2024, aiming to improve transparency and enhance regulatory predictability. Previously, CRLs were only shared with product sponsors, limiting broader industry visibility into the deficiencies that blocked approval. This lack of transparency has contributed to downplayed disclosures by some sponsors; a 2015 analysis found that 85% of safety and efficacy issues cited in CRLs were not publicly disclosed. In roughly 40% of cases where the FDA requested new clinical trials to address safety or efficacy concerns, that requirement was omitted from company press releases.6
Replimune Plans Type A Meeting to Clarify Path Forward
Replimune intends to request a Type A meeting within 30 days to engage with the FDA on a viable path forward for accelerated approval.1
“The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews, continued Patel, in the press release. “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.”
References
- Replimune Receives Complete Response Letter from FDA for RP1 Biologics License Application for the Treatment of Advanced Melanoma. Replimune. July 22, 2025. Accessed July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-receives-complete-response-letter-fda-rp1-biologics/
- Study of RP1 Monotherapy and RP1 in Combination With Nivolumab (IGNYTE). Clinicaltrials.gov. Accessed July 22, 2025. https://clinicaltrials.gov/study/NCT03767348
- 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, June 1, 2025. Accessed July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-presents-new-analyses-ignyte-study-rp1-plus-nivolumab
- Replimune Announces First Patient Dosed in IGNYTE-3 Clinical Trial in Advanced Melanoma. Replimune. August 13, 2024. Accessed July 22, 2025. https://ir.replimune.com/news-releases/news-release-details/replimune-announces-first-patient-dosed-ignyte-3-clinical-trial
- Capricor Therapeutics Provides Regulatory Update on Deramiocel BLA for Duchenne Muscular Dystrophy. GlobeNewswire. July 11, 2025. Accessed July 22, 2025. https://www.globenewswire.com/news-release/2025/07/11/3113911/0/en/Capricor-Therapeutics-Provides-Regulatory-Update-on-Deramiocel-BLA-for-Duchenne-Muscular-Dystrophy.html
- New FDA Initiative Reveals Common Reasons for Drug Application Rejection. Applied Clinical Trials. July 11, 2025. Accessed July 22, 2025. https://www.appliedclinicaltrialsonline.com/view/new-fda-initiative-reveals-common-reasons-drug-application-rejection
