FDA Issues CRL for RP1 in Advanced Melanoma

Replimune Group Inc. today announced that it has received a complete response letter (CRL) from the FDA regarding its biologics license application (BLA) for RP1 (vusolimogene oderparepvec), an oncolytic immunotherapy, in combination with nivolumab (Opdivo) for the treatment of advanced melanoma.¹

The FDA indicated that it was unable to approve the BLA in its current form, primarily citing concerns that the pivotal IGNYTE trial (NCT03767348) was not considered an adequate and well-controlled clinical investigation to provide substantial evidence of effectiveness.

The CRL highlighted several specific issues, including the interpretability of the IGNYTE trial results due to heterogeneity within the patient population. Furthermore, the agency raised questions regarding the design of the confirmatory trial, IGNYTE-3, (NCT06264180), specifically concerning the contribution of components, which is a critical aspect for combination therapies seeking accelerated approval. Notably, the FDA did not raise any safety concerns with RP1 in the CRL.

In a press release, Sushil Patel, PhD, CEO of Replimune, said, "We are surprised and disappointed by the FDA's decision, as the issues raised in the CRL were not communicated to us during earlier review cycles. We had engaged extensively with the agency and believed we were aligned on the design of our confirmatory study."

In response to the CRL, Replimune plans to request a type A meeting with the FDA within the next 30 days. The objective of this meeting will be to engage in a detailed discussion about a potential path forward for accelerated approval. The company has underscored the urgency of this dialogue, asserting that without an accelerated approval pathway, the continued development of RP1 for advanced cancer patients with limited treatment options would not be viable. This stance highlights the high unmet medical need in this patient population and the substantial investment required for late-stage clinical development.

RP1 is Replimune’s lead investigational product candidate, representing a novel approach in oncolytic immunotherapy. It is based on a proprietary strain of the herpes simplex virus (HSV) that has been engineered to maximize its anti-tumor efficacy. This involves the incorporation of a fusogenic protein (GALV-GP R-) and granulocyte-macrophage colony-stimulating factor (GM-CSF). The mechanism of action is designed to promote direct tumor cell killing, enhance the immunogenicity of tumor cell death, and stimulate a robust systemic anti-tumor immune response. By inducing immunogenic cell death, vusolimogene oderparepvec aims to turn "cold" tumors into "hot" ones, thereby enhancing the effectiveness of checkpoint inhibitors like nivolumab.

The initial positive data from the phase 1/2 IGNYTE trial had formed the basis for the BLA submission. This study evaluated RP1 in combination with nivolumab in patients with advanced melanoma, particularly those who had progressed on prior anti–PD-1 therapy.² The results indicated a promising overall response rate and duration of response in a heavily pretreated population, suggesting its potential to address a critical need for patients who have exhausted standard immunotherapy options.¹ The ongoing phase 3 confirmatory IGNYTE-3 trial is a randomized, controlled, multicenter study designed to further evaluate the efficacy and safety of RP1 in combination with nivolumab against physician's choice in patients with advanced melanoma that has progressed on anti–PD-1 and anti–CTLA-4 therapy.³

REFERENCES:

1. Replimune receives complete response letter from fda for rp1 biologics license application. News release. Replimune Group, Inc. July 22, 2025. Accessed July 22, 2025. https://tinyurl.com/2x2zvr58

2. Study of RP1 monotherapy and RP1 in combination with nivolumab (IGNYTE). ClinicalTrials.gov. Updated January 24, 2025. Accessed July 22, 2025. https://clinicaltrials.gov/study/NCT03767348

3. An expanded access program for VO (RP1) in combination with nivolumab in patients with advanced melanoma (RPL-EAP-001). ClinicalTrials.gov. Updated March 19, 2025. Accessed July 22, 2025. https://clinicaltrials.gov/study/NCT06590480