FDA Raises Efficacy Concerns Over Replimune’s RP1 Before Advisory Committee

The U.S. Food and Drug Administration (FDA) has released its briefing document ahead of the July 30, 2026 Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) meeting, highlighting significant concerns about Replimune’s Biologics License Application (BLA) for vusolimogene oderparepvec (RP1) in combination with nivolumab for adults with unresectable advanced cutaneous melanoma that progressed after PD-1 inhibitor therapy. The agency concluded that the available evidence from the Phase 2 IGNYTE trial does not adequately establish the treatment’s efficacy or demonstrate RP1’s contribution to the combination regimen.

FDA Questions Reliability of the IGNYTE Trial

The BLA relies primarily on the single-arm Phase 2 IGNYTE (RPL-001-16) study (NCT03767348) involving 140 patients with anti-PD-1-refractory unresectable cutaneous melanoma. The primary endpoint was objective response rate (ORR) assessed by an independent review committee using RECIST v1.1 criteria. FDA reviewers identified three central concerns:

• The reported efficacy results are difficult to interpret because of limitations in the response assessment methodology.
• The study design cannot determine whether RP1 contributes meaningfully to the observed treatment effect when combined with nivolumab.
• Overall survival findings from the single-arm study cannot establish clinical benefit without a randomized comparator.

Scientific and Clinical Context

RP1 is a genetically modified herpes simplex virus type 1 (HSV-1) engineered for intratumoral administration. The virus contains deletions that enhance tumor selectivity and inserts encoding GM-CSF and a fusogenic glycoprotein intended to stimulate antitumor immune responses and promote tumor cell destruction. Patients receive RP1 through repeated intratumoral injections while nivolumab is administered intravenously.

Patients with advanced melanoma who progress after anti-PD-1 therapy have limited treatment options. Although immunotherapy has substantially improved long-term survival, many patients eventually develop resistant disease, creating an ongoing need for effective second-line therapies.

FDA Finds Major Limitations in Efficacy Assessment

Replimune reported an ORR of 33.6%, including complete responses in 16.4% of patients and a median duration of response of 24.8 months.

However, FDA’s review concluded that these findings may overestimate treatment benefit. Nearly half of responding patients had all target lesions injected with RP1, making it difficult to distinguish local tumor destruction from systemic antitumor activity. After excluding these patients from the primary efficacy analysis, FDA calculated an ORR of 15.7%, substantially lower than the applicant’s reported value. Median duration of response also declined to 14.1 months.

The agency also questioned the appropriateness of applying RECIST v1.1 criteria to intratumoral therapies, noting that these criteria were originally developed for systemic treatments and may not reliably capture responses produced by locally injected agents. Additional concerns included retreatment of progressing lesions, changes in protocol during the study, and heterogeneity of the enrolled patient population.

FDA Cites Longstanding Regulatory Concerns

According to the briefing document, FDA repeatedly advised Replimune during development that a randomized controlled trial would be necessary to isolate RP1’s contribution to the combination regimen. Despite receiving Complete Response Letters in July 2025 and April 2026, the company resubmitted substantially similar datasets rather than relying on interim results from the ongoing Phase 3 IGNYTE-03 trial.

FDA stated that the additional analyses and limited Phase 3 interim data did not resolve concerns regarding response assessment, patient heterogeneity, or the absence of an adequate control arm.

Advisory Committee to Review Key Questions Before FDA Decision

The July 30 advisory committee will consider whether the efficacy results from the IGNYTE study are reliable, clinically meaningful, and sufficient to support approval. Panel members will also discuss whether the reported tumor responses represent genuine systemic antitumor activity attributable to RP1 or primarily reflect local effects of intratumoral treatment.

The committee’s recommendation will inform, but not determine, the FDA’s final regulatory decision on Replimune’s BLA for RP1 in combination with nivolumab.

Reference

Cellular, Tissue, and Gene Therapies Advisory Committee July 30, 2026 Meeting Briefing Document- FDA