The FDA reiterated major concerns over Replimune’s investigational melanoma gene therapy RP1, questioning whether available evidence supports efficacy after advisers review the company’s application again. The agency’s briefing materials flagged issues with the single-arm design and whether the data isolate RP1’s treatment effect versus the background of concurrent PD-1 blockade. In separate FDA staff communications, the agency also pointed to statistical-method concerns raised in the context of prior adcomm discussions, maintaining that the trial setup was not sufficient to evaluate RP1’s own contribution and any potential systemic benefits from the locally injected approach. Replimune disputes the need for additional randomized data on top of PD-1 therapy. These developments keep Replimune’s regulatory path highly uncertain, as the company is already navigating a pattern of FDA complete response letters and renewed scrutiny of trial design and endpoint interpretation. The outcome will likely influence how regulators weigh single-arm evidence in locally administered gene therapies used with established immunotherapies. For investors and pipeline strategists, the FDA’s stance signals a continued preference for evidence designs that more directly test treatment effect in the target setting—especially when external therapies are involved.