The agency’s assessment, released in briefing materials ahead of an upcoming advisory committee meeting, concluded that the company’s biologics license application does not contain sufficient evidence from a well-controlled clinical trial to establish the treatment’s benefit. Replimune is seeking approval of RP1 in combination with Bristol Myers Squibb’s immune checkpoint inhibitor Opdivo (nivolumab) for patients with advanced melanoma.

FDA Questions Study Design and Efficacy Claims

At the center of the FDA’s concerns is the design of the primary clinical study supporting the application. The trial lacked a randomized control group, making it difficult for reviewers to determine whether observed tumor responses were attributable to RP1, Opdivo, or the combination of both therapies.

According to FDA staff, the absence of a comparator arm limits the ability to draw clear conclusions about RP1’s independent contribution to treatment outcomes. Reviewers noted that several aspects of the response assessment process may have exaggerated key efficacy measures, including overall response rates.

The agency stated that these methodological issues create uncertainty regarding the reliability and clinical significance of the reported results.

Longstanding Regulatory Concerns

The latest review follows an earlier setback for Replimune. In April, the FDA declined to approve the therapy and requested additional evidence from a more rigorously controlled study. Regulators specifically cited concerns about relying on data from a single-arm trial, emphasizing the need for stronger evidence demonstrating the treatment’s effectiveness.

In its latest analysis, FDA reviewers reiterated that tumor shrinkage observed in the study could not be definitively linked to RP1 because all participants also received Opdivo, an established immunotherapy for melanoma.

Survival Data Considered Inconclusive

Replimune also submitted three-year survival findings in support of the application. However, FDA reviewers indicated that survival outcomes from a non-randomized study cannot reliably establish a treatment effect.

Without a control group, differences in survival may reflect factors such as patient selection, baseline characteristics, or other variables unrelated to the investigational therapy, the agency noted.

Advisory Committee Vote Looms

An FDA advisory panel is scheduled to vote on July 30 regarding whether the available data are both interpretable and clinically meaningful. The outcome could influence the regulatory path forward for RP1, although advisory committee recommendations are not binding on the agency.

Investors reacted sharply to the FDA’s critical assessment, sending Replimune shares down roughly 31% in early trading following publication of the briefing documents.

The upcoming panel discussion is expected to focus on whether the current evidence adequately demonstrates clinical benefit and whether RP1’s role in the treatment combination can be clearly established based on the existing data package.