FDA CRL - Replimune, Inc.

The U.S. Food and Drug Administration (FDA) issued a Complete Response Letter to Replimune, Inc. on July 21, 2025, concerning its Biologics License Application for vusolimogene oderparepvec. The agency concluded that the application could not be granted final approval due to significant clinical deficiencies.

The main issues centered on the RPL-001-16 Phase 2 trial, which was deemed not to provide substantial evidence of effectiveness, as required by the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act. Concerns included the heterogeneity of the patient population, making response rates difficult to interpret, and the trial's design, which did not adequately isolate the individual contribution of vusolimogene oderparepvec when combined with nivolumab.

Additionally, deficiencies were noted in the ongoing Phase 3 RP1-104 trial. The FDA observed that its design might not allow for a clear assessment of vusolimogene oderparepvec’s specific impact due to the presence of single-agent chemotherapy in the control arm. There was also insufficient data to support the statistical assumption of a 6-month improvement in overall survival, a key efficacy endpoint.

To resolve these issues, Replimune, Inc. must conduct and provide results from new, adequate, and well-controlled clinical trials demonstrating substantial evidence of effectiveness. For the RP1-104 trial, a revised protocol is required to assess the drug's individual contribution, alongside a detailed justification for statistical assumptions. Replimune must either resubmit or withdraw the application within one year or request an extension, and may also request a post-action meeting to discuss the necessary steps for approval.