Complete Response Letter BLA 125827 (Jul 21, 2025)

Summary

The U.S. Food & Drug Administration (FDA) issued a Complete Response Letter for Replimune, Inc.'s Biologics License Application (BLA) for vusolimogene oderparepvec. Final approval cannot be granted due to significant clinical deficiencies in the RPL-001-16 and RP1-104 trials, which failed to provide substantial evidence of effectiveness or adequately isolate the drug's contribution, and unaddressed Chemistry, Manufacturing, and Controls (CMC) issues.

Key points

• Conduct and provide results from adequate and well-controlled clinical trial(s) which demonstrate substantial evidence of effectiveness for vusolimogene oderparepvec.
• Submit a revised study protocol for the RP1-104 trial that assesses the individual contribution of vusolimogene oderparepvec to the observed Overall Response Rate (ORR).
• Provide a detailed justification for the statistical assumptions that support the primary efficacy endpoints for the RP1-104 trial.
• Address all identified Chemistry, Manufacturing, and Controls (CMC) issues.
• Resubmit the application with all deficiencies fully addressed or withdraw the application within one year from the date of this letter.
• The single-arm Phase 2 trial RPL-001-16 is not considered an adequate and well-controlled clinical investigation. The numerically higher response rate cannot be adequately interpreted due to heterogeneity of the patient population and the trial's inability to isolate the contribution of vusolimogene oderparepvec when administered in combination with nivolumab.
• Several issues identified with the RP1-104 trial, including a study design that may not isolate the contribution of vusolimogene oderparepvec due to the inclusion of single-agent chemotherapy options in the control arm. Additionally, there is inadequate data to support the statistical assumption of a 6-month improvement in the primary endpoint of overall survival.
• The agency reserves additional comment on the proposed labeling until the clinical deficiencies described have been resolved.

Cited reasons

• Inadequate evidence of effectiveness from RPL-001-16 trial
• Issues with RP1-104 Phase 3 trial design and statistical assumptions
• Labeling comments reserved
• The application lacks substantial evidence of effectiveness due to significant design flaws and interpretability issues in the submitted clinical trials (RPL-001-16 and RP1-104), failing to adequately demonstrate the individual contribution of vusolimogene oderparepvec. Additional clinical trials are required.

Recommended actions

• Conduct and provide results from adequate and well-controlled clinical trial(s) which demonstrate substantial evidence of effectiveness for vusolimogene oderparepvec.
• Submit a revised study protocol for the RP1-104 trial that assesses the individual contribution of vusolimogene oderparepvec to the observed Overall Response Rate (ORR).
• Provide a detailed justification for the statistical assumptions that support the primary efficacy endpoints for the RP1-104 trial.
• Address all identified Chemistry, Manufacturing, and Controls (CMC) issues.
• Resubmit the application with all deficiencies fully addressed or withdraw the application within one year from the date of this letter.

Deficiency summary

The application lacks substantial evidence of effectiveness due to significant design flaws and interpretability issues in the submitted clinical trials (RPL-001-16 and RP1-104), failing to adequately demonstrate the individual contribution of vusolimogene oderparepvec. Additional clinical trials are required.

Findings

Regulatory context

Submission stage

final decision

Regulatory pathway

BLA

Impact

Impact score

0.95

Estimated delay

730 days

Estimated rework cost

$0

Subsequent action

resubmission

Strategic insights

The primary theme is the lack of substantial evidence of effectiveness due to fundamental flaws in clinical trial design and execution, particularly concerning the ability to demonstrate the drug's individual contribution to efficacy. New, well-controlled clinical trials are required.

Regulatory change impact: Pending sponsor mitigation plan

Approval likelihood after response: 5%