FDA Rejects Promising Melanoma Drug RP1 Twice, Raising Concerns About Drug Approval Process

The FDA has twice rejected RP1, an oncolytic immunotherapy melanoma drug developed by Replimune Group, despite granting it fast-track and breakthrough therapy designations in 2024. The IGNYTE trial showed 33 percent of treatment-resistant advanced melanoma patients improved with RP1 combined with nivolumab, compared to only 6-7 percent with nivolumab alone, but the FDA cited concerns about the heterogeneous study population and uncertainty whether results stemmed from RP1 or nivolumab. After a second rejection on April 10, the physician leading the trial and 22 oncology researchers sent an open letter defending RP1, while Replimune laid off employees and saw its stock plummet. The rejections come as approximately 110,000 new melanoma cases are diagnosed annually in the U.S., with metastatic melanoma carrying only a 16 percent five-year survival rate, raising concerns among medical professionals about the FDA's approval process for innovative cancer treatments.

FDA's Repeated Rejection of RP1 Melanoma Drug

• ▪Secretary of Health and Human Services Robert F. Kennedy Jr. distanced himself from the FDA's RP1 rejection decision
• ▪The FDA's first rejection letter expressed uncertainty that RP1's positive results were linked to RP1 rather than nivolumab
• ▪The FDA replaced the RP1 review team before evaluating the resubmission to maintain objectivity and account for potential bias
• ▪The FDA gave RP1 breakthrough therapy designation to expedite effective therapies for serious conditions
• ▪Replimune Group resubmitted the RP1 application in October 2025 with additional data from the IGNYTE phase 3 trial
• ▪The FDA issued a complete response letter rejecting RP1 on July 21, 2025
• ▪The FDA released the second complete response letter online before Replimune Group had a chance to analyze the concerns
• ▪The FDA placed RP1 melanoma drug development on a fast track at the end of 2024

Clinical Trial Results and Treatment Need for Advanced Melanoma

• ▪Approximately 110,000 new cases of melanoma are diagnosed each year in the United States
• ▪Early-stage melanoma skin cancer has a greater than 99 percent survival rate
• ▪The IGNYTE phase 1/2 clinical trial showed nearly 33 percent of patients with treatment-resistant advanced melanoma improved with RP1 combined with nivolumab
• ▪RP1 triggers the body's immune system to kill similar cancer cells without damaging healthy tissue
• ▪2.2 percent of people will be diagnosed with melanoma at some point during their life
• ▪RP1 gets injected directly into melanoma tumors where the virus causes cancer cells to burst
• ▪RP1 is an oncolytic immunotherapy drug made of an engineered modified herpesvirus
• ▪Melanoma that has spread to other areas of the body has a five-year survival rate of roughly 16 percent

Concerns About Shifting FDA Approval Standards and Processes

• ▪FDA commissioner Marty Makary and CBER director Vinay Prasad announced in February a shift away from requiring two phase 3 trials
• ▪The Department of Health and Human Services did not respond to a request for comment about the FDA's rejection of RP1 as of publication
• ▪Replimune Group laid off employees working on RP1 marketing and manufacturing in April following the rejections

Perspective of Replimune Group

• ▪Replimune Group suffered significant financial and operational damage from the FDA's two rejections of RP1