Rejected Twice: Replimune's RP1 and the 22 Scientists Who Disagreed
FDA rejected Replimune’s RP1 for advanced melanoma for the second time on April 10, citing the same reason it cited last July: heterogeneity of the RPL-001-16 trial patient population.
RP1, proposed in combination with Bristol Myers Squibb’s PD-1 inhibitor Opdivo, posted around 33% overall response rate and a 15% complete response rate in clinical trials. Twenty-two scientists who designed and ran the Phase 1/2 IGNYTE study pushed back in an open letter to FDA in August 2025, arguing the heterogeneous population was intentional: current treatment guidelines “show multiple treatment pathways in both the adjuvant and advanced disease setting funneling to the point of IGNYTE eligibility,” they wrote. FDA assigned a second group of reviewers to “maintain objectivity and account for potential bias.” Both groups reached the same conclusion.
Peter Pitts, former FDA associate commissioner for external relations, wrote Tuesday that sponsors need regulatory expectations that hold stable from trial design through final decision. When heterogeneity concerns weren’t clearly determinative during earlier review stages but emerge as decisive at the end, the result is unpredictability, not greater scientific rigor.
FDA issued guidance last year encouraging cell and gene therapy developers to use externally-controlled and innovative trial designs. But a former FDA oncology division director told BioSpace this month that whether an external control is acceptable “really can’t be determined until the review process is complete.” Sponsors designing trials around that guidance are now in an uncomfortable position.
On April 14, FDA published new draft guidance standardizing safety assessments for gene editing therapies. Replimune CEO Sushil Patel said after the April 10 rejection that the FDA “has not exercised regulatory flexibility to meet patients’ needs.”
— Sarah Chen
