The FDA AdComm Reboot: Part 2; Lessons from the Meeting on Replimune’s RP1

The day after CBER’s Cellular, Tissue, and Gene Therapies Advisory Committee meeting on Capricor Inc.’s Deramiocel for the treatment of cardiomyopathy in DMD, the Advisory Committee met on July 30, 2026, to discuss Replimune’s BLA resubmission seeking accelerated approval of RP1 (vusolimogene oderparepvec) in combination with nivolumab for advanced melanoma after progression on anti-PD-1 therapy.

Replimune submitted a BLA on November 22, 2024, based on a single-arm Phase 2 IGNYTE study.  FDA issued a CRL on July 21, 2025, concluding that the application lacked substantial evidence of effectiveness.  Replimune resubmitted the BLA, but FDA issued a second CRL in April 2026, reiterating the same concerns. At issue in the advisory committee meeting was Replimune’s second BLA resubmission.

The FDA found that because all patients received RP1 plus nivolumab, without a nivolumab-alone control arm, it could not determine whether the observed responses were attributable to RP1, nivolumab, or the combination.  Where FDA’s review of Capricor’s application centered on data analysis issues, review of Replimune’s hinged on study design issues which the agency stated challenged interpretation, e.g.:

• Because all lesions were treated with RP1 instead of leaving a portion of lesions untreated, evaluating systemic effect in a single-arm trial may have been confounded.
• Using histopathology to reclassify disease progression, where lesions originally classified as having progressed were permitted to have been reclassified, may have inflated the objective response rate (ORR) or duration of response (DOR).
• Re-injecting lesions following disease progression and conducting additional procedures like excising lesions, may also have affected progression analysis and inflated the ORR or DOR.
• Using RECIST v1.1 response assessments to determine RP1’s contribution to systemic activity was questioned, given RP1’s intratumoral mechanism of action and the potential limitations of conventional tumor burden assessments like RECIST here.

Similar to Capricor’s situation, given the issues the agency identified, FDA conducted a more conservative sensitivity analysis and found a much lower ORR and DOR (15.7% and 14.1 months, respectively) than Replimune (who reported an ORR and DOR of 33.6% and 24.8 months, respectively).  The question for the advisory committee thus centered on whether this lower ORR and DOR were clinical meaningful.  By a vote of 10 to 3, the committee found in favor of the drug.  Their decision was largely swayed by the unmet need, the devastating nature of the disease (communicated heartbreakingly by the patients and caregivers during the open public portion of the meeting), and the fact that the confirmatory randomized controlled trial was well underway.

On August 6, 2026, four days after Replimune’s August 2, 2026 PDUFA date, FDA granted accelerated approval to RP1 (TUDRIQEV, vusolimogene oderparepvec-wtpg) in  combination with nivolumab for the treatment of adult patients with unresectable advanced cutaneous melanoma who experienced disease progression with a PD-1-blocking antibody-based regimen based on ORR and DOR of 24.2% and 14.1 months, respectively.

So what are key lessons to take away from this process?

• Proceed with caution when conducting single-arm arm studies. FDA maintains that a very large treatment effect is necessary to demonstrate efficacy when an outcome may be impacted by bias; however, how large that effect needs to be is subject to wide discretion.  FDA’s bar as expressed during the meeting was quite high, and certainly higher than the advisory committee’s.  While acknowledging the challenges identified by the agency, the advisory committee nevertheless found the bar to have been met when taking the unmet need, devastating nature of the disease, and patient perspective into account.  The patient voice proved to be particularly persuasive here.
• Remember that when FDA evaluates single-arm studies, they preserve the right to conduct sensitivity analyses taking a more conservative approach when study design issues are identified and can base their decision on such analyses. For this reason, when feasible, sponsors should consider erring on the side of making more conservative study conduct and design related decisions from the outset when conducting single-arm studies.  Alternatively, sponsors should seek more explicit alignment with the agency when planning these design features to ensure alignment with planned approaches.

Baseline-controlled studies remain an important tool in the arsenal of serious diseases with significant unmet medical need, often rare, however FDA’s review is a good reminder to design with intent to overcome FDA concerns of bias and interpretability challenges (see our previous coverage of successful single arm programs here and here).

Ultimately the advisory committee’s perspective, coupled with the patient voice, appeared to have swayed the agency to not only approve Replimune’s therapy, but to cite a higher ORR and DOR in the prescribing information than they presented at the meeting.

Overall, last week’s advisory committee meetings brought back much needed transparency into the agency’s thinking.  Limitations raised by the agency in reviewing both Capricor’s and Replimune’s BLA resubmissions have, by and large, been validated by the advisory committees, but the committee seemed more willing to exercise flexibility in the final analysis.  At least in Replimune’s case, the agency was persuaded to do the same.