Rejected Twice, Then Approved: What Replimune’s FDA Reversal Means for Drug Developers 

On August 6, 2026, the FDA granted accelerated approval to Replimune’s Tudriqev (vusolimogene oderparepvec-wtpg, formerly RP1) in combination with nivolumab for adults with unresectable advanced cutaneous melanoma whose disease had progressed following anti-PD-1 therapy. 

Under ordinary circumstances, another oncology approval might not have attracted unusual attention. But Tudriqev had already been rejected by the FDA. Twice. 

The story offers a rare look at how regulatory decisions can evolve and an important lesson for sponsors navigating uncertainty around evidence, trial design, and accelerated approval. 

From Breakthrough Therapy to FDA Rejection 

RP1 is a genetically modified oncolytic viral therapy developed in combination with nivolumab for patients with advanced melanoma whose disease had progressed despite prior anti-PD-1 therapy. 

The pivotal evidence came from IGNYTE, an open-label, single-arm study, a design that became central to the regulatory debate. 

The FDA first declined to approve RP1 in July 2025, questioning whether the study could reliably attribute the observed benefit to RP1. Replimune resubmitted, but in April 2026 received a second Complete Response Letter. 

At the heart of the disagreement was not simply whether patients responded to treatment. The more difficult question was whether the trial could demonstrate why they responded. With no randomized control arm and all patients receiving RP1 plus nivolumab, separating RP1’s contribution was difficult. 

For many programs, a second rejection over fundamental efficacy questions could have ended development. For RP1, it did not. 

The Regulatory Conversation Changed 

Replimune continued discussions with the FDA and ultimately secured a path to resubmission. On July 30, the FDA convened its Cellular, Tissue, and Gene Therapies Advisory Committee to examine whether the single-arm IGNYTE data were reliable and clinically meaningful. 

The committee voted 10–3 in favor, and less than a week later, the FDA granted accelerated approval to Tudriqev. 

The decision was based on 91 efficacy-evaluable patients, with a 24.2% objective response rate and 14.1-month median duration of response. Approval still requires confirmatory evidence, but the outcome marked a striking reversal after two CRLs. 

Why This Case Matters 

The program’s fundamental limitation, its reliance on a single-arm study, did not disappear. What changed was how the FDA weighed that uncertainty against response durability, unmet medical need, expert input, and the possibility of confirming benefit after approval. 

For sponsors, the case offers three important lessons: 

• Trial design matters long after enrollment ends: without a randomized comparator, demonstrating that benefit comes from the investigational therapy can become a major regulatory challenge. 

• A CRL does not necessarily end a program: understanding exactly why regulators remain unconvinced and maintaining regulatory engagement around those concerns can be critical to finding a path forward. 

• Clinical context matters alongside the data: response rates and durability are interpreted within the broader context of unmet need, available treatments, and what constitutes meaningful benefit for patients. 

The Bigger Picture 

Tudriqev’s journey from two FDA rejections to accelerated approval shows how regulatory decisions can evolve even when uncertainty remains. 

For drug developers, the lesson is not that regulatory concerns can be overcome through persistence alone. Development programs must generate evidence that directly addresses the questions regulators need resolved.  

Sometimes the decisive question is not whether uncertainty exists, but whether the totality of evidence makes that uncertainty acceptable relative to the potential benefit for patients. For Replimune, the FDA ultimately decided that it did.