Here we go again. The U.S. Food and Drug Administration (FDA) on Friday told Replimune Group Inc. (REPL) that its skin cancer therapy isn't ready for prime time. The agency concluded that the company's Biologics License Application (BLA) for vusolimogene oderparepvec in combination with nivolumab doesn't provide enough evidence that it actually works for treating advanced melanoma.

This marks the second time the FDA has said no to this therapy, and they're not being subtle about why.

For those keeping score at home, Bristol-Myers Squibb Co. (BMY) markets nivolumab under the Opdivo brand name. So this is a combination therapy where Replimune's drug would be used alongside an existing treatment.

The FDA's Stance: Consistent and Unwavering

The agency reviewed Replimune's resubmitted application—which included updated analyses from study RPL-001-16 and early data from the ongoing Phase 3 trial RP1-104—and basically said: "Nice try, but not good enough."

What's interesting here is that regulators emphasized their stance hasn't changed since 2021. They're reiterating that the submitted data doesn't establish substantial evidence of clinical benefit in patients with unresectable advanced cutaneous melanoma who progressed on prior PD-1 therapies.

Even more telling: a newly assigned review team, separate from the initial evaluation, independently reached the same conclusion. When you bring in fresh eyes and they see the same problems, that's usually not a great sign for the applicant.

Where the Trials Went Wrong

The FDA pointed to multiple deficiencies in the Phase 2 RPL-001-16 study. The biggest issue? The trial design couldn't isolate what vusolimogene oderparepvec was actually contributing when used alongside nivolumab.

Think of it like this: if you're testing whether adding chocolate syrup makes a milkshake better, but you also change the ice cream flavor at the same time, how do you know what's making the difference? That's essentially the problem here.

Additional concerns included heterogeneity in the patient population and inconsistencies in how responses were assessed. The agency noted that deviations from standard RECIST v1.1 criteria (the usual way doctors measure tumor response) complicated the interpretation of the data.

And here's another wrinkle: surgical interventions and reinjection of lesions before confirmed disease progression introduced confounding variables. Translation: there were too many other things happening to patients to know whether any observed responses were actually due to the therapy being tested.

The Phase 3 Data Wasn't Ready for Prime Time

Replimune tried to bolster its application with early data from the Phase 3 RP1-104 trial. The problem? It was really early data—representing just 10% of the intended enrollment.

The FDA said this limited dataset—comprising 22 treated patients and 18 controls—was inadequate to support efficacy claims. Key gaps included a lack of independently verified response assessments, no duration-of-response data, and challenges in interpreting progression-free survival due to missing pre-specified statistical controls.

Basically, the FDA is saying: "Come back when you have more complete data from a properly designed study."

What Comes Next for Replimune

The agency reiterated that approval would require results from well-controlled clinical trials capable of clearly demonstrating efficacy. They also indicated that exploratory analyses submitted from earlier studies didn't change their original conclusions.

The good news (if you can call it that) is that the FDA said Replimune may request a Type A meeting within three months to discuss next steps. That's the regulatory equivalent of "let's talk about what you need to do to get this right."

Meanwhile, investors aren't waiting around to see how that conversation goes. Replimune shares were down 19.46% at $4.76 at the time of publication on Friday. When the FDA says no twice, the market tends to listen.