For patients whose skin cancer doesn’t respond to traditional treatments, a new drug called RP1 provides a lifeline, at least for those who can participate in a clinical trial. The drug showed so much promise in such trials that, in late 2024, its development was placed on a fast track, with all signs pointing to rapid approval by the Food and Drug Administration. But since last month, the FDA has twice chosen not to approve RP1, perplexing researchers and worrying drug developers.
Approximately 110,000 new cases Melanomas are diagnosed every year in the United States, and 2.2 percent of people will be diagnosed with it at some point in their lives. In its early stages, melanoma skin cancer is highly treatable, with a survival rate greater than 99 percent. However, once the disease has spread to other parts of the body, treatment becomes much more difficult and the five-year survival rate drops to about 16 percent. Adding just one new option, like RP1, for people whose melanoma has not responded to first-line treatments could make a big difference to patients’ prognosis.
“There really is no second-line treatment” for some patients, says Yana Najjar, director of the clinical and translational research center at the Hillman Cancer Center at the University of Pittsburgh Medical Center (UPMC). “This is a population that has been left behind. This is where I was hoping RP1 would come in.”
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Called an oncolytic immunotherapy drug, RP1 is made from a modified virus – in this case, a modified version of a herpes virus – that is injected directly into melanoma tumors. Once inside, the virus causes cancer cells to burst and, in doing so, triggers the body’s immune system to kill all similar cancer cells without damaging healthy tissue.
The first trials of the drug were SO effective that the FDA gave RP1 designation “breakthrough therapy”which the agency uses to ensure that effective therapies for serious illnesses can reach patients as quickly as possible. Despite this fast-track status, RP1 has faced more hurdles from the agency than Replimune Group, the company that produces the drug, expected.
“I’ve just never seen the agency behave like this,” says Sushil Patel, CEO of Replimune. “It actually puts us in a very, very difficult position.”
The Department of Health and Human Services did not respond as of publication to a request for comment on the FDA’s rejection of RP1 and apparent changes in drug approval processes.
Last year, the phase 1/2 clinical trial of the drug, IGNYTE, showed that almost 33 percent of patients with treatment-resistant advanced melanoma saw their condition improve with a combination of RP1 and a widely used immunotherapy drug called nivolumab. This is a much higher success rate than the 6 to 7 percent of similar patients who responded to nivolumab alone. The FDA’s initial review panel recommended that the drug be approved, but just days before the deadline, July 21, 2025, Replimune received a “complete response letter» (CRL) from the FDA: a rejection.
That letter highlighted two main problems with the trial: The study population was too heterogeneous — defined by participants’ different prior treatments, the extent of disease, and other factors — and reviewers were unsure whether the positive results were related to RP1 rather than nivolumab. This second problem stemmed from the trial setup, in which no control group received a placebo instead of RP1. This decision was made because not all participants had previously responded to medications like nivolumab alone, and it would be unethical to keep patients on a medication that had not previously worked for them. Many researchers, clinicians and patient advocates quickly rushed to defend RP1, saying the FDA made a mistake in rejecting the project.
In a open letter At the FDA, the physician in charge of the IGNYTE trial and 22 other oncology researchers noted that, as a condition of entry into the trial, participants had tried drugs like nivolumab alone without improvement and that “this real-world patient population will, by necessity, be heterogeneous.”
“There are a lot of strong feelings about this, understandably,” says Michael Postow, a medical oncologist and chief of the melanoma service at Memorial Sloan Kettering Cancer Center. “This is an area where patients need new advancements the most…It’s always nice to have another option for them.”
The FDA has given Replimune the opportunity to resubmit the application this year and provide additional data and analysis from the ongoing IGNYTE Phase 3 trial. Replimune was resubmitted in October 2025, with officials confident they could bring the drug to market soon, Patel said. And again the company was rejected.
The second LCRpublished on April 10, highlighted many of the same concerns about trial design as the 2025 letter — concerns that the company believed greater communication with the review team before and during the resubmission process had alleviated. However, upon carefully reading the April 10 letter, Replimune realized that the FDA review team that had overseen the application for several years had been replaced before the new submission was evaluated “to maintain objectivity and account for potential bias,” which is not typical of resubmissions.
“This is all unexpected,” says Patel, noting that the second CRL was posted online before Replimune had a chance to analyze the FDA’s new list of concerns and discuss it with company employees. “It’s been a very concerning situation…, just the changing goals of FDA regulations and requirements.”
This second rejection was welcomed new backlash clinicians and patients, and even Health and Human Services Secretary Robert F. Kennedy, Jr., distanced himself of the controversial decision. For the research community, the rejection is particularly disconcerting, given the trial’s apparent success in treating patients with few other approved therapies to try.
“I and many others have seen patients benefit from the treatment,” says Najjar, who oversees UPMC patients enrolled in the IGNYTE trial as the site’s principal investigator. “It’s well tolerated, so my point of view was: why not approve it? Let’s give it to patients because we all want it.”
Despite support from oncologists, the rejection puts Replimune in a “very difficult position,” Patel says. In April, the company, whose shares plunged after CRL, laid off employees working on marketing and manufacturing the new drug. Replimune officials must now determine whether there is a feasible path forward for RP1. Meanwhile, others in the field are growing increasingly concerned that RP1’s rejection could indicate broader changes at the FDA that would make it harder to approve new melanoma drugs.
“I think the lack of clarity and [the] The inconsistency with the FDA… actually creates a lot of anxiety for drug developers who are wondering, “Do we have a path forward now?” “, says Patel.
Under the Trump administration, the FDA has undergone several personnel and leadership changes, many of which appear to explain the changing landscape of drug approval. In February, FDA Commissioner Marty Makary and the director of the agency’s Center for Biologics Evaluation and Research (CBER), Vinay Prasad, announced a shift away from the approval process the agency has used for decades: instead of requiring two Phase 3 trials, a “pivotal” test– a generally randomized and controlled type – will suffice. The goal of this change, according to the announcement, was to streamline and accelerate drug development.
It would be difficult to get drug trials for advanced cancers to meet the new specifications. For example, drugs such as RP1 are intended for patients for whom other cancer therapies have not worked. This means that a randomized controlled trial would not be feasible because participants in a control group would have to continue using medications that had not worked for them previously. For now, many researchers and clinicians in the oncology field are still waiting for clarification from the FDA.
“I understand the challenges of the regulatory environment,” Postow says. “I really want to make sure we all know what to do next here because we need guidance.