FDA Rejects Replimune Melanoma Treatment RP1

The Food and Drug Administration declined to grant approval to RP1, a genetically engineered virus intended to treat advanced melanoma, the company Replimune reported. One-third of the 140 patients in the company's clinical trial experienced tumor shrinkage or disappearance while receiving RP1 in combination with the immunotherapy Opdivo.

Doctors who participated in the trial described the decision as a setback for patients with limited options. "It was devastating news," said Trisha Wise-Draper, a dermatologist at the University of Cincinnati who had patients enrolled in the trial. Eric Whitman, medical director of the Atlantic Health System's oncology service, added that the treatment could have affected as many as 2,000 patients.

Melanoma is the fifth most commonly diagnosed cancer in the United States, with about 112,000 new cases each year. The American Cancer Society projects that about 8,500 people will die from melanoma this year. If the treatment performed as observed in the trial, Whitman said as many as 2,500 of those patients could potentially be saved.

The FDA had warned Replimune in July that the trial design risked denial of approval. The single-arm study lacked a control group receiving only an approved melanoma treatment for comparison. All patients in the trial had already stopped responding to Opdivo or similar immunotherapies before receiving the RP1 combination.

Replimune argued that assigning patients to a control arm with Opdivo alone would have been unethical given their prior lack of response. "Having a control arm would have been unethical," Wise-Draper said. Some of her patients responded extremely well to RP1 and no longer have evidence of melanoma.

The FDA stated it was not convinced that the observed benefits were attributable to RP1 rather than partly to Opdivo. The agency has approved other melanoma drugs, including Merck's Keytruda 12 years ago, based on single-arm trials.

Replimune said it is firing more than half its staff and closing some operations following the decision. The company is conducting a larger trial that includes a control arm, but Whitman noted that the immediate question is whether the company will survive without accelerated approval to secure further investment.

Marty Makary, who served as FDA commissioner until his resignation this week, defended the agency's action. " HHS Secretary Robert F. Kennedy Jr. supported the decision during a congressional budget hearing, though he incorrectly stated that patients in the trial had also received chemotherapy.

The FDA decision followed repeated suggestions from the agency that Replimune alter its trial design.

Grossman, a regulatory consultant and former official at the Department of Health and Human Services, said the decision would have drawn little notice in prior years but has drawn attention because of changes at the agency under Makary. Paul Kim, a former FDA staffer now working as a pharmaceutical industry consultant in Boston, said uncertainty about decision standards affects patients, sponsors and investors.

Kim noted that accelerated approval is intended to allow provisional market entry while confirmatory trials proceed. He said the FDA's emphasis on methodology over results in its denial statement represents a recalibration for sponsors considering similar study designs.

Replimune did not respond to requests for comment.