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Replimune plans to urgently interact with the agency to find a path forward. \n The FDA has rejected Replimune’s request for approval of RP1, adding the melanoma drug candidate to the list of assets to receive complete response letters from the new-look agency. Investors sent the biotech’s share price down 76% to below $3 in premarket trading.Replimune filed for accelerated approval of RP1, a virus designed to kill cancer cells and turn the immune system against the tumor, on the strength of the phase 1/2 Ignyte trial. The study tested RP1 in combination with Bristol Myers Squibb’s checkpoint inhibitor Opdivo in 140 patients who had previously progressed on a PD-1 drug. Replimune reported an objective response rate of 32.9%. The FDA reportedly found fault with the study. According to Replimune, the agency said the trial is not considered “an adequate and well-controlled clinical investigation that provides substantial evidence of effectiveness.” The FDA added that “the trial cannot be adequately interpreted due to the heterogeneity of the patient population,” Replimune said.Officials also called out perceived issues with Replimune’s phase 3 confirmatory trial. The biotech said the FDA noted “items related to the confirmatory trial study design which need to be addressed, including contribution of components.” Replimune CEO Sushil Patel, Ph.D., expressed surprise and disappointment at the FDA’s ruling. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews. Additionally, we had also aligned on the design of the confirmatory study,” the CEO said in a statement.Patel’s comments are reminiscent of Capricor Therapeutics’ response to its CRL earlier this month. Linda Marbán, Ph.D., CEO of Capricor, voiced surprise and disappointment at the CRL, explaining that her team had followed the guidance provided by the FDA at every stage from submission through inspection and review. Replimune enrolled a broad population in Ignyte, including patients with different stages of disease and treatment histories. The decision resulted in a heterogeneous patient population, a feature that the FDA reportedly cited as a problem in the CRL. Patel has previously said the breadth of the study population was informed by talks with the FDA. “The FDA gave us a lot of direction on what they wanted to see. One of the key things was to make sure that we had a real-world population, that we saw clinically meaningful activity across subgroups,” Patel said at a Goldman Sachs event last year. Replimune plans to request a meeting with the FDA and to urgently interact with the agency to find a path forward. Without timely accelerated approval of RP1, the biotech said the development of the drug candidate for advanced cancer patients with limited options will not be viable. The company ended March with $483.8 million to its name. Talking on an earnings call in May, Patel said he expected the RP1 confirmatory trial to “take a couple of years to complete enrollment given the study population and size of the study.”

The FDA on Tuesday issued a complete response letter for Replimune’s oncolytic virus therapy to treat certain patients with advanced melanoma, after taking issue with the company’s design and enrollment of the clinical trial, the company said. The agency said that the study Replimune used in its submission was not “an adequate and well-controlled” trial due to the “heterogeneity” of the patient population, according to a press release from the company. Replimune was attempting to win accelerated approval while enrolling patients in a follow-up study, and the FDA also took issue with the design of that confirmatory study, Replimune said. “We are surprised by this FDA decision and disappointed for advanced melanoma patients who have limited treatment options,” Replimune CEO Sushil Patel said in a statement. “The issues highlighted in the CRL were not raised by the agency during the mid- and late-cycle reviews. Additionally, we had also aligned on the design of the confirmatory study.” Replimune’s sharex $REPL cratered early Tuesday morning, falling more than 75%. The company’s comments about the CRL are almost certain to be closely scrutinized by other drug developers as they feel out the agency’s evolving standards under the Trump administration. Replimune was attempting to win approval by testing its therapy RP1 in combination with Bristol Myers Squibb’s PD-1 inhibitor Opdivo. The open-label trial enrolled 140 patients who had previously progressed on an anti-PD-1 drug. There were 75 patients in the study who had received a single-agent PD-1 inhibitor, and 65 who received a combination of anti-PD-1 and anti-CTLA-4 drugs. As of this past June, the trial had been running for over three years, and the median overall survival had not yet been reached. Overall response rate, the study’s primary endpoint, came in at 32.9%, and the three-year survival rate was 54.8%. Comparatively, makers of PD-1 agents have not run many studies in previously treated advanced melanoma, as PD-1 became the new standard of care in the first-line setting about a decade ago. Most trials have tested PD-1 inhibitors after treatment with a CTLA-4. In one such study from 2015, Merck’s Keytruda had an overall response rate of 33.7% when administered every two weeks, though the study was placebo-controlled and the primary endpoint was progression-free survival. RP1 would have become just the second oncolytic virus therapy to receive FDA approval after Amgen’s Imlygic, which came to market in 2015. Imlygic is also approved to treat melanoma, but only in skin and lymph node lesions that can’t be removed by surgery. In an interview ahead of Tuesday’s decision, Patel told Endpoints News that one of the challenges is that there isn’t really a standard of care in advanced melanoma. Many patients are able to have their tumors surgically removed, and if they can’t, they receive PD-1 checkpoint inhibitors, which have been enormously successful. But Patel said that about half of melanoma patients still see their cancers return, usually rapidly upon onset, and often, patients’ only options are chemotherapy or another PD-1 inhibitor. “These tumors become primary or secondary resistant to checkpoint inhibition, and patients really don’t do very well,” Patel said.