FDA blocks RP1 melanoma drug as Makary sparks approval chaos

RP1 melanoma – The U.S. Food and Drug Administration withheld approval for RP1, a genetically engineered treatment for melanoma that in a trial shrank or erased tumors in about one-third of participants. Doctors and industry analysts say the agency’s decision was shaped by c

The FDA’s decision to withhold approval of a melanoma treatment landed with particular force on patients and doctors who had pinned their hopes on trial results that appeared to extend lives for a meaningful share of participants.

Clinician Trisha Wise-Draper. a dermatologist at the University of Cincinnati who had patients enrolled in the RP1 study. called the outcome “devastating news.” Eric Whitman. medical director of the oncology service at the Atlantic Health System. said the stakes were measured in thousands: “This is life or death for maybe 2. 000 patients.”

The rejection also quickly became a test case for how FDA decisions are being made under commissioner Marty Makary. who took charge about 13 months ago and resigned this week.. Regulatory consultant Steven Grossman. a former official at the Department of Health and Human Services. said Makary’s approach has damaged trust painstakingly built over decades at an agency that regulates roughly 20% of U.S.. consumer spending.. “People have to speculate about the standards and processes by which the agency makes decisions,” Grossman said.. “And that uncertainty is bad for everybody — patients and sponsors and investors.”

A Wall Street Journal editorial argued the ruling would “have a chilling effect on drug development.” Supporters of the science behind RP1 say the FDA’s concerns were legitimate, but they point to a separate problem: the way decision-making has been politicized and made unpredictable.

In response to criticism over the melanoma drug. Makary accused Replimune. the manufacturer. of “corruption. ” saying the company was “engaging in corporate spin” to make the FDA look bad.. Makary told CNBC on May 5, “I don’t work for Replimune.. I work for the American people.” Kennedy. the HHS secretary. backed him during a congressional budget hearing in which Kennedy mistakenly claimed that patients in Replimune’s clinical trial had also received chemotherapy.. Makary did not respond to requests for comment.

FDA professionals, critics say, have been forced into an environment where even scientifically grounded disputes risk looking like political maneuvering.. “All the norms have been thrown out the window. so we don’t know what underlines an agency decision. ” said Paul Kim. a former FDA staffer and Senate aide to Sen.. Edward Kennedy who is now a pharmaceutical industry consultant in Boston.. “Even when there are legitimate scientific and regulatory reasons why a drug will not be approved. we’re left guessing whether it’s legitimate grounds or just a political play.”

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. It estimates that about 8,500 people will die from melanoma this year in the USA.

Replimune’s treatment, RP1, is a genetically engineered virus intended to destroy tumor cells and alert the immune system.. In the company’s push for accelerated approval. it presented trial data showing that tumors shrank or disappeared in roughly one-third of 140 participants.. Whitman said that. if the results translated into real-world benefit as well as they did in the study. as many as 2. 500 of those patients could potentially be saved.

Accelerated approval is designed as a shortcut: a product can enter the market while a larger confirmatory trial is completed. The FDA, however, had already warned Replimune in July that it risked denial unless it changed how the medication was tested.

The key problem. according to the FDA’s concerns as described by critics and analysts. was the absence of a control arm.. Patients were all given RP1 together with Opdivo, an immunotherapy drug.. The FDA said the trial lacked an arm that would allow researchers to compare the combination against an approved melanoma treatment on its own.. Replimune argued that adding Opdivo-only controls would have been unethical because all enrolled patients had stopped improving while taking Opdivo or similar drugs.

Wise-Draper rejected that characterization, saying at least some patients under her care responded extremely well. She said some participants no longer had evidence of melanoma after receiving RP1.

Replimune’s scientists have not fully pinned down exactly how the drug works. but research indicates RP1 both kills cancer cells and releases chemicals that revive Opdivo’s ability to stimulate the immune system.. The company maintains that this biology is part of why it believes the trial design was reasonable.

Replimune currently has a larger trial under way that includes a control arm.. Whitman said the accelerated-approval pathway would have helped attract investors willing to fund the larger study to completion.. After the FDA ruling, Replimune told reporters it is firing more than half its staff and closing some operations.

The RP1 decision also sits in an older regulatory tradition: it would not have been the first melanoma drug approved on the basis of a single-arm trial. Keytruda, the Merck cancer drug, was approved about 12 years ago to treat melanoma using a trial design that did not rely on a control arm.

But in its denial statement. the FDA said it was not persuaded that the positive effects from the RP1 regimen were attributable only to RP1 rather than partly to Opdivo.. Kim said Replimune arguably could have found an ethical way to create a control arm. though he also noted that it was possible the FDA could have used the accelerated-approval framework differently—offering what he described as a “provisional yes.”

Kim said the point of the three-decade-old accelerated approval program is to “take a gamble. ” and he characterized the FDA’s messaging as a shift in how much confidence sponsors can be expected to bring when they use similar studies.. “The agency’s statement. stressing the company’s methodology over the result. is a recalibration of how confident sponsors can be with similar studies. ” Kim said.

The controversy around RP1 has unfolded alongside mounting scrutiny of Vinay Prasad. an oncologist who has become a focal point for critics of FDA oversight during the Trump era.. Prasad was fired and later rehired last summer. held leadership roles. and repeatedly intervened in approval processes for drugs and vaccines that are usually determined by lower-ranking FDA professionals.. Prasad did not respond to requests for comment.

Prasad resigned for good on May 1, three weeks after the RP1 decision. Kim said the public still has uncertainty over whether the chain of events reflected Prasad’s final push or an objective choice made by careful scientists.

Makary’s tenure also drew attention from political quarters.. He ran into opposition from Trump administration officials, including over his reluctance to approve flavored vapes for smoking cessation.. Anti-abortion supporters in Trump’s orbit also pushed to remove him over allowing a generic form of mifepristone onto the market and for failing to speed up studies they hoped would lead to the abortion drug’s withdrawal.

Within the industries that the FDA regulates—gene therapy. vaccines. cancer drugs—officials and analysts have expressed frustration over what they describe as an agency that swings between extremes.. In earlier administrations. Grossman said. the FDA generally moved within a narrow band between loosening and tightening requirements for drug approvals.. Under Makary, he said, it has moved in ways that are harder to predict.. “It’s been swinging in every conceivable direction,” Grossman said.

Whitman said the inconsistency is part of what worries people. “It’s very inconsistent; it’s all over the place,” he said. “The inconsistency is part of the concern.”

During his time as commissioner. Makary made a series of categorical statements that either claimed credit for progress made in prior administrations or overstated the agency’s ability to achieve goals.. Kim said Makary set a target of ending animal testing. which he described as impractical at the moment. and moved to implement artificial intelligence more aggressively than critics believe was ready.. Makary and Prasad also promised to reduce the standard number of required clinical trials from two to one.. FDA statutes require two well-controlled clinical trials for drug approvals, but exceptions to that rule are already frequent.

Others see the direction of travel differently depending on what kind of product is under review.. Aaron Kesselheim. a Harvard Medical School professor and an expert on the drug industry. said the FDA appears to be sending signals that it wants to lower the amount of evidence needed for some types of drug approvals.. At the same time. he said the FDA has taken the opposite direction for vaccines. making it harder to get them approved.

The turmoil inside the agency has also included workforce upheaval. The FDA fired about 4,000 staffers at the start of the Trump administration, and Makary promised to bring back thousands. Grossman said filling those positions may be difficult given upheavals at both HHS and the FDA.

Even if the RP1 rejection could have been expected on scientific grounds. it has become entangled in wider arguments about FDA governance.. “The unfortunate thing is that there has been so much chaos at FDA that this Replimune decision. which may have needed to happen. has gotten mired in the controversy. ” Evan Seigerman. leader of healthcare research at BMO Capital Markets. said.

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