The FDA has been trying to mend fences with rare disease drug developers and patient groups since the departure of former Commissioner Marty Makary three months ago. But advisory committee meetings last week for Replimune and Capricor Therapeutics only created more confusion and frustration.
The FDA has taken great strides since the end of the Makary administration to rebuild trust with industry—and the rare disease space, in particular. Two advisory committee meetings last week may have blown all that goodwill out of the window.
“There were some really disingenuous things that were done to put together the analysis that they came up with,” Mindy Leffler said of the FDA’s arguments to the FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) last Wednesday regarding Capricor Therapeutics’ Duchenne muscular dystrophy (DMD) cardiomyopathy cell therapy.
The consultant and mother of a patient in the Phase 2 trial for deramiocel appeared shell-shocked by the adcomm when she spoke with me from a hotel lobby after testifying the previous day. The committee voted 9-3 against recommending the therapy’s approval. Leffler said her son Aidan’s left ventricular ejection fraction (LVEF) had fallen by 5% prior to treatment with the cell therapy in deramiocel’s Phase 2 trial. Five years later, his cardiac function is stable, she said. If deramiocel is not approved, Aidan will lose access to it.
Capricor CEO Linda Marbán was similarly stunned by how the adcomm unfolded. She told me that she would not rule out legal action over the statistical analysis of the company’s Phase 3 HOPE-3 trial.
Replimune’s adcomm meeting, held the following day, delivered a more positive outcome for the company, with the CTGTAC voting 10-3 in favor of approving RP1 for advanced melanoma. But the FDA’s presentation was consistent with its previously released briefing documents, in which reviewers argued Replimune’s registrational trial was “not interpretable.” Now, the decision date for the drug has come and gone without word from the FDA. Replimune, the medical community—which has voiced its strong support for RP1—and patients are now back in an indeterminate limbo.
This is exactly the type of PR nightmare the FDA had been trying to rise over since former Commissioner Marty Makary left in the middle of May. Under his leadership, alongside former Center for Biologics Evaluation and Research (CBER) Director Vinay Prasad, rare disease drug developers endured a regulatory rollercoaster the past 18 months—one they didn’t realize they’d bought a ticket to ride. Previous FDA guidance was reversed and therapies including deramiocel and RP1 were unexpectedly rejected, throwing programs—and stock prices—into turmoil.
Soon after Makary and Prasad departed the agency this spring, Acting Commissioner Kyle Diamantas met with rare disease groups seeking to “repair relations with a sector disappointed by his predecessor,” according to Reuters.
Indeed, the clouds appeared to be clearing for the rare disease space, as the FDA’s temporary leaders reversed recent decisions made under Makary and Prasad. In June, the agency agreed that three-year data from the Phase 1/2 trial of uniQure’s Huntington’s disease gene therapy could support an accelerated approval application and that a sham surgery–controlled Phase 3 study may not be necessary. This directly contradicted guidance given by CBER in November 2025 and cleared the way for a biologics license application submission this quarter.
Next aboard the regulatory reversal train was REGENXBIO, which plans to resubmit its Hunter syndrome gene therapy—rejected in February—in Q3 for approval after the new FDA leadership deemed existing clinical data sufficient for consideration for accelerated approval. Just a few days later, the FDA accepted Replimune’s resubmission and assigned an August 2 action date for the twice rebuffed RP1.
When the regulator then scheduled advisory committee meetings for RP1 and deramiocel—whose resubmission was accepted by the FDA in March under Makary and Prasad—many assumed it was part of Diamantas’ bid to restore transparency at the agency after what Capital Alpha in May declared the “most damaging period in FDA history.”
But attending both CTGTAC meetings last week, I wondered: Was it all for show?
At the very least, it’s not a good look letting Replimune’s action date pass by without a mention. Now, it’s a waiting game.
All for show?
Replimune’s adcomm was scheduled for just three days before the PDUFA date—giving the FDA precious little time to consider the advisors’ feedback.
What’s more, per internal FDA and CBER standard practice, when a PDUFA date falls on the weekend—August 2 was Sunday—the actual target action date becomes the preceding Friday, according to Don Fink, cell and gene therapy master practice expert and former FDA expert biologist. That means the agency was supposed to render a decision the day after the adcomm and is currently four days late.
Does Replimune have a chance, or was the FDA simply going through the motions with the adcomm?
“My take is FDA went to great lengths in their briefing document and presentation to support what I judge to be their already determined position at the time of the advisory committee (AC) meeting that the clinical results are insufficient to support an accelerated approval and will issue a third Complete Response Letter (CRL),” Fink said in a LinkedIn post on Friday.
Indeed, Sundeep Agrawal, associate director of clinical programs at the FDA’s oncology center of excellence, was blunt when he described the agency’s position. “Contribution of effect and the need for each product has not been demonstrated, and the applicants that submitted overall survival or [overall survival] data and analysis is not interpretable,” he told the CTGTAC. Specifically, the FDA says it cannot determine how much of the effect could be attributed to RP1 versus the approved drug with which it was paired, BMS’ Opdivo.
But Replimune seems to have an ace in its pocket—the very public support of several cancer specialists. Last August—after RP1’s initial rejection in July—22 scientists who designed the drug’s Phase 3 IGNYTE trial wrote an open letter to the FDA petitioning for re-review. So it was reasonably foreseeable that the temporary voting members on the adcomm’s roster—many oncology and melanoma experts—would come down on the side of their peers and recommend RP1’s approval.
Despite some misgivings—one panelist who voted yes called the data “messy”—the FDA’s advisors voted largely in concert with their petition-penning peers.
The FDA is not obligated to follow the advice of its advisory committees, but typically does not counter an adcomm’s vote. And it certainly would raise eyebrows just as interim leadership has begun to gain traction with a frustrated industry and patient groups. Has FDA now backed itself into a corner with a drug it never wanted to approve?
For Capricor as well, the FDA appeared to have already stacked the cards against deramiocel.
“It was very clear from the voting question and sort of how [FDA] pitched it with stat plan 1.1 that they seem to have some type of ulterior motive in trying to take this therapeutic down, and I can’t figure out why,” Marbán told me after last Wednesday’s adcomm.
As for transparency, Capricor was unaware that the FDA had any issues with its data as late as the end of June.
“We really thought that it’s a very clean data set,” Marbán told me in June after the adcomm was scheduled. “We have not gotten any issues that they want to discuss.”
The non-communication wasn’t for lack of trying on Capricor’s part. Marbán said last week that the biotech had requested a meeting with the FDA weeks before the adcomm took place.
Here, a lack of transparency led to an adcomm where the two parties were misaligned on which statistical analysis plan to review, the endpoints that should have been studied, and even the target indication, which did not align with the Phase 3 trial’s primary endpoint. This is not a good look for the FDA, particularly as it tries to right the ship after months of mayhem.
Now talk of legal action is flying around after the Capricor adcomm—both from and at the biotech—and Replimune is stuck in limbo. It seems that turbulent waters still persist at the FDA.
