A dispute over an experimental Huntington’s disease treatment has escalated concerns over the FDA’s decision-making on rare disease drugs. The departure of Center for Biologics Evaluation and Research Director VINAY PRASAD, whose office handled discussions with the treatment’s developer uniQure, could deepen uncertainty over how the FDA is applying promised flexibility.
The FDA, uniQure and a regulatory rift
- FDA Commissioner MARTIN MAKARY wants his agency to accelerate development of rare disease treatments. Together with key deputies, Makary has pushed forward a new approval process designed for medicines that affect a small number of patients. Called the “plausible mechanism” pathway, the framework would substantially ease the FDA’s traditional clinical evidence requirements in scenarios when randomized clinical trials are not feasible, as is often the case in ultrarare conditions. While the pathway is intended for “individualized” therapies, FDA leaders have signaled they envision it applying to more common conditions as well, provided the relevant criteria are met. The FDA published draft guidance detailing the pathway on Feb. 23, 2026, which AgencyIQ has analyzed in depth. Makary has also touted new flexibilities for cell and gene therapies, which can be especially well suited for targeting rare diseases, and discussed how the FDA’s recent adoption of innovative statistical methods could aid the field. “I bring a sense of urgency, and a sense of we’ve got to do something about this community, to my role at the agency,” Makary said in a Feb. 26, 2026, interview with CNBC.
- However, a series of negative FDA decisions on experimental rare disease drugs threatens to undercut Makary’s pledge. This year and last, the FDA has rejected or otherwise set back a number of high-profile rare disease treatments, raising questions about how consistently it applies the regulatory flexibility it promotes. Capricor Therapeutics, Biohaven, Pierre Fabre Pharmaceuticals and Regenxbio have all received – for various reasons – Complete Response Letters denying their medicines’ approval. And FDA feedback to uniQure looks set to substantially delay its treatment’s chance at a regulatory review. The companies all said the FDA’s decisions were unexpected or disagreed with the agency’s position. The rejections, and in some cases seeming reversals by the agency, have drawn scrutiny. At a recent Senate committee hearing, Sens. RICK SCOTT (R-Fla.) and KIRSTEN GILLIBRAND (D-N.Y.) criticized the FDA and, as Gillibrand put it, the agency’s shifting of “its regulatory position on trial design at the last minute.” Witness testimony was even more stark: “We are now living in fear, not because science failed, not because companies stopped fighting rare disease, but because of regulatory inconsistency,” said ANNIE KENNEDY, chief mission officer of the EveryLife Foundation for Rare Diseases. [Read AgencyIQ’s full analysis of the hearing here.]
- A dispute between uniQure and the FDA further highlights the discordance. The agency asked uniQure to run a randomized, controlled study of its gene therapy for Huntington’s disease, arguing that recent Phase 1/2 data comparing the experimental treatment to an external control insufficiently demonstrated effectiveness. UniQure claims this demand is a reversal of earlier agreement between it and the FDA on what supporting evidence would be necessary for an approval application. But the FDA has pushed back. A senior agency official, speaking on background during a March 5, 2026, call with multiple news publications, called uniQure’s product a “failed therapy” and accused the company of lying about its prior interactions with the agency, according to reports from The Wall Street Journal and CNN. The official also criticized the study uniQure ran to evaluate its therapy and questioned the validity of the data it obtained, according to a report by FierceBiotech from the same call. (AgencyIQ did not participate in this call, nor was it invited.) In a statement posted to the social media site X, uniQure said the FDA’s comments were “highly irregular, unprecedented, and are either incomplete or entirely incorrect.” The official’s statements do not “reflect a fair and faithful reading of the documents we have submitted or those we have received from the agency,” the company added.
- The exchange is highly unusual. The FDA does not typically comment directly on individual companies and their experimental products, a practice that helps the agency preserve its reputation as an objective arbiter. And sponsors, motivated to maintain positive relations with the agency, usually don’t directly criticize remarks by FDA officials. The escalating war of words could ripple beyond uniQure in its impact, eroding trust just as the FDA works to convince the rare disease community it’s willing to be even more flexible than previously. Already, there seems to have been consequences. Late on the afternoon of March 6, the Journal reported Center for Biologics Evaluation and Research Director VINAY PRASAD, whose background matches comments reportedly made by the anonymous FDA official, would depart the agency in April. Makary confirmed Prasad’s departure in a statement on X soon after. Prasad’s center oversaw the review of the therapies from Capricor, Pierre Fabre, Regenxbio and uniQure. He was previously ousted in July 2025, in part due to furor over a decision on another rare disease therapy, only to return a month later.
UniQure’s case and the FDA’s objections
- UniQure’s principal supporting data come from two dozen Huntington’s patients treated with its therapy, dubbed AMT-130, and followed for three years. The company announced summary results in September 2025. Among 12 patients given a high dose of AMT-130, treatment significantly slowed disease progression on a commonly used disease rating scale by 75% compared to a “propensity score-matched external control.” Treated patients declined by 0.38 points on the composite Unified Huntington’s Disease Rating Scale, compared to a decline of 1.52 points observed among matched patients in the natural history study. There was no similarly significant difference between the 12 patients given a low dose of AMT-130 and their matched control. (Another five patients received the high dose but haven’t been followed for three years yet.) Patients in both the low- and high-dose groups also had reductions from baseline in cerebrospinal fluid levels of neurofilament light protein, a biomarker associated with increasing disease severity.
- Upon announcing the results in September, uniQure signaled plans to quickly submit a Biologics License Application. During a subsequent pre-BLA meeting in October, however, the FDA shared its view that the Phase 1/2 would not be enough to merit filing for approval. This was a surprise to uniQure, which had understood the FDA to be comfortable with its use of an external control. In a statement Nov. 3, 2025, when uniQure shared the FDA’s position publicly, company CEO Matt Kapusta described the agency’s feedback as a “drastic change from the guidance the FDA provided in November 2024 that data from the ongoing Phase I/II studies, compared to a natural history external control, may serve as the primary basis for a BLA submission under the Accelerated Approval pathway.” A Type A meeting in January 2026 and meeting minutes received the next month confirmed the FDA’s position. The agency instead recommended uniQure run a double-blind Phase 3 study that randomizes patients to receive with AMT-130 or sham surgery. (AMT-130 is delivered via micro-catheter infusions to the brain during an eight- to 10-hour procedure conducted under anesthesia.)
- There are no disease-modifying therapies for Huntington’s, a neurodegenerative disease caused by mutations to the “HTT” gene. Roughly 40,000 people in the U.S. are estimated to have the condition, which is progressive and can result in significant disability. While available treatment can help mitigate certain symptoms, such as chorea, they don’t slow the disease’s advance. Huntington’s disease advocates were optimistic uniQure’s September results represented a meaningful step forward. And, once the FDA’s opposition to uniQure filing AMT-130 became clear last fall, the Huntington’s disease community delivered a petition asking the agency to “honor its prior guidance and expedite review” of uniQure’s drug.
- Statements by an anonymous senior FDA official to reporters provided further detail of the agency’s apparent objections. In an interview with STAT News, an anonymous agency official said FDA review staff were not convinced “there’s any therapeutic benefit” to AMT-130, according to a story published March 3. Follow-up details from that interview, published by STAT in a March 5 story, indicated the official had doubts about early results from the Phase 1/2 study, which compared treated patients to a sham control for an initial 12-month period. That data, which uniQure released in June 2022 and in 2023, did not show a clear benefit to AMT-130 and were described by the official to STAT as “negative.” (Patients initially randomized to the sham arm were allowed to cross over and remain on study, which continued as open label.) The official also raised concerns about the external control used by uniQure in its September 2025 analysis, a complaint echoed by the anonymous FDA leader who spoke with reporters in the March 5 call held on background. “We do not dispute the claim that it’s 75% better than those people,” that official told reporters, according to a report from Fierce Biotech. “What FDA disputes is that those people are a fair comparator.” (As Huntington’s symptoms can be heterogenous, an external control may not be sufficiently representative, for instance.) Per Fierce, the official also denied that the agency ever promised to accept an external control, which he described as a “distorted comparison.”
Analysis: What does the uniQure controversy mean for the rare disease field?
- The senior FDA official’s comments risk stressing the agency’s relationship with the rare disease community. Recent drug rejections had already created an unfavorable split screen between agency leaders’ pledges of maximal flexibility and a pattern of decisions that, collectively, seemed to demonstrate hesitation to widely apply such accommodation. The official escalated this tension, placing the FDA in a “he said”-“she said” dispute that asked patients and disease advocates for trust at a moment when it’s in short supply. The FDA can, of course, change its mind about what constitutes sufficient evidence and that past promises don’t guarantee approval or even a review. But rather than explain an evolving position, the official chose to anonymously attack a sponsor and denigrate an experimental product the agency has not yet reviewed. His comments followed an interview in which Makary also appeared to dismiss uniQure’s therapy, referencing a product administered to the brain via “burr holes” that he said the FDA was “pressured to approve.” There are precedents for the FDA signaling its objections to an experimental therapy, but the agency’s communications in at least one past example of an ALS treatment looked much different.
- Lawmakers could intervene more forcibly to support rare disease development. Sens. Scott and Gillibrand’s comments at the Feb. 26 hearing held by the Senate Committee on Aging showed the FDA’s rare disease decision-making is already high on legislators’ radars. Sen. RON JOHNSON (R-Wis.), who reportedly pressured the FDA over Prasad’s imposition of restrictions on a Duchenne muscular dystrophy drug last summer, has also signaled he’s paying close attention. “Dr. Makary is saying all the right things, but underneath him, they’re just saying no, and that has to be stopped,” Johnson said in an interview with the Journal published March 5. Congress has directed the FDA to provide flexibility to rare disease therapies on several occasions and the upcoming renewal of user fee legislation may prompt lawmakers to take a closer look at how the agency is performing.
- Escalation may beget more escalation. Several times now, drug developers set back by the FDA have put forward their own accounts of interactions with the agency. They’ve succeeded in bringing significant media attention to their cases, which in Moderna’s case appeared to have earned it a reversal of the FDA’s initial decision. Similarly, uniQure is drawing support from the Huntington’s disease community and industry groups. Whereas previously companies may have chosen to lie low and comply with unexpected FDA requests, they may now see it in their interest to challenge the agency – especially if they see Makary or other FDA leaders sharing information publicly that they considered to be confidential. UniQure’s Kapusta, for instance, told STAT that some of the information shared by the unnamed FDA official had never been communicated directly to the company. This environment could make it harder for the FDA to get stakeholders on its side when confronted with sponsors that have much weaker cases to make.
- Prasad’s departure raises further questions about the FDA’s position on rare disease drugs. According to Makary, the CBER head plans to leave the agency in April. While Makary has claimed recent agency decisions reflect the position of staff reviewers, Prasad pursued an interventionist style of leadership that put him in the middle of high-profile decisions, including several instances where he appeared to overrule his subordinates. Most notably, Prasad signed a refuse-to-file letter knocking back an application from Moderna for approval of its seasonal influenza vaccine. In that case, too, Moderna claimed the FDA walked back earlier agreement on what kind of comparator would be acceptable. The agency reversed its decision soon after and has agreed to review Moderna’s shot. [Read AgencyIQ’s full analysis here.] Prasad has also set higher standards for studies of other therapies under his purview and, prior to his time at agency, regularly criticized instances of drugs winning approval with mixed or equivocal clinical data. While AgencyIQ can’t confirm whether the senior FDA official who spoke with reporters last week and Prasad are the same person, the anonymous official did reportedly disclose a background that matches Prasad’s. “You all know that as background, I’m a professor and I’m a practicing [hematology-oncology] doctor,” STAT quoted the official as saying on the March 5 call.
- Will Prasad’s exit mean the FDA provides more flexibility to therapies it previously rebuffed? Wall Street appears to think so: Shares in uniQure, Regenxbio and Capricor all rose by double digits Monday morning following Friday’s news of the CBER head’s coming exit. At the very least, Prasad’s exit will provide a test of sorts about whether Makary’s recent statements claiming agreement between agency leaders and reviewers holds true. But regulatory flip-flopping – if changes do come to pass – will present its own risks. In a March 6 note to clients, RBC Capital Markets analyst Brian Abrahams described news of Prasad’s departure as a “double-edged sword.” While his exit may lift the fortunes of some companies, “this news perpetuates the regulatory leadership volatility that has kept companies uncertain about their developmental direction,” he wrote. RICHARD PAZDUR, the longtime head of the FDA’s Oncology Center of Excellence and briefly director of its Center for Drug Evaluation and Research, raised similar concerns at a recent event hosted by the Friends of Cancer Research, arguing the FDA should be made more apolitical to protect against large swings in regulatory position as leaders and administrations change.
- Is the plausible mechanism pathway as open as FDA leaders have indicated? The guidance outlining the pathway’s operations focuses on custom therapies designed to treat a small number of patients. In writing and in comments, however, FDA leadership has signaled they’ll consider its application to rare diseases that are more prevalent or even outright common diseases. “When we were writing the draft guidance, we were very careful to leave it open-ended, to not limit this to ultrarare diseases,” TRACY BETH HØEG , acting director of CDER, said during a Feb. 23, 2026, event hosted by HHS. “This could really apply to any disease, even common, if they meet the criteria for the plausible mechanism pathway.” Judging by the pathway’s criteria and Høeg’s statements, uniQure could make a case for AMT-130 – albeit an imperfect one. Huntington’s disease is caused by a “distinct molecular or cellular abnormality” and, while its presentation is heterogenous in the short term, there’s a clear progression in disability that happens over time. AMT-130 is designed to lower huntingtin protein, which, when malformed, is at the root of the neuronal damage that causes Huntington’s. And while the FDA appears to disagree, uniQure believes its data show treatment leads to improvement in disease course. (Less clear are the biomarker signs that would indicate how well AMT-130 has successfully drugged its target in the brain: cerebrospinal fluid levels of mutant huntingtin protein and neurofilament light chain varied over time.) However, on the March 5 call with reporters, the anonymous FDA official indicated AMT-130 did not meet the pathway’s intent or criteria, according to Fierce’s report. With the pathway currently untested, the comments are one “data point” for developers trying to ascertain where its limits lie.
Key documents and dates
- Press release: uniQure Provides Regulatory Update on AMT-130 for Huntington’s Disease (March 2, 2026)
- Press release: uniQure Announces Positive Topline Results from Pivotal Phase I/II Study of AMT-130 in Patients with Huntington’s Disease (Sept. 24, 2025)
- Press release: uniQure Announces Update on Low-Dose Cohort in Phase I/II Clinical Trial of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease (June 23, 2022)