STAT+: A Huntington’s researcher on the UniQure-FDA fray
For decades, Huntington’s disease was a diagnosis that offered no hope of slowing its relentless march through the brain. Then in September 2025, a small biotech and a team at University College London announced what looked like a turning point: a gene therapy called AMT-130 had slowed disease progression by 75% in the patients who received the highest dose. It was the first time any drug had demonstrably held back Huntington’s, an inherited neurodegenerative condition that kills by dismantling the mind and body over 15 to 25 years.
Today, that breakthrough sits in regulatory limbo — caught between data that researchers call transformative and an FDA that has since called the same data insufficient, demanded an entirely new trial, and, in the words of a senior agency official, dismissed AMT-130 as a “failed product.”
“This result changes everything,” said Professor Ed Wild, principal investigator of the UCL trial site and one of the investigators who had described the September 2025 results as “the result we’ve been waiting for.” In follow-up comments reported by HDBuzz, Wild has called the moment a “save point” — a milestone the Huntington’s community can build on even when the path forward hits unexpected obstacles.
That language is deliberately careful. Behind the scenes, UniQure and the FDA are in open conflict.
The reversal
UniQure had alignment with the FDA as recently as June 2025. The company had been working toward a Biologics Licensing Application (BLA) submission in the first quarter of 2026, and had received both Breakthrough Therapy designation and Regenerative Medicines Advanced Therapy (RMAT) status — designations granted in part because the agency had accepted the trial’s design, which compared treated patients against an external cohort from the long-running Enroll-HD natural history study rather than against a placebo group.
That was the sticking point. Randomizing Huntington’s patients to a sham surgery control — a placebo group that would receive the same hours-long neurosurgical procedure as the treatment group, minus the gene therapy — was considered unethical by UniQure. The therapy is delivered directly into the striatum via stereotactic surgery, requiring general anesthesia and holes drilled through the skull.
In November 2025, UniQure disclosed that the FDA had reversed its position. The agency would no longer accept the external control comparison as the primary evidence for a BLA. A new placebo-controlled trial was required.
By March 2026, the dispute had escalated into open warfare. Following an agency meeting on March 2, UniQure said plans to seek approval remained blocked. Then, on March 5, an unnamed senior FDA official told reporters that UniQure was “the latest company to make a failed therapy for Huntington’s patients,” and that the company was “performing a distorted or manipulated comparison.” The official disputed UniQure’s characterization of the required study as akin to “superficially drill” a hole in the skull, calling that description “false.”
UniQure fired back. “The recent statements made by anonymous FDA sources to the press have been highly irregular, unprecedented, and are incomplete or entirely incorrect,” the company said in a statement. “We do not believe they reflect a fair and faithful reading of the documents we have submitted or those we have received from the agency.”
FDA Commissioner Marty Makary, in a separate interview, had earlier offered a pointed critique of the therapy without naming UniQure directly.
The data
What hasn’t changed: the data themselves.
In the Phase I/II trial, 12 high-dose patients were followed for 36 months. Their scores on the composite Unified Huntington’s Disease Rating Scale declined by 0.38 points, compared with a decline of 1.52 points in the matched Enroll-HD external cohort — a 75% difference. Neurofilament light protein (NfL), a marker of neuronal damage that typically rises 20–30% over three years in Huntington’s patients, was lower than baseline in treated patients, suggesting the disease process itself had slowed. Side effects were manageable.
Professor Sarah Tabrizi, lead scientific advisor on the trial and co-founder of the UCL Huntington’s Disease Centre, called the results “the most convincing evidence in the field to date.” One of her patients — the only medically-retired Huntington’s patient in the trial — had returned to work.
Tabrizi and Wild were instrumental in designing the trial. The UCL Centre, which Gillian Bates co-founded after co-discovering the Huntington’s gene in 1993, is the largest Huntington’s clinical group in Europe and has driven the field’s experimental therapy pipeline for a decade.
What the FDA wants, and why it matters
The FDA’s position is not without regulatory logic. Randomized, placebo-controlled trials are the gold standard precisely because external comparisons are subject to selection bias — patients who enroll in an experimental gene therapy trial may differ in meaningful ways from those in a natural history registry. Even with careful matching, the agency’s skepticism on external controls is well-grounded in principle.
But the agency’s timing is the problem. UniQure’s RMAT and Breakthrough Therapy designations were both granted on the basis of the external control design. The agency had multiple interactions with the company over years and, according to UniQure, had indicated alignment as recently as mid-2025. The reversal, five months before a planned BLA submission, is the kind of regulatory whiplash that erodes trust and raises costs — in both money and time.
UniQure shares have fallen 56% year-to-date. The company says it is seeking clarity from the FDA and continues to engage with regulators in Europe and the UK. An approval in either market would be a significant development for the roughly 75,000 people living with Huntington’s disease in the US, UK, and Europe, plus the hundreds of thousands who carry the genetic mutation and will develop symptoms.
The ethical fault line
The real question is whether a prospective, randomized, sham surgery-controlled trial is practically or ethically feasible at this stage. Patients receiving AMT-130 undergo major neurosurgery. Asking people to accept that risk for a procedure that might be a placebo — knowing their disease is progressive and their time is finite — is a genuine ethical dilemma, not a convenient excuse. The FDA’s counterargument, that a “small scalp incision” could serve as a sufficient sham, underestimates either the invasiveness of the procedure or the difficulty of recruiting patients willing to take that gamble.
Wild’s framing of the moment as a “save point” is deliberate. The Huntington’s community has been here before: the field saw its first huntingtin-lowering trial in 2015, also at UCL, and has climbed steadily since. AMT-130’s data remain what they were in September 2025. The scientific question of whether the therapy works hasn’t changed. What has changed is the regulatory environment — and for patients with a disease that steals years and then decades from them, regulatory timelines are not abstract.
UniQure is reportedly planning to contest the FDA’s position and continue pursuing the BLA. For now, the first disease-modifying therapy for Huntington’s disease exists — and patients are waiting.
Sources: UCL News (September 2025 trial results) https://www.ucl.ac.uk/news/2025/sep/gene-therapy-appears-slow-huntingtons-disease-progression | Reuters (March 5, 2026) https://www.reuters.com/business/healthcare-pharmaceuticals/fda-official-says-uniqure-fell-short-huntingtons-trial-defends-new-study-request-2026-03-05/ | CNBC (March 5, 2026) https://www.cnbc.com/2026/03/05/fda-uniqure-gene-therapy-huntingtons-disease.html | HDBuzz (November 2025) https://en.hdbuzz.net/uniqure-and-fda-no-longer-in-alignment-on-approval-pathway-for-amt-130/ | STAT News (March 2, 2026) https://www.statnews.com/2026/03/02/uniqure-huntingtons-disease-fda-blocked/