The US Food and Drug Administration (FDA) has rejected a marketing application for AMT-130, uniQure's investigational gene therapy for Huntington's disease (HD), declaring that Phase I/II clinical data compared against an external natural history control are insufficient to support approval.
The agency is instead demanding a prospective, randomised, double-blind, sham-surgery-controlled Phase III study — a requirement that uniQure says is both scientifically unnecessary and ethically problematic.
AMT-130 is a one-time gene therapy administered directly into the brain via intracranial injection, designed to silence the mutant huntingtin (mHTT) protein that drives HD pathology.
The therapy had generated significant clinical excitement after topline data from the Phase I/II study, announced in September 2025, showed a statistically significant 75% slowing of disease progression on the Unified Huntington's Disease Rating Scale (UHDRS) total motor score after three years, compared with matched patients drawn from the Enroll-HD natural history database.
FDA escalates rhetoric in rare public dispute
In a highly unusual move, a senior FDA official speaking anonymously to reporters reportedly escalated the agency's position last week, describing AMT-130 as a "failed" therapy and accusing uniQure of performing a "distorted or manipulated comparison."
The official was said to have stated that the external control patients (drawn from a natural history database) cannot serve as a fair comparator because they do not experience a placebo effect, unlike patients enrolled in an interventional trial who believe they may have received treatment.
The official also reportedly pointed to a potential internal inconsistency in uniQure's data package.
A subset of US patients was compared against a small sham-controlled cohort at 12 months and that randomised comparison showed no treatment effect — in contrast to the benefit seen at the same time point in the external control analysis.
"If both of those statements are true, why do we see a benefit at one year in the external controlled data, but not in the randomised data?" the official had asked, according to reporting from Fierce Biotech.
uniQure hits back around shifting guidance
uniQure has strongly contested the FDA's characterisation of events, arguing that the agency had, in writing, confirmed as recently as June 2025 that the external control design would be acceptable as the primary basis for a Biologics License Application (BLA).
The company had planned to file that BLA in early 2026 before receiving contrary feedback at a pre-BLA meeting in November 2025 and then confirmation of the reversal following a formal Type A meeting on 30 January 2026.
On the ethics of a sham-controlled study, uniQure's Chief Medical Officer, Walid Abi-Saab, argued on an investor call last week that subjecting patients to hours of general anaesthesia for a burr hole procedure they may not benefit from raises serious ethical concerns.
The unnamed FDA official refuted this in last Thursday's call, purportedly saying that the proposed sham procedure — a skin incision and one to three scalp nicks, without cranial drilling — would take approximately 30 minutes under anaesthesia and does not constitute an unreasonable burden.
A long-standing FDA policy for Huntington's candidates
The FDA defended its position by citing a policy it says has been in place for at least two decades requiring randomised internal controls for Huntington's disease therapeutics, given the condition's heterogeneity, the subjectivity of clinical endpoints and the high susceptibility of patients to a placebo effect.
The agency pointed to the cautionary precedent of tominersen, an antisense oligonucleotide co-developed by Roche and Ionis Pharmaceuticals that also targets mHTT, which appeared promising in earlier studies but failed in a Phase III placebo-controlled trial in 2021.
What happens next?
uniQure has said it plans to request a Type B meeting with the FDA in Q2 2026 to discuss Phase III trial design options, while simultaneously pursuing regulatory dialogue with authorities in the EU and UK.
Until those discussions conclude, a therapy the Huntington's disease community had hoped might reach patients through an accelerated pathway faces a timeline measured in years, rather than months.