In the agonizingly slow world of Huntington disease research, hope is usually measured in microscopic increments. So when uniQure announced last year that its investigational gene therapy, AMT-130, slowed disease progression by 75%, it looked like a historic milestone.

By spring 2026, the path forward had become far less certain.

In March, the FDA declined to accept uniQure’s phase 1/2 results as sufficient for the accelerated approval of AMT-130. Instead, the FDA strongly recommended that the company conduct a larger, randomized, double-blind phase 3 trial with a sham-surgery arm. This would require some patients to undergo a control procedure for a one-time therapy delivered directly into the brain and could add years to the development timeline for AMT-130.

The company is now considering regulatory pathways in the UK and elsewhere, even as it readies to discuss the design of a possible phase 3 or confirmatory trial with US regulators.

Targeting Huntingtin

Huntington disease is a rare, inherited neurodegenerative condition that progressively impairs motor, cognitive, and psychiatric function, typically leading to death 15-20 years after symptoms appear. It affects about 40,000 people in the US and is caused by a single mutated gene that produces a toxic version of the huntingtin protein that misfolds and accumulates in cells. Approved therapies manage symptoms such as chorea, but none targets the underlying genetic cause.

AMT-130 uses an MRI-guided neurosurgical infusion to deliver a microRNA directly into targeted regions of the brain, including the striatum — a deep brain structure damaged by the illness. The goal is to silence the gene and reduce the production of the protein believed to drive neurodegeneration.

The phase 1/2 trial began enrolling patients in 2019 and tested low and high doses of AMT-130 in sham-controlled cohorts, followed by longer-term open-label follow-up. The clearest signal emerged in the high-dose group, where 10 patients received the gene therapy immediately and six were assigned to sham surgery before crossing over to treatment at 12 months.

Victor Sung, MD, director of the Huntington’s Disease Clinic at the University of Alabama at Birmingham and a principal investigator in the trial, treated seven participants: Six received the high-dose infusion, and one initially had the sham procedure and later received AMT-130.

Sung said the FDA’s decision adds a significant hurdle, but the results he observed continue to reinforce his confidence in the treatment signal.

“Families, researchers, and doctors have been waiting generations for a breakthrough,” said Sung, who serves on the steering committee for uniQure’s clinical program evaluating AMT-130. “This multiyear delay of a highly promising, progression-slowing treatment is a massive blow to patients who do not have time to wait.”

The patients Sung treated, all in the early stages of Huntington disease, have now been followed for more than 4 years.

“All of my patients who were working full-time are still working full-time,” he said. “Generally, everyone is stable. That is not what we expect to see over this length of time in untreated Huntington disease.”

How Strong Is the AMT-130 Signal?

The FDA’s concern centers on how much weight can be placed on findings from a small study that did not maintain a randomized sham-control comparison beyond the initial blinded period. To evaluate the patients over time, uniQure compared them with matched participants from Enroll-HD, a large observational study that follows people with Huntington disease over time.

Natural history data can be useful in rare diseases, where large trials may be difficult to conduct. But such comparisons leave room for confounding.

Sung acknowledged the concern. Comparing a small, treated group with a much larger historic dataset can make a signal look more persuasive than it is.

Still, the trajectory of treated patients remains difficult to dismiss, he said. On the composite Unified Huntington’s Disease Rating Scale (cUHDRS), a measure that combines motor, cognitive, and functional outcomes, patients with early Huntington disease would typically be expected to worsen by about one point a year. In the AMT-130 high-dose group, uniQure reported a mean change of -0.38 points over 3 years vs -1.52 points in the matched external control group.

Sung described the treated group’s course as striking even without focusing on the 75% figure or the external comparator. The progression over 3 years, he said, was “closer to zero than it is to one point of progression.”

Other findings have also encouraged trial investigators. uniQure reported that neurofilament light, a marker of nerve-cell injury that typically rises as Huntington disease progresses, fell below baseline after treatment and remained at or below baseline over 3 years.

Critics Push Back

Alberto Espay, MD, MSc, a neurologist at the University of Cincinnati in Cincinnati, is among the most outspoken critics of the AMT-130 data. He argues that the 75% slowing figure overstates the drug’s effect because it is based on a relative difference from an external comparator rather than a randomized control group. In a presentation, he described the mean -0.38-point change in the cUHDRS score over 3 years as well below meaningful.

Espay said the FDA’s request for a phase 3 trial is a necessary safeguard, not a barrier to progress. The findings may justify further study, he said, but they do not yet prove that AMT-130 is responsible for the apparent slowing of disease.

The concern, Espay said, is that without randomization, it is difficult to know whether the treated patients did better because of AMT-130 or because they differed in ways the analysis could not fully capture.

The Ethics of Sham Surgery

Matt Kapusta, CEO of Netherlands-based uniQure, said the company recognizes the FDA’s need for rigorous evidence.

“Our primary concern is that we want to make sure the development path is feasible, ethical, and, of course, balanced,” Kapusta said. Considerations for a sham-controlled study in this case are “uniquely complex and nuanced.”

The concern is that some participants with a fatal, progressive disease would undergo a procedure with no possibility of immediate therapeutic benefit.

The sham procedure under discussion would involve anesthesia and superficial scalp incisions — essentially nicks in the scalp — but would not include the steps required to deliver the gene therapy: drilling holes into the skull and infusions into the brain.

Treatment with AMT-130 requires 10-12 hours of anesthesia, neurosurgical access, and direct infusion of the therapy at the target sites. That distinction makes a prolonged sham-controlled study difficult to design and recruit, Kapusta said, and could affect whether participants are willing to enroll and remain in the trial.

Another challenge is “that by the time patients in a blinded control become unblinded, they will likely have progressed with their disease and may no longer be candidates for treatment.”

Espay views the issue differently. The invasiveness of AMT-130, he said, strengthens the argument for a randomized sham-controlled trial because regulators need to know the therapy works before approving a neurosurgically delivered gene therapy.

Previous neurologic intervention studies underscore the value of blinding, Espay said. In some Parkinson’s disease stem cell trials, for example, patients who underwent sham surgery improved as much as those who received the active intervention, complicating interpretation of the results.

Tominersen and Earlier Disappointments

The regulatory debate is unfolding in a field shaped by years of disappointment. Promising approaches have failed in later-stage testing before.

One of the most closely watched was tominersen, an antisense oligonucleotide developed by Roche and Ionis to lower huntingtin protein. The drug, delivered into the spinal fluid, was once among the field’s most important experimental therapies. Roche stopped the phase 3 GENERATION HD1 trial in 2021 after an independent data monitoring committee concluded that the drug was not showing overall clinical benefit and that some patients receiving more frequent dosing were doing worse than those on placebo.

Roche later redesigned the program based on post hoc analyses, and tominersen is now being studied in a narrower group of patients with early-stage Huntington disease. Sung was a principal investigator in the tominersen clinical trial program, and patients at his clinic have had access to both tominersen and AMT-130 protocols.

Looking Ahead

For now, the immediate US focus is a type B meeting with the FDA, where uniQure plans to discuss additional analyses, including 4-year follow-up data from the phase 1/2 study, as well as potential designs for a phase 3 or confirmatory trial.

Kapusta said the UK regulatory path may move more quickly. The Medicines and Healthcare products Regulatory Agency (MHRA) contacted uniQure after the company presented its September 2025 data to discuss whether the evidence could support a regulatory filing.

“We provided MHRA with the 3-year follow-up results,” Kapusta said. “They encouraged us to include those results as part of an application for a license.”

Sung said the possibility of approval outside the US raises difficult questions for patients and families, including whether some might travel for treatment if AMT-130 becomes available elsewhere first. Because the therapy requires specialized neurosurgical delivery and intraoperative MRI, broad access would take time even if it were approved.

“This is not going to go like wildfire,” Sung said. “It will go very slow because of the invasiveness of the procedure.”

Even with those constraints, Sung said, the patient community’s response to the FDA decision has been clear. “If I could summarize their stance, it has been ‘let us be the arbiter of our own risk tolerance,’” he said.

As AMT-130 moves on several fronts — a possible UK filing, renewed FDA discussions over longer-term follow-up, and a public campaign by Huntington disease family groups pressing regulators and lawmakers for accelerated approval — the path ahead keeps shifting.

Sung recalled learning of the FDA’s March decision while he was at a theme park.

“I was literally riding a roller coaster when I found out that the trial data had been rejected,” he said. “There is something symbolic in that.”

Espay reported no relevant disclosures. Kapusta reported being the CEO of uniQure. Sung reported serving on the steering committee for uniQure’s clinical program evaluating AMT-130.