A therapy that slowed Huntington's disease progression by 75% over 3 years now faces a regulatory wall the FDA itself dismantled just 9 months ago. In June 2025, the agency granted AMT-130 both Breakthrough Therapy and RMAT designations, partly based on uniQure's plan to use external controls from the 20,000-family Enroll-HD database instead of sham surgery. By November, the FDA reversed course. By January 2026, the reversal was official. The agency should reverse itself again, because its own prior judgment was correct.
What a Sham Trial Actually Means for a Brain
Sham surgery is not swallowing a sugar pill. It means anesthesia, stereotactic head frames, burr holes drilled through skull bone, and recovery from an invasive neurosurgical procedure that delivers nothing. That is the placebo arm. Patients who draw that lot sit in the control group for 3 to 5 years while their disease progresses.
Edward Wild, consultant neurologist at UCL's Huntington's Disease Centre, put the math plainly: untreated patients who enter this trial in early stages will, over the required observation window, progress to needing wheelchairs or walking assistance. A substantial portion will advance so far that they become ineligible for actual treatment. The disease ate the years they volunteered to science.
I think about this the way I think about flight test. You do not fly a test pilot into a mountain to confirm that mountains are hard. You gather every piece of telemetry you have, you model the risk, and you make the call. The Enroll-HD database is telemetry. It tracks disease trajectories across thousands of patients over years. It is not perfect. No external control is. But it is real data, and the FDA agreed it was sufficient when it handed AMT-130 its most prestigious designations.
The Agency's Own Paper Trail
The FDA's RMAT designation carries specific regulatory meaning. It signals the agency's willingness to consider innovative trial designs, including external controls, for therapies addressing serious conditions with unmet need. Huntington's qualifies on every count: 40,000 Americans living with it, roughly 1,000 deaths per year, and zero approved disease-modifying treatments.
The June 2025 designations were not rubber stamps. They followed review of the Phase I/II data showing AMT-130 compressed 4 years of expected decline into the progression you would see in 1 untreated year. The agency looked at those results, looked at the external control strategy, and said yes.
Then came November. New leadership. New position. The stated rationale: 12-month data showed no detectable treatment effect relative to sham subjects. Fair enough as a data point. UniQure's own chief medical officer acknowledged that 1 year is generally insufficient to detect meaningful progression in early Huntington's patients. Slow-moving diseases require long observation windows. The 3-year data showed the effect clearly. Demanding that a 12-month snapshot carry the same signal as a 36-month dataset is not rigor. It is selecting the wrong measurement interval and calling the result inconclusive.
The EMA reached a different conclusion. European regulators determined that sham-controlled brain surgery was unethical and designed their trial accordingly. Two regulatory bodies, same data, opposite answers. That gap should trouble the FDA.
I will grant one thing to the sham-trial advocates: placebo effects in neurosurgery are real and documented. Patients who believe they received treatment sometimes show measurable improvement. A sham arm controls for that bias in a way external data cannot. That concern is legitimate. But it does not outweigh the certainty that control-arm patients will lose years of independent function, years some will never recover, to a disease with a known, well-characterized trajectory already captured in the largest observational database in Huntington's research.
The 48,000 petition signatures delivered to FDA headquarters in January were not just advocacy. They represented a patient community that understands the tradeoff better than any regulator. These are people watching their own timelines compress.
The FDA should honor its own prior scientific judgment, accept the external control pathway it already endorsed, and let AMT-130 move toward approval. Every month of bureaucratic reversal is a month of cognitive function that someone with Huntington's will not get back.
