A one time gene therapy for a fatal inherited disease gets a second chance at the FDA after its ousted regulator demanded a sham brain surgery as a placebo control.
For families living with Huntington's disease, the math is cruel. The fatal inherited disorder typically arrives in midlife and, over the next decade or so, dismantles movement, cognition, and personality. There is no approved treatment that slows it down, only the wait for decline. That is what makes UniQure's one-time gene therapy AMT-130 more than another experimental drug: a single injection, delivered during a 10-to-12-hour brain surgery, designed to lower the mutant huntingtin protein that drives the disease.
Early data from a small trial, using external untreated patients as a comparator rather than a placebo arm, suggested up to 75% slowing of disease progression. That figure is preliminary, drawn from a handful of patients in an early-stage, externally controlled study, and should be read as a signal worth following rather than proof of benefit. It is, however, the most striking signal yet for a fatal disease with no alternatives.
In 2024, the Food and Drug Administration told UniQure that, given the seriousness of Huntington's and the limits of running a placebo-controlled trial for a one-time neurosurgical therapy, the company could file for accelerated approval using external untreated patients as a comparator. That path disappeared when Vinay Prasad took charge of the FDA's gene-therapy office. Prasad, a hematologist-oncologist who became the agency's top vaccine and gene-therapy regulator under Health and Human Services Secretary Robert F. Kennedy Jr., reversed course and demanded a sham-surgery control: some patients in any confirmatory trial would undergo a 10-to-12-hour neurosurgical procedure, including skull drilling, even though they would receive no therapy.
The demand set off a rare public fight. Janet Woodcock, who retired in 2024 after roughly 40 years at the FDA, told The New York Times the sham-surgery requirement was "truly evil." Prasad, by then, had escalated in the other direction, holding an extraordinary press briefing in which he called AMT-130 a "failed therapy" and accused UniQure of manipulating its data. Both characterizations belong to a political-coded fight over how to weigh a small, externally controlled signal in a fatal disease against the cost of demanding a rigorous but ethically loaded placebo condition.
Prasad's tenure at the FDA is now over. FDA Commissioner Marty Makary announced on X that Prasad would depart and return to his academic post at UCSF, and Tracy Beth Høeg, the agency's top drug regulator, has also left amid controversy. On June 17, UniQure said in a press release that the FDA had agreed, in a recent meeting, that the company can pursue accelerated approval using a standard-of-care external control rather than a sham-surgery arm. UniQure said it expects to file its Biologics License Application in the third quarter of 2026. "This is a genuine commitment to addressing the unmet need of Americans living with Huntington's disease," CEO Matt Kapusta said in the release.
The reversal hands a fatal-disease community a path it had been told to give up. It also reopens a harder question the FDA will face again, with AMT-130 and the next generation of one-time, surgery-delivered gene therapies: how do you design a rigorous trial when the only credible placebo is a multi-hour brain operation that exposes control patients to real surgical risk for no possible benefit? External comparators, drawn from natural-history cohorts and registry data, are imperfect. They can hide real effects, especially in a slowly progressive disease where the placebo arm would otherwise be observed carefully over years. Sham surgery, by contrast, is rigorous and ethically severe. There is no clean third option yet, and the agency's decision to accept an external control for AMT-130 does not resolve that tension. It only kicks it down the road, into the confirmatory study UniQure will still have to run if its BLA is accepted.
What to watch next: whether the FDA's June 17 agreement holds through the BLA review, whether the confirmatory study design can be agreed upon without re-opening the sham-surgery question, and whether the 75% slowing signal survives the scrutiny of a larger, longer, externally controlled comparison. For the Huntington's community, the next eighteen months will determine whether a one-time brain surgery, performed once in a lifetime, becomes the first approved treatment in a disease that has never had one.