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FDA Reverses Course on UniQure's Huntington's Gene Therapy, Demanding Sham Surgery Trial in Setback That Could Add Years to Approval Timeline

The FDA rejected uniQure's Phase I/II data for AMT-130 and now demands a sham surgery-controlled Phase 3 trial, reversing its own prior guidance and sending shares down 40 percent.

Biotech & Medicine Gene Therapy
gene-therapy fda huntingtons-disease biotech rare-disease regulation clinical-trials
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Overview

The U.S. Food and Drug Administration has reversed its prior regulatory guidance on uniQure’s AMT-130, a one-time gene therapy for Huntington’s disease, telling the company that its Phase I/II trial data are insufficient to support a marketing application and demanding instead a prospective, randomized, double-blind trial in which control patients would undergo sham brain surgery. The announcement, disclosed by uniQure on March 2, sent the company’s stock down roughly 40 percent and cast uncertainty over the most advanced gene therapy program for a devastating neurodegenerative disease that has no approved disease-modifying treatment.

What AMT-130 Is

AMT-130 is an AAV5-based gene therapy that delivers engineered microRNA into brain cells to silence the huntingtin gene, addressing the root genetic cause of Huntington’s disease rather than merely managing symptoms. The treatment is administered as a single, one-time procedure through MRI-guided stereotactic neurosurgery, in which the therapy is injected directly into the striatum — specifically the caudate and putamen, the brain regions most affected by Huntington’s degeneration.

Huntington’s disease is a fatal inherited neurological disorder affecting roughly 30,000 people in the United States, with another 200,000 at risk of inheriting the gene mutation. There is currently no approved therapy that slows or halts the disease’s relentless progression.

What the Phase I/II Data Showed

uniQure’s Phase I/II program enrolled 39 patients across two multi-center trials in the United States and Europe, with 29 treated patients (17 high-dose, 12 low-dose) and 10 sham surgery controls. In September 2025, the company reported what it called landmark results: at 36 months, patients receiving the high dose showed a 75 percent slowing of disease progression as measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS), with a mean change from baseline of -0.38 compared to -1.52 for propensity score-matched external controls (p=0.003).

A key secondary endpoint — the Total Functional Capacity (TFC) scale, which measures patients’ ability to function independently — showed a statistically significant 60 percent slowing of decline (p=0.033). Cerebrospinal neurofilament light protein (CSF NfL), a biomarker of neurodegeneration, decreased 8.2 percent from baseline. The therapy was generally well-tolerated, with no new serious drug-related adverse events reported since December 2022.

What the FDA Now Demands

Despite these results, the FDA told uniQure in final meeting minutes from a January 30, 2026 Type A meeting that it “cannot agree that data from the Phase I/II studies of AMT-130, in comparison to an external control, are sufficient to provide the primary evidence of effectiveness required to support a marketing application,” as reported by BioPharma Dive.

The agency “strongly recommended” that uniQure conduct a prospective, randomized, double-blind, sham surgery-controlled study — meaning control-arm patients would undergo actual neurosurgical procedures, including having holes drilled into their skulls, without receiving the therapeutic agent.

This represents a direct reversal. The FDA had previously granted AMT-130 both Breakthrough Therapy designation and Regenerative Medicines Advanced Therapy (RMAT) designation, which are specifically intended to expedite development and review of therapies for serious conditions. As recently as June 2025, uniQure maintained it was in alignment with the FDA on the clinical endpoints needed for a successful Biologics License Application submission, according to STAT News.

The Sham Surgery Dilemma

The FDA’s demand for a sham-controlled trial has ignited an ethical and scientific debate. The proposed Phase 3 design would require Huntington’s patients — people living with a progressive, fatal disease — to volunteer for brain surgery knowing they may receive no therapeutic benefit.

uniQure’s chief medical officer argued that a multiyear sham-controlled study “could impose significant risks and burden to patients” and that some may consider it unethical, according to BioSpace. The contradiction was noted by analysts: Leerink analyst Joseph Schwartz observed that it seems contradictory for the FDA to be concerned about the morbidity associated with burr holes while simultaneously requiring a trial in which control patients undergo the same invasive procedure for no therapeutic purpose.

The earlier Phase I/II trials had included a sham surgery control arm, but because Huntington’s is progressive and some placebo participants deteriorated past the point of eligibility over the multi-year follow-up period, uniQure shifted to using external controls drawn from the Enroll-HD natural history database — a methodological choice the FDA initially appeared to accept but has now rejected.

The Makary Factor

The regulatory reversal comes amid broader shifts at the FDA under Commissioner Martin Makary. In a recent CNBC interview, Makary appeared to reference AMT-130 without naming it directly, stating: “There was a product where the researchers drilled a burr hole, literally a hole in people’s skulls, to inject intrathecally into the ventricle a therapy. At the end of the randomization period, it found no benefit, and yet this is one of the drugs that we were pressured to approve.”

Notably, Makary’s description of “intrathecal” injection “into the ventricle” does not match AMT-130’s documented delivery route. AMT-130 is injected directly into the striatum — the caudate and putamen — via intraparenchymal delivery, not into the ventricles, as detailed in uniQure’s published trial design and confirmed by BioSpace. This discrepancy raises the question of whether Makary was referring to AMT-130 at all, or whether his anatomical description was imprecise.

Additionally, Makary’s characterization that the therapy “found no benefit” conflicts with the published Phase I/II data, which showed statistically significant benefit on both primary and secondary endpoints. The comment has raised concerns that the FDA’s position may be influenced by factors beyond the clinical evidence.

What We Don’t Know

  • Whether alternative trial designs might satisfy the FDA. uniQure plans to request a Type B meeting in Q2 2026 to discuss study design approaches that could balance scientific rigor with ethical constraints. Whether the agency would accept a modified design — perhaps with a shorter sham-control period or adaptive elements — remains unclear.

  • How long a Phase 3 trial would take. Designing, enrolling, and completing a sham surgery-controlled trial in a rare, progressive neurological disease would likely add years to the development timeline. Patients who might have benefited from earlier approval face continued disease progression during that interval.

  • The fate of parallel regulatory submissions. uniQure has concurrent discussions underway with European and UK regulators. Whether those agencies will take a different view of the existing data could create a situation where AMT-130 is available in some countries but not others.

  • The broader precedent. The decision sends a signal to the gene therapy field about the evidentiary bar the FDA expects for one-time, surgically delivered treatments, potentially discouraging investment in similar programs for rare neurological diseases.

Market Reaction

uniQure shares fell from a February 27 close of $15.63 to a March 2 open of $9.19, a decline of approximately 41 percent, erasing hundreds of millions of dollars in market capitalization, according to BioSpace. The sell-off reflects investor concerns that the path to U.S. approval has been extended by years and that the additional Phase 3 trial will require substantial capital that the company may struggle to raise in its current position.

CEO Matt Kapusta stated that the company “did not reach alignment on a submission pathway based on Phase I/II data” but believes the clinical evidence warrants continued dialogue with the agency, according to uniQure’s press release.