uniQure BLA Filed as AMT-130 Shows 4-Year Huntington’s Functional Benefit

Key Points

• uniQure submitted a BLA to the FDA for AMT-130 and expects an acceptance decision in the fourth quarter; its U.K. marketing application has also been validated.
• At 36 months, high-dose AMT-130 was associated with an 80% slowing of cUHDRS decline and a 67% slowing of functional-capacity decline versus an external natural-history cohort. Four-year data showed a 61% slowing in TFC decline, though the cUHDRS result was not statistically significant in the updated comparison.
• The therapy was generally well tolerated, with procedure-related adverse events typically resolving; uniQure plans to begin screening for a confirmatory study before year-end, using TFC as its planned primary endpoint.

uniQure NASDAQ: QURE reported updated Phase I/II data for its investigational Huntington’s disease gene therapy, ifezuntirgene inilparvovec, or AMT-130, including 36-month results from all high-dose patients and 48-month results from the first 12 high-dose patients to reach that milestone.

The company said it has submitted a biologics license application, or BLA, to the U.S. Food and Drug Administration and expects an acceptance decision during the fourth quarter. uniQure also said its marketing authorization application to the U.K. Medicines and Healthcare products Regulatory Agency has been validated. The company plans to begin screening patients for a confirmatory study before the end of the year.

Updated clinical results

At 36 months, the analysis included 15 high-dose patients, including three patients added since the company’s September 2025 update. uniQure compared the treated group with a propensity-score-matched external natural-history cohort from ENROLL-HD.

According to Chief Medical Officer Walid Abi-Saab, the 36-month analysis showed an 80% slowing in decline on the Composite Unified Huntington’s Disease Rating Scale, or cUHDRS, and a 67% slowing on Total Functional Capacity, or TFC. The company reported nominal P values of 0.005 for cUHDRS and 0.011 for TFC.

The cUHDRS was the primary endpoint supporting the company’s regulatory filings, while TFC is a key secondary endpoint and is planned as the primary endpoint for uniQure’s confirmatory study. TFC measures functional abilities such as managing finances, working, performing household tasks and maintaining independence.

For the 48-month analysis, the company reported data from 12 high-dose patients. In its prespecified comparison with an updated ENROLL-HD dataset, uniQure said AMT-130 showed a 44% slowing of cUHDRS decline, which did not reach statistical significance, with a P value of 0.144. The company reported a 61% slowing on TFC, with a nominal P value of 0.008.

Chief Executive Officer Matt Kapusta said the 48-month results continued to show a treatment benefit, particularly on functional capacity. “At 48 months, we continue to see meaningful treatment effects,” Kapusta said.

External-control discussion

uniQure devoted much of the update to differences between two ENROLL-HD data releases used as external controls. The earlier dataset, ENROLL-HD A, was used in the company’s BLA submission and its prior 36-month presentation. The newer ENROLL-HD B dataset contains an additional 2.5 years of follow-up for existing participants and approximately 6,000 additional participants, according to the company.

Abi-Saab said the updated dataset had more than 50% missing data by year four and that participants remaining in the natural-history study for longer periods appeared to progress more slowly than those who exited earlier. He characterized this as survivor bias that could understate disease progression in the external-control group and, in turn, understate AMT-130’s treatment effect at longer time points.

In a post hoc analysis using the earlier ENROLL-HD A dataset, uniQure said the high-dose group showed a 54% slowing in cUHDRS decline at 48 months, with a nominal P value of 0.041, and a 68% slowing in TFC decline, with a nominal P value below 0.001.

Company officials said the 36-month time point remains the principal basis for the BLA and the planned confirmatory trial. They also said uniQure has conducted more than 10 sensitivity analyses specified in its statistical analysis plan, with the company reporting that more than half reached statistical significance.

Safety and biomarker findings

AMT-130 was generally well tolerated, according to uniQure. The company said the most common adverse events were related to the administration procedure and resolved. Since its September 2025 update, uniQure reported no new treatment-related serious adverse events in cohorts one and two at either dose.

The company reported one case of central nervous system inflammation in a high-dose patient in cohort four, described as the low cerebral-volume cohort. The event resolved following a short course of corticosteroids. uniQure also disclosed one suicide in a low-dose patient about five years after treatment, which it assessed as unrelated to therapy.

On an exploratory biomarker measure, uniQure said cerebrospinal-fluid neurofilament light-chain levels at 48 months were 4% above baseline in the high-dose group and 8% below baseline in the low-dose group. The company said these levels were below increases it would expect in untreated patients with early manifest Huntington’s disease.

Clinician perspective and next steps

Victor Sung, professor of neurology at the University of Alabama at Birmingham and an investigator in the trial, said the results were encouraging given the lack of approved disease-modifying therapies for Huntington’s disease. He emphasized the relevance of TFC as a measure of patients’ real-world capabilities.

“A sustained treatment difference on that measure through four years suggests to me that the treatment effect may be translating into real functional capacity for these patients,” Sung said, while noting that the 48-month primary cUHDRS analysis was less conclusive.

During the question-and-answer session, Kapusta said the BLA contains the data presented in 2025: 12 high-dose patients assessed at 36 months against the ENROLL-HD A dataset. Company executives said they could not speculate on whether the FDA would independently rerun analyses using the newer external-control dataset or consider any resulting submission a major amendment.

About uniQure (NASDAQ:QURE)

uniQure N.V. is a biotechnology company focused on developing gene therapies for serious and life-threatening diseases. The company uses adeno-associated virus (AAV) technology to deliver genetic material intended to address the underlying causes of disease, with research activities spanning neurological, neuromuscular, metabolic and cardiovascular conditions.

uniQure's pipeline has included AMT-130, an investigational gene therapy for Huntington's disease, as well as programs targeting other conditions such as amyotrophic lateral sclerosis and Fabry disease.

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