Huntington’s Disease

uniQure is developing a gene therapy for Huntington’s disease (HD), a rare, fatal, neurodegenerative genetic disorder that affects motor function and leads to behavioral symptoms and cognitive decline in young adults, resulting in total physical and mental deterioration. HD is caused by the expansion of CAG trinucleotide in exon 1 of a multifunctional gene coding for protein called huntingtin.

Huntington’s disease affects approximately 75,000 people in the U.S., Europe and UK, making this one of the largest clinical unmet needs in the rare disease field. Despite the clear etiology of the disease, there are no therapies available to treat the disease, delay its onset, or slow the progression of a patient’s decline.

Our investigational gene therapy candidate AMT-130 consists of an AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene, leveraging our proprietary miQURE™ silencing technology. The therapeutic goal is to inhibit the production of the mutant protein (mHTT). Using AAV vectors to deliver micro-RNAs directly to the brain for non-selective knockdown of the huntingtin gene represents a highly innovative and promising approach to treating Huntington’s disease.

In April 2025, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to AMT-130. In June 2024, the U.S. Food and Drug Administration granted Regenerative Medicine Advanced Therapy (RMAT) designation for AMT-130 based on the potential of AMT-130 to address the major unmet medical need among patients with Huntington’s disease. The designation follows the FDA’s review of interim Phase I/II clinical data for AMT-130 announced in December 2023 and is based on an analysis comparing these 24-month clinical data to a non-concurrent criteria-matched natural history cohort. RMAT designation allows for increased collaboration with the FDA to accelerate development, potentially facilitating earlier access for patients with life-threatening medical conditions. AMT-130 is the first therapeutic candidate to receive RMAT Designation for Huntington’s disease.

Previously, the FDA granted orphan drug designation for AMT-130 in Huntington’s disease, and AMT-130 has also received an Orphan Medicinal Product Designation (OMPD) from the European Medicines Agency, making it the first investigational AAV gene therapy in Huntington’s disease to receive such designation. In April 2019, we announced that the U.S. Food and Drug Administration (FDA) granted Fast Track designation for AMT-130, underscoring the high unmet medical need for patients suffering from Huntington’s disease.

uniQure is conducting two multi-center, dose-escalating, Phase I/II clinical studies to explore the safety, tolerability, and exploratory efficacy signals of AMT-130 for the treatment of Huntington’s disease. Based on interactions with the FDA, it was agreed that data from the Phase I/II studies could be compared to a propensity score-matched external control derived from the Enroll-HD natural history data set, under a prespecified statistical analysis plan, which may serve as the primary basis for a BLA submission. 

In the U.S. study, a total of 26 patients with early manifest Huntington’s disease were randomized to treatment (n=6 low dose; n=10 high dose) or an imitation (sham) procedure (n=10). Treated patients received a single administration of AMT-130 through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen). The study consists of a blinded 12-month core study period followed by unblinded long-term follow-up of treated patients for five years. An additional four control patients crossed over to treatment. The European open-label Phase 1b/2 study of AMT-130 enrolled 13 patients with early manifest Huntington’s disease (n=6 low dose; n=7 high dose). 

A third cohort enrolled an additional 12 patients across sites in the U.S. and EU. This cohort was randomized to explore both doses of AMT-130 in combination with immunosuppression, using the current, established stereotactic administration procedure. 

We’ve initiated a fourth U.S. based cohort, evaluating high-dose AMT-130 in up to 6 patients with lower striatal volumes compared to those of patients enrolled in previous cohorts. Additional details are available on www​.clin​i​cal​tri​als​.gov (NCT04120493).

The ongoing phase I/II AMT-130 studies are supplemented by two additional protocols, each with a statistical plan that was discussed with and submitted to the FDA. The new protocols, among other things, provide for the pooling of data across the ongoing U.S. and EU studies, and also pre-specified the pivotal comparison of AMT-130 clinical end points compared to a propensity score matched external control from the Enroll-HD dataset.

In September 2025 we announced positive topline data from the pivotal Phase I/II study of AMT-130 for the treatment of Huntington’s disease. Topline 36-month efficacy results for 12 patients receiving high-dose AMT-130 included the following (data cutoff as of June 30, 2025):

• A statistically significant 75% slowing in disease progression measured by the composite Unified Huntington’s Disease Rating Scale (cUHDRS) was observed which met the primary endpoint compared to a propensity score-matched external control (p=0.003).
• A key secondary endpoint of Total Functional Capacity (TFC) demonstrated a statistically significant 60% slowing of disease progression compared to a propensity score-matched external control (p=0.033).
• A mean reduction from baseline in cerebrospinal neurofilament light protein (NfL) of ‑8.2% was observed at 36 months in the high-dose of AMT-130 of the Phase I/II studies.
• AMT-130 was generally well-tolerated across both doses, with a manageable safety profile and no new drug-related serious adverse events observed since December 2022. The most common adverse events in the treatment groups were related to the administration procedure.
   

In the fourth quarter of 2025, dosing was completed in a fourth cohort of six patients receiving high-dose AMT-130 to evaluate safety and efficacy in patients with lower baseline striatal volumes compared to previous cohorts in the U.S. Phase I/II study.

On February 23, 2026, we presented new analyses at the 21st Annual Huntington’s Disease Therapeutics Conference in Palm Springs, California showing that propensity score methodology using clinical covariates with TRACK-HD/TRACK-ON and PREDICT-HD datasets effectively substitutes for baseline striatal volume in predicting Huntington’s disease progression. These covariates were the same as those used in the 3‑year data analysis to match AMT-130-treated patients to the external comparator cohort derived from Enroll-HD.

uniQure held a pre-BLA meeting with the U.S. Food and Drug Administration (FDA) in October 2025 and a Type A meeting in January 2026 to discuss the regulatory path forward. Following receipt of final meeting minutes from the Type A meeting, we announced that the FDA stated it cannot agree that data from the Phase I/II studies, compared to an external control, are sufficient to provide the primary evidence of effectiveness required to support a marketing application for AMT-130. The FDA strongly recommended the Company conduct a prospective, randomized, double-blind, sham surgery-controlled study. The Company intends to continue engaging with the FDA regarding Phase III development considerations and plans to request a Type B meeting in the second quarter of 2026 to further discuss potential study design approaches.