Regulatory Developments in Gene Therapy for Huntington’s Disease: Perspectives from uniQure’s Engagement with the U.S. Food and Drug Administration

uniQure N.V., a prominent entity in the gene therapy domain focused on developing innovative interventions for individuals with profound medical conditions, recently disclosed outcomes from a pre-Biologics License Application (BLA) interaction with the U.S. Food and Drug Administration (FDA) concerning AMT-130, an experimental adeno-associated virus-based gene therapy targeting Huntington’s disease (HD). This neurodegenerative disorder, characterized by progressive motor dysfunction, cognitive decline, and psychiatric symptoms due to CAG repeat expansions in the huntingtin gene, remains without approved disease-modifying therapies.

Preliminary interpretations of the dialogue indicate a notable divergence from earlier regulatory positions. Specifically, the FDA appears to have revised its stance, suggesting that evidence derived from Phase I/II trials of AMT-130, when benchmarked against an external natural history cohort according to predefined experimental designs and analytical frameworks previously communicated to the agency, may no longer suffice as the principal substantiation for BLA endorsement. This alteration contrasts with insights from several Type B consultations conducted over the preceding twelve months, thereby introducing uncertainty regarding the schedule for AMT-130’s BLA filing.

Anticipating the issuance of formalized meeting records within a thirty-day timeframe post-conference, uniQure intends to pursue expeditious follow-up engagements with the FDA to delineate viable strategies for expedited authorization of AMT-130 under accelerated approval mechanisms. Such pathways are designed to facilitate access to promising therapeutics for serious conditions based on surrogate endpoints reasonably predictive of clinical benefit.

Notably, the FDA had previously conferred Breakthrough Therapy status to AMT-130 in April 2025, predicated on comparative analyses from the Phase I/II investigations relative to external controls, alongside a Regenerative Medicine Advanced Therapy (RMAT) designation in May 2024. These recognitions underscore the potential of AMT-130 to address unmet needs in HD by modulating mutant huntingtin expression through microRNA-mediated silencing, potentially attenuating neuronal degeneration in affected brain regions such as the striatum and cortex.

In reflecting on the regulatory feedback, uniQure’s leadership expressed unanticipated concern over the deviation from November 2024 directives, which had posited that ongoing Phase I/II data, juxtaposed with natural history comparators, could underpin a BLA via the Accelerated Approval route. This development highlights challenges in relying on external controls for rare neurodegenerative disorders, where randomized controlled trials pose ethical and logistical hurdles. Nonetheless, the organization maintains confidence in AMT-130’s capacity to confer meaningful therapeutic advantages, emphasizing a dedication to collaborative resolution with the FDA to accelerate delivery to the HD patient population in the United States.

Concurrently, uniQure is advancing dialogues with international regulatory bodies, encompassing those in the European Union and the United Kingdom, to broaden the developmental trajectory of AMT-130 while sustaining momentum in U.S.-centric efforts.

uniQure exemplifies advancements in genomic medicine by realizing the paradigm of one-time administrations yielding sustained efficacy. The regulatory endorsement of its hemophilia B gene therapy, culminating from extensive preclinical and clinical endeavors, marks a pivotal advancement in hematologic disorder management. Presently, the company’s portfolio encompasses investigational gene therapies for HD, intractable temporal lobe epilepsy, amyotrophic lateral sclerosis, Fabry disease, and additional grave pathologies, accessible via http://www.uniQure.com.

This communiqué incorporates prospective declarations, identifiable through terminology such as “anticipate,” “believe,” “could,” “establish,” “estimate,” “expect,” “goal,” “intend,” “look forward to,” “may,” “plan,” “potential,” “predict,” “project,” “seek,” “should,” “will,” “would,” and analogous phrases or their negations. These projections stem from executive assessments and contemporaneous data available at the release date. Illustrative forward-looking elements encompass assertions regarding advancement of AMT-130 within the U.S., encompassing strategies for FDA collaboration to enable prompt accelerated approval and patient access; anticipated timelines and results of regulatory engagements for the AMT-130 initiative, including parallel pursuits with entities in the European Union and United Kingdom; expected receipt of pre-BLA meeting documentation within thirty days; prospective BLA submission chronology for AMT-130; perceptions of the FDA’s evolving view on Phase I/II data adequacy relative to external controls for BLA support; and AMT-130’s prospective patient benefits.

Actual outcomes may substantially deviate from these anticipations owing to various contingencies, including those associated with Phase I/II evaluations of AMT-130, such as potential inadequacies in generating data supportive of continued advancement or approval; possibilities of emergent patient information altering initial topline interpretations; uncertainties in regulatory interfacing impacting trial commencement, duration, and approval trajectories; evaluations of endpoint robustness and sensitivity in tracking disease advancement; implications of RMAT and Breakthrough Therapy designations, or other expedited routes, on ultimate approval; capabilities to execute and finance requisite Phase III or confirmatory investigations for AMT-130; maintenance of operational infrastructure and staffing; proficiency in overseeing ongoing and prospective trials alongside regulatory compliance; demonstration of gene therapy candidate efficacy in clinical settings; ongoing evolution and societal integration of gene therapies; intellectual property safeguarding; and financial sustainability through capital procurement on favorable conditions. Comprehensive delineations of these perils appear under “Risk Factors” in uniQure’s SEC submissions, notably the Annual Report on Form 10-K dated February 27, 2025, Quarterly Reports on Form 10-Q dated May 9, 2025, and July 29, 2025, plus subsequent filings. Accordingly, reliance on these prospective statements should be tempered, with no commitment to revisions absent legal mandates, notwithstanding subsequent developments.

For investor inquiries: Chiara Russo, reachable at 781-491-4371 (direct) or 617-306-9137 (mobile), via c.russo@uniQure.com. For media correspondence: Tom Malone, contactable at 339-970-7558 (direct) or 339-223-8541 (mobile), through t.malone@uniQure.com.