FDA Reverses Course on AMT-130, Citing Insufficient External Data for Submission

In a recent company announcement, uniQure disclosed that the FDA has reconsidered its stance on AMT-130, the company’s investigational gene therapy for Huntington disease (HD). After meeting with regulators, the company learned that the phase 1/2 program data (NCT0543017; NCT04120493) will not be enough to support an approval filing at this time.¹

Given the shift from earlier FDA guidance, the schedule for submitting a BLA is now in question. uniQure expects to promptly re-engage with the agency to determine how AMT-130, a gene therapy designed to lower mutant huntingtin production, might still move toward accelerated approval.

The announcement came weeks after uniQure announced promising data from its phase 1/2 program, which showed that treatment with high doses of AMT-130 led to statistically significant slowing of disease progression in patients with HD. Based on the available information, it seems the FDA no longer believes the external control used in the trial was sufficient enough to support AMT-130’s BLA submission as a potential disease-modifying treatment for HD.

"We are surprised by the FDA’s feedback at the recent pre-BLA meeting, which is a drastic change from the guidance the FDA provided in November 2024 that data from the ongoing Phase I/II studies, compared to a natural history external control, may serve as the primary basis for a BLA submission under the Accelerated Approval pathway," Matt Kapusta, chief executive officer at uniQure, said in a statement.¹ "This news is unexpected, and we are truly disappointed for people living with HD, who have no disease-modifying treatment options for this devastating disease."

Using a cutoff date of June 30, 2025, the recently released phase 1/2 data included 12 patients in both the high- and low-dose AMT-130 groups who had 36-month outcomes. These patients were then compared with a propensity score-matched external control from the Enroll-HD natural history data set, with 940 matched controls for high dose and 626 for low dose.²

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At the conclusion of the study, treatment with the gene therapy led to a 75% statistically significant (P = .003) slowing of disease progression, as measured by the comprehensive Unified Huntington’s Disease Rating Scale (cUHDRS). The study, which had protocol aligned with the FDA, revealed a mean cUHDRS change of –0.38 for those on AMT-130 vs changes of –1.52 for patients in the propensity score-matched external control.

Kapusta added, "We strongly believe that AMT-130 has the potential to bring substantial benefit to patients, and we remain fully committed to working with the FDA to determine the best path forward to rapidly bring AMT-130 to patients and their families in the US."¹

The change in stance from the FDA comes as a shock to some, considering uniQure and the agency aligned on the pathway for AMT-130 in December 2024. Through their discussions, the groups agreed that the data from the phase 1/2 program could serve as a primary basis for a BLA submission, with no need for an additional presubmission study. In addition, the two agreed that cUHDRS could serve as an intermediate end point, supported by cerebrospinal fluid (CSF) neurofilament light (NfL) reductions, for an accelerated approval.³

In the latest data update, treatment with AMT-130 led to a mean 8.2% decrease in CSF NfL, reinforcing the therapy’s potential for HD. AMT-130 also met its secondary end point, showing a mean total functional capacity (TFC) change of –0.36, a 60% difference compared with matched external controls. Additional motor and cognitive measures favored treatment, including slower decline on the SDMT (88% slowing), Swoop Word Reading Test (113% slowing), and Total Motor Score (59% slowing), with mean changes consistently improved relative to external controls.²

In addition to the FDA, uniQure plans to discuss the regulatory path with other regulatory agencies, including the European Union and United Kingdom.

REFERENCES
1. uniQure Provides Regulatory Update on AMT-130 for Huntington’s Disease. News release. November 3, 2025. Accessed November 25, 2025. https://www.globenewswire.com/news-release/2025/11/03/3179114/0/en/uniQure-Provides-Regulatory-Update-on-AMT-130-for-Huntington-s-Disease.html
2. UniQure announces positive topline results from pivotal phase I/II study of AMT-130 in patients with Huntington’s disease. News release. UniQure. September 24, 2025. Accessed November 25, 2025. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-positive-topline-results-pivotal-phase-iii
3. UniQure announces alignment with FDA on key elements of accelerated approval pathway for AMT-130 in Huntington’s disease. News release. UniQure. December 10, 2024. Accessed November 25, 2025. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-alignment-fda-key-elements-accelerated