uniQure N.V. (NASDAQ: QURE) has announced promising initial results from its Phase I/IIa clinical trial of AMT-191, an investigational AAV5-based gene therapy for Fabry disease. The preliminary data, presented at the International Congress of Inborn Errors of Metabolism (ICIEM) in Kyoto, Japan, demonstrate sustained increases in α-galactosidase A (α-Gal A) enzyme activity and successful discontinuation of enzyme replacement therapy (ERT) in all patients treated at the highest dose.
Robust Enzyme Activity and ERT Discontinuation
As of the July 24, 2025 study cutoff date, all four patients in Cohort A (6x10^13 genome copies/kilogram) showed substantial increases in α-Gal A activity, ranging from 27- to 208-fold above the mean normal level. These elevated enzyme levels remained sustained in all four patients through the study cutoff, with the longest follow-up being 45 weeks post-treatment for the first treated patient and 12 weeks for the most recently treated patient.
Notably, all four patients in the first cohort were successfully withdrawn from enzyme replacement therapy and maintained stable plasma lyso-Gb3 levels through the cutoff date. Lyso-Gb3 serves as a key biomarker of disease burden in Fabry disease, making this stability particularly significant for demonstrating therapeutic efficacy.
"These initial findings from the first cohort are encouraging, with all patients showing robust increases in α-Gal A activity and an ability to withdraw from ERT," stated Walid Abi-Saab, M.D., chief medical officer of uniQure. "The early data highlight the potential of AMT-191 as a transformative one-time treatment option for people living with Fabry disease."
Safety Profile and Dose Exploration
AMT-191 demonstrated a manageable safety profile at the highest dose tested. At the 6x10^13 gc/kg dose, two serious adverse events (SAEs) were deemed unrelated to AMT-191, including stroke and diplopia. Two related SAEs (chest pain and increased troponin) and one possibly related SAE (leptomeningeal enhancement) were observed in two patients. Additionally, one patient experienced an asymptomatic Grade 3 liver enzyme elevation that resolved with corticosteroid therapy and was classified as a dose-limiting toxicity per protocol, though it was not considered serious and did not require hospitalization. Importantly, no loss of α-Gal A expression was observed in this patient.
The second cohort, Cohort B (2x10^13 gc/kg), consisting of three patients, has completed enrollment. As of the study cutoff date, all patients in this lower-dose cohort had less than three months of follow-up, and no SAEs were reported. uniQure expects to present updated results from the Phase I/IIa clinical trial in the first half of 2026.
Addressing Unmet Medical Need
Fabry disease is an X-linked genetic lysosomal storage disorder caused by a deficiency of the α-galactosidase A enzyme, leading to toxic accumulation of globotriaosylsphingosine (lyso-Gb3) that can damage the kidneys, heart, nervous system, eyes, gut, and skin. Based on a 2020 study published in the Journal of Therapeutics and Clinical Risk Management, the prevalence is estimated to be between one in 40,000 and one in 117,000 individuals.
The current standard of care involves bi-weekly infusions of enzyme replacement therapy, a treatment with limited effectiveness in many patients due to poor cross-correction and inefficient clearance of substrates in target organs, particularly the kidney and heart. AMT-191 is designed as a one-time, intravenously administered gene therapy that incorporates a proprietary, highly potent promoter designed to achieve supraphysiological α-Gal A expression.
Market Potential and Regulatory Support
The Fabry disease treatment market, dominated by ERT with a 68.43% revenue share in 2024, is projected to reach $3.87 billion by 2030. Gene therapies are projected to grow at a 9.52% compound annual growth rate and are increasingly viewed as the next frontier due to their potential for single-dose, long-term efficacy.
AMT-191 has received both Orphan Drug and Fast Track designation from the U.S. Food and Drug Administration, providing regulatory advantages for development and approval. The regulatory environment is highly favorable for rare disease therapies, with 26 of 50 2024 FDA approvals being orphan-designated.
Clinical Trial Design
The Phase I/IIa clinical trial is a multi-center, open-label study being conducted in the United States consisting of three dosing cohorts of three or more adult male patients each receiving an intravenous infusion of AMT-191. Patients were not excluded from the trial based on pre-existing neutralizing antibodies to AAV5. Patients continue to receive their regular enzyme replacement therapy until meeting withdrawal criteria and will be followed for a period of 24 months. The trial explores safety, tolerability, and early signs of efficacy by measuring the expression of lysosomal enzyme α-Gal A.
