UniQure has ceased dosing in two cohorts in a Phase I/IIa trial of its adeno-associated viral (AAV) gene therapy, AMT-191, in Fabry disease following concerns over its safety.
Of the 11 patients enrolled in the study (NCT06270316), two patients given the medium dose of AMT-191 (4x1013 genome copies/kilogram (gc/kg)) experienced Grade 3 liver enzyme elevations, with both cases confirmed as a result of a dose-limiting toxicity following an Independent Data Monitoring Committee (IDMC) review.
While both patients have responded to corticosteroid therapy and remain in follow-up, the company will stop administering the gene therapy to patients in the medium and high-dose (6x1013 gc/kg) cohorts until further investigation is done.
There were no additional serious treatment-emergent adverse events (TEAEs) reported in patients given the high dose, though patients given AMT-191 have previously experienced treatment-related chest pain and increased troponin levels. A patient treated with the gene therapy also developed a case of leptomeningeal enhancement, though it is currently unclear if this was associated with AMT-191.
While AMT-191’s safety profile raises questions, the gene therapy did demonstrate early efficacy, as it triggered an elevation in α-galactosidase A (α-Gal A) activity, a key marker associated with Fabry disease across all three evaluated doses - 6x1013 genome copies/kilogram (gc/kg), 4x1013 gc/kg, and 2x1013 gc/kg.
This increase was dose-dependent, with patients given the highest dose of the gene therapy experiencing a 27.7 to 223.7-fold increase in α-Gal A activity. Meanwhile, patients given a medium or low dose of the drug exhibited a 1.6 to 312.52-fold or 0.34 to 82.2-fold increase in α-Gal A activity, respectively.
AMT-191’s capacity to heighten enzymatic activity was also durable, with one patient in the high-dose cohort demonstrating elevations in α-Gal A activity after more than a year. The patient with the shortest follow-up period of four months also experienced this outcome.
Patients treated with AMT-191 also maintained stable levels of plasma globotriaosylsphingosine (lyso-Gb3) – another common biomarker used to measure disease severity and progression. Lyso-Gb3 generally accumulates in the plasma when a patient is deficient in α-Gal A, as the enzyme is responsible for the compound’s breakdown within the lysosome.
Of the 11 patients enrolled onto the study, six stopped enzyme replacement therapy (ERT) after meeting pre-specified criteria. Currently, ERT is the only treatment option for patients with Fabry disease – requiring patients to make a lifelong commitment to biweekly intravenous infusions at a dedicated healthcare centre.
This data was presented at the WORLDSymposium in San Diego.
Gene therapies and the liver enzyme challenge
While gene therapies have shown strong potential across a range of rare diseases, questions remain on the benefit-risk profile of some therapies, as multiple trials have reported liver enzyme elevations in patients that have – in some cases – been fatal.
A notable example of this is Sarepta Therapeutics’ AAV therapy for Duchenne muscular dystrophy (DMD), Elevidys (delandistrogene moxeparvovec-rokl), which was associated with the death of two patients with non-ambulatory DMD through acute liver injury (ALI). This led to a temporary pause of Elevidys sales in the US, as well as certain trials involving the drug following pressure from the US Food and Drug Administration (FDA). These pauses have since been lifted. The company is now running trials in patients with non-ambulatory DMD to see if treatment with an immunosuppressant before and after Elevidys administration may mitigate these TEAEs.
Intellia Therapeutics’ lipid nanoparticle (LNP)-based gene therapy, nexiguran ziclumeran, was also linked to severe hepatic events, with a patient experiencing a Grade 4 liver-based TEAE in the Phase III MAGNITUDE trial (NCT06128629). While a patient death following the event required Intellia to pause the trial initially, dosing later resumed in January 2026. Intellia CEO also confirmed that the AE was due to an infection and not ALI.
Novartis’ AAV-based spinal muscular atrophy (SMA) drug, Zolgensma (onasemnogene abeparvovec-xioi) also caused two patient fatalities through acute liver failure.
