uniQure falls 8% on Fabry gene therapy safety concerns, efficacy data
AMT-191 trial shows strong enzyme activity but dose cohorts paused after liver toxicity, stroke
uniQure NV shares declined 8% on Friday after the gene therapy company reported mixed clinical trial data for its AMT-191 Fabry disease treatment, highlighting a tension between robust efficacy signals and dose-related safety concerns that have prompted a pause in higher-dose cohorts.
The Amsterdam-based company, trading at $24.52 with a market capitalization of $1.66 billion, released updated preliminary results from its Phase I/IIa trial showing that all 11 patients across three dose cohorts achieved elevated levels of α-galactosidase A (α-Gal A) enzyme activity—the protein deficient in Fabry disease patients. Six of those 11 patients have successfully discontinued enzyme replacement therapy while maintaining stable plasma lyso-Gb3 levels, a key biomarker for the disease.
The efficacy data demonstrate dose-dependent enzyme increases ranging from 0.34- to 82.2-fold above normal levels at the lowest dose, 1.6- to 312.5-fold at the mid-dose, and 27.7- to 223.7-fold at the highest dose. Supraphysiological expression has been maintained for more than a year in the longest-treated patient, according to the company's press release.
However, the safety profile at higher doses has prompted the company to pause dosing in the mid- and high-dose cohorts pending further evaluation. Two patients in the mid-dose cohort experienced asymptomatic Grade 3 liver enzyme elevations, confirmed as dose-limiting toxicities by an independent data monitoring committee. Both patients responded to corticosteroid therapy and remain in follow-up.
At the highest dose level, five serious adverse events occurred across two patients, including stroke and diplopia deemed unrelated to treatment, as well as chest pain, increased troponin, and leptomeningeal enhancement classified as related or possibly related to AMT-191. One patient in this cohort also experienced a Grade 3 liver enzyme elevation that resolved with corticosteroid treatment.
"These updated preliminary data reinforce our confidence in the biological activity of AMT-191, including sustained and dose-dependent increases in α-Gal A activity across all dose cohorts of the treated patients," said Walid Abi-Saab, chief medical officer at uniQure. "While the study remains ongoing, we believe the preliminary data collected are supportive of the potential for AMT-191 as a one-time administered gene therapy for people living with Fabry disease."
The safety setbacks arrive at a critical juncture for uniQure, which faces intensifying competition in the Fabry disease gene therapy market. Rival Sangamo Therapeutics presented positive data from its registrational Phase 1/2 STAAR study for ST-920 in February and initiated a rolling Biologics License Application submission to the FDA in December 2025, putting it ahead in the regulatory race.
Despite Friday's decline, uniQure maintains strong analyst support. Analysts have a consensus "Buy" rating with an average price target of $56.25, suggesting potential upside of approximately 114% from current levels. Barclays initiated coverage in late January with an "Equal-Weight" rating and $31 price target, reflecting cautious optimism amid clinical development uncertainty.
The Fabry disease treatment market, which includes enzyme replacement therapies from Sanofi's Genzyme and Takeda Pharmaceutical, is projected to reach $2.65 billion to $2.83 billion in 2026, according to market research firms Mordor Intelligence and Precedence Research. Gene therapies like AMT-191 aim to provide one-time treatments that could displace lifelong biweekly infusions, representing a significant commercial opportunity if safety and regulatory hurdles can be cleared.
AMT-191 has received Orphan Drug and Fast Track designations from the U.S. Food and Drug Administration, which could accelerate its path to market if the company successfully navigates the safety concerns at higher doses. Investors will be watching for updates on the company's dose optimization strategy and timeline for resuming enrollment in the paused cohorts.