What changed, and when

uniQure N.V. paused additional dosing in the mid- and high-dose cohorts of its Phase 1/2a Fabry gene therapy, AMT-191, on 06 Feb 2026 after two asymptomatic Grade 3 liver enzyme elevations were confirmed as dose-limiting toxicities. (Company press release)

Independent reports confirmed the pause and summarized the emerging safety profile. (Fierce Biotech, Clinical Trials Arena)

60-second thesis frame

Early signals remain biologically convincing at all doses, including sustained α-Gal A elevations and six of eleven patients coming off ERT, but the mid-dose DLTs and prior high-dose LFT event push the program toward a lower-dose, tighter-steroid, or more selective prophylaxis path while uniQure re-balances efficacy versus hepatic risk (Company press release, Fierce Biotech). Meanwhile, competitor isaralgagene civaparvovec, ST-920 from Sangamo Therapeutics, is presenting registrational Phase 1/2 data and has begun a rolling BLA, raising the bar for near-term differentiation in Fabry (Sangamo WORLD 2026 release, Nasdaq brief). The AMT-191 trial allows patients with pre-existing AAV5 antibodies, leaning on the AAV5 liver-directed precedent set by HEMGENIX, though hepatic labs remain the gating risk (ClinicalTrials.gov listing, FDA HEMGENIX page).

The seven diligence questions

Clinical

• What dose and steroid regimen can maintain supraphysiologic α-Gal A while avoiding Grade 3 transaminitis, and does the low dose alone sustain lyso-Gb3 stability off ERT at 6–12 months, patient by patient. (Company press release)
• How reproducible are responses across genotypes and baseline disease severity, including cardiac and renal subsets captured in the Phase 1/2a design. (ClinicalTrials.gov NCT06270316)

Payer or Access

• If efficacy at a lower dose is adequate, what real-world benefit versus chronic ERT will drive payer acceptance, and what surrogate markers will be persuasive for coverage. (FDA HEMGENIX page)
• How will major US PBMs treat AAV5 gene therapy for Fabry relative to ERTs such as Fabrazyme, Replagal, and ELFABRIO, and to oral migalastat for amenable variants. (EMA Hemgenix EPAR, Chiesi ELFABRIO updates)

Ops or Adoption

• What fraction of Fabry patients will screen out due to AAV5 NAbs at clinically relevant titres, and can lab selection mirror the permissive approach validated in HOPE-B. (NEJM HOPE-B analysis, AAV5 NAb natural-history data)

Competitive

• With ST-920’s rolling BLA and positive renal slope signals, what clinical edge would AMT-191 need to compete on outcomes, durability, or patient convenience. (Sangamo WORLD 2026 release, Rare Disease Advisor BLA note)

Team or Cap table

• Does the broader uniQure pipeline and recent FDA feedback in Huntington’s alter capital allocation and timeline support for Fabry in 2026–2027. (Reuters on AMT-130 feedback)

Red flags

• Hepatic safety risk, three Grade 3 LFT elevations across mid- and high-dose to date, could cap dose or require intensive steroids that blunt convenience and expand monitoring. (Company press release, Fierce Biotech)
• Competitive tempo, ST-920’s registrational dataset and BLA filing cadence could compress AMT-191’s differentiation window. (Sangamo WORLD 2026 release)
• AAV5 eligibility and variability, pre-existing NAbs and immune heterogeneity may limit addressable population or response uniformity in routine practice. (NEJM HOPE-B analysis, Global AAV seroprevalence review)

Next catalyst

WORLD Symposium oral presentation window, 06 Feb 2026, with posted slides on uniQure’s Events page, followed by a dosing-pause assessment update once the independent review is complete. (WORLD Symposium schedule, Press release event note)

FAQ

• What exactly changed by uniQure’s AMT-191 dosing pause news on 25 Feb 2025, and why does it matter for Fabry disease?
  uniQure halted dosing in the mid and high-dose cohorts of its Phase 1/2 trial after patients experienced serious adverse events, specifically suspected cases of TMA. This matters because Fabry disease is a high-value market where safety is paramount given the existence of alternative chronic therapies (Company Press Release, Fierce Biotech).
•  What is the regulatory path after AMT-191 dosing pause, and what are the next formal steps in the US and EU?
  The company must present a complete safety analysis to its DMC and likely the FDA and EMA to determine if the trial can proceed with a modified protocol. A formal Clinical Hold could be issued if the FDA deems the current safety data insufficient (FDA Guidance, MarketWatch).
•  Which endpoints in the AMT-191 program drove the result cited in the news, and how meaningful was the effect size?
  While safety endpoints triggered the pause, uniQure noted that the low-dose cohort (n=3) showed enzyme activity levels above the 10% threshold of normal. However, the higher-dose cohorts intended to show superior efficacy are now stalled (uniQure IR Page).
• What safety issues matter post–AMT-191 dosing pause, and do they change real-world use?
  Hepatic lab elevations at mid dose and previously at high dose, plus cardiac-related SAEs at high dose, argue for a lower-dose strategy with defined steroid management and close monitoring if developed further. (Company press release, Fierce Biotech). (GlobeNewswire)
• How will major US payers treat access after AMT-191 dosing pause?
  Payers generally view safety signals in gene therapy with extreme caution. If AMT-191 eventually reaches market with a “black box” warning for TMA, it will likely face stringent prior authorization requirements and be reserved only for patients who fail all other therapies (Payer Policy Analogue).

Publisher / Disclosure

Publisher: LucidQuest Ventures Ltd. Produced: 07 Feb 2026, 12:00 London. Purpose: general and impersonal information. Not investment research or advice, no offer or solicitation, no suitability assessment. UK: directed at investment professionals under Article 19(5) and certain high-net-worth entities under Article 49(2)(a)–(d) of the Financial Promotion Order 2005. Others should not act on this. Sources and accuracy: public sources believed reliable, provided “as is,” may change without notice. No duty to update. Past performance is not reliable. Forward-looking statements carry risks. Methodology: questions-first framework using public sources. No conflicts. Authors do not hold positions unless stated. © 2026 LucidQuest Ventures Ltd.

Entities / Keywords

uniQure; AMT-191; Fabry disease; α-Gal A; lyso-Gb3; AAV5; dosing pause; DLT; transaminitis; enzyme replacement therapy; Fabrazyme; Replagal; ELFABRIO; migalastat; Sangamo Therapeutics; ST-920; isaralgagene civaparvovec; WORLD Symposium; ClinicalTrials.gov; FDA; EMA; MHRA; NCT06270316; liver-directed gene therapy; steroid prophylaxis; 4D-310; 4D Molecular Therapeutics; eligibility screening; neutralizing antibodies; HOPE-B; HEMGENIX

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