Why uniQure's Huntington Filing Rests on Twelve Patients and Two FDA Reversals
uniQure asked FDA for accelerated approval of AMT-130 on a 12-patient, 36-month high-dose dataset, after the agency twice reversed itself on external-control evidence.
uniQure N.V. on September 2, 2026 submitted a biologics license application to the U.S. Food and Drug Administration seeking accelerated approval of ifezuntirgene inilparvovec (AMT-130) for Huntington's disease, plus a marketing authorisation application to the U.K. MHRA. The company (NASDAQ: QURE) also requested priority review. If granted, the review cycle is six months after FDA's 60-day BLA filing review period.
The package is a three-year Phase I/II analysis versus a propensity score-matched Enroll-HD external control, which the company says demonstrated a slowing of disease progression. The high-dose 36-month case is 12 patients. By uniQure's updates, FDA reversed itself twice on whether that dataset can be primary evidence for accelerated approval.
Twelve patients, 75 percent slowing, and a motor miss
On September 24, 2025, uniQure said high-dose AMT-130 met its primary endpoint: statistically significant 75 percent slowing at 36 months on cUHDRS versus a propensity score-matched external control (p=0.003), mean change -0.38 versus -1.52. Total functional capacity slowed a statistically significant 60 percent (p=0.033), mean change -0.36 versus -0.88. Mean cerebrospinal fluid neurofilament light was 8.2 percent below baseline at 36 months, per the same release.
A prospectively defined statistical analysis plan aligned with FDA counted 29 treated patients, 17 high dose and 12 low dose, with 12 patients per dose at 36 months, according to the filing. Enroll-HD supplied 940 high-dose and 626 low-dose matches, with a June 30, 2025 data cutoff. Stroop Word Reading Test slowing was 113 percent (p=0.0021) in that analysis. Symbol Digit Modalities Test slowing was 88 percent (p=0.057) and not statistically significant. Total motor score slowing was 59 percent (p=0.1741) and not statistically significant. uniQure said the pattern suggests a dose-dependent response. No new drug-related serious adverse events were reported since December 2022; procedure-related events resolved. A first-quarter 2026 BLA plan later slipped. Four-year data are due before the current third quarter ends.
A striatal infusion and a sham that never entered the skull
AMT-130 is a miQURE miRNA designed to silence huntingtin and a potentially highly toxic exon 1 fragment, given once by MRI-guided, convection-enhanced stereotactic delivery into the caudate and putamen, the company said. The U.S. randomized study enrolled 26 patients: 6 low dose at 6x10^12 genome copies, 10 high dose at 6x10^13 genome copies, and 10 sham, with four crossovers after about 12 months, per NCT04120493. Sham used skin incisions only, with no burr holes and no intrastriatal injections. Specified cohorts required early manifest disease, total functional capacity 9 to 13, ages 25 to 65, and at least 40 CAG repeats.
uniQure described a European open-label study of 13 patients; ClinicalTrials.gov lists enrollment of 14. A third cohort of 12 patients received both doses plus immunosuppression, the company said. The European protocol lists dexamethasone, sirolimus, and rituximab as that regimen. A fourth U.S. cohort enrolled six high-dose patients with lower striatal volumes. Huntington's is an autosomal-dominant neurodegenerative disorder of chorea, behavioral change, and cognitive decline from a CAG expansion in huntingtin. About 75,000 people have the disease in the United States, the European Union, and the United Kingdom combined, the company estimates. There are no approved therapies to delay onset or slow progression, uniQure says.
Yes, then no, then yes
AMT-130 is the first investigational Huntington's therapy to receive Breakthrough Therapy and RMAT designations and also holds Fast Track, uniQure stated. Breakthrough Therapy came in April 2025 on Phase I/II data versus external controls. RMAT came in May 2024, the first such designation in Huntington's disease, according to a later update.
On November 3, 2025, uniQure said it believed FDA no longer agreed that Phase I/II data versus an external control may be adequate as primary evidence for a BLA. The company called it a key shift from November 2024 FDA guidance that Phase I/II versus a natural history external control may serve as the primary basis for a BLA under accelerated approval.
On June 17, 2026, after another Type B meeting, uniQure said FDA found the three-year Phase I/II analysis acceptable as the primary basis of a BLA for accelerated approval. FDA sought to align on confirmatory study design before submission, including a concurrent standard-of-care control instead of a sham procedure. uniQure committed to a confirmatory study without delay and planned a third-quarter 2026 BLA. The September 2 submissions meet that window.
What the application is asking FDA to accept
Accelerated approval would rest on 12 high-dose patients at 36 months against 940 Enroll-HD matches, with CSF NfL below baseline, while total motor score did not separate statistically, as the 2025 topline showed. The sham comparison was time-limited, and sham patients never received burr holes or striatal injections, so it cannot fully isolate surgery from vector. FDA asked to align a confirmatory trial before filing, including a standard-of-care control. The September 2 announcement does not say that alignment was finished. The filing asks whether a one-time striatal AAV gene therapy can receive accelerated approval on external-control evidence after FDA twice changed its position, for a disease with no approved therapy to delay onset or slow progression.