Two timepoints read against the same updated external control, and the one the filing was built on
At 48 months, AMT-130's pre-specified primary endpoint did not reach significance, while TFC showed 61% slowing.
The external control changed too: 53% of its data was missing by month 48.
uniQure reported new Phase I/II data for AMT-130 in Huntington's disease on September 29: at 48 months, cUHDRS showed 44% slowing (p=0.144) while Total Functional Capacity showed 61%. The company says missing data in its external control likely understated the effect. None of these results were in the BLA it filed on September 2.
What was announced
uniQure announced additional data from its ongoing Phase I/II studies of ifezuntirgene inilparvovec in Huntington’s disease on September 29, with a data cutoff of June 30, 2026. Twenty-nine patients have been treated across the first two cohorts, 17 at the high dose and 12 at the low dose. The 36-month analysis now includes 15 high-dose patients, and the 48-month analysis includes 12 at each dose.
Both timepoints were compared with propensity score-matched external controls from an updated ENROLL-HD natural history dataset, with a September 2025 cutoff. There is no concurrent placebo arm in these analyses. Every percentage below is a comparison against an external cohort, which is why the cohort itself becomes part of the story.
The readout, in short
- Product: ifezuntirgene inilparvovec (AMT-130), a one-time gene therapy using a miRNA designed to silence the huntingtin gene.
- 36 months, high dose (n=15): 80% slowing on cUHDRS (nominal p=0.005) and 67% on TFC (nominal p=0.011).
- 48 months, high dose (n=12): 44% slowing on cUHDRS, which did not reach statistical significance (p=0.144), and 61% on TFC (nominal p=0.008).
- Primary endpoint: cUHDRS is the pre-specified primary endpoint for the 48-month analysis; all other p-values are nominal.
- Filing status: BLA submitted to the FDA for accelerated approval, and a Marketing Authorisation Application submitted in the UK, announced September 2, 2026.
- Designations: Breakthrough Therapy, RMAT and Fast Track from the FDA.
What changed between 36 and 48 months
At 36 months, high-dose patients had a mean cUHDRS change from baseline of -0.28, against -1.39 for the external control. That is a treatment difference of 1.12 and 80% slowing. On TFC, the change was -0.27 against -0.82, a difference of 0.55 and 67% slowing.
At 48 months, the high-dose cUHDRS change was -0.90, against -1.61 for the external control. The difference narrowed to 0.71, which is 44% slowing, and the p-value was 0.144. On TFC, the change was -0.37 against -0.94, a difference of 0.57 and 61% slowing.
cUHDRS, the pre-specified primary endpoint at 48 months: 44% slowing, p=0.144.
The two measures moved differently. The TFC treatment difference held at roughly the same size, 0.55 at 36 months and 0.57 at 48. The cUHDRS difference fell from 1.12 to 0.71, while the treated arm's own cUHDRS change grew from -0.28 to -0.90.
uniQure’s chief medical officer describes TFC as the primary measure of the company’s confirmatory study. That matters when reading the split. The endpoint that held is the one the next trial is built around, and the endpoint that missed is the one this analysis pre-specified.
The external control is doing a lot of work
Missing data in the updated ENROLL-HD matched controls reached 53% at 48 months. uniQure says its analysis showed patients who stopped follow-up were progressing materially faster than those who stayed. It believes this likely understated progression in the control, and so the treatment effect.
53% of the matched external control data was missing by month 48.
In a post-hoc sensitivity analysis using the prior ENROLL-HD external control, uniQure reported 53.5% slowing on cUHDRS (nominal p=0.041) and 68.3% on TFC (nominal p=0.001) at 48 months. The company’s own footnote adds that percentage slowing was sensitive to the magnitude of decline in the external control.
Dr. Victor Sung, professor of neurology at the University of Alabama at Birmingham, says the comparator’s slower decline appears to reflect some attrition in the longitudinal data. That is a plausible reading, and the sensitivity analysis behind it is post-hoc. The same 12 treated patients produce 44% or 53.5% slowing depending on which version of the natural history cohort sits beside them.
What the BLA rests on
At a June 2026 Type B meeting, the FDA said 36-month data from 12 high-dose patients would be acceptable as the primary basis for a BLA under accelerated approval. uniQure filed accordingly. The BLA predated the September 29 results, which were not part of it.
The September 2 announcement said the BLA and the UK application were supported by the three-year analysis against a propensity score-matched Enroll-HD control. uniQure requested priority review. If granted, it would bring a six-month review after the FDA’s 60-day filing period.
So the four-year data do not change what the FDA has in front of it. They do change the record a reviewer, an advisory committee or an investor will read beside that filing, because the TFC effect held while the external control moved. GTC covered how the FDA arrived at accepting this external control in an earlier piece.
Delivery and safety
The Phase I/II studies have dosed 51 patients across four cohorts, each through a single MRI-guided neurosurgical infusion into the striatum.
As previously disclosed, five high-dose participants (17%) had a treatment-related serious adverse event related to central nervous system inflammation, all fully resolved. Since the September 2025 readout, one low-dose patient died by suicide about five years after treatment. The study investigator assessed it as unrelated to treatment.
What this means for a CGT program
GTC analysis: the regulatory exposure here sits in the comparator, not the treated arm. The treated patients did not change between the two 48-month analyses; the registry cut did. For any program anchored to natural history, comparator attrition is a risk the sponsor cannot control, only plan for.
On timeline, the timepoint agreed with the FDA for this filing was 36 months. Longer follow-up kept running, and a weaker primary-endpoint result was reported four weeks after submission, while the filing sits with the FDA.
On endpoint choice, the 48-month analysis pre-specified cUHDRS, while the confirmatory study is built on TFC. At 48 months, only TFC held.
If you have designed or defended an external control arm built on natural history data, GTC's Expert Network matches regulatory experts like you to paid consulting work: join free.
Frequently asked questions
What did uniQure announce on September 29, 2026?
uniQure announced additional 36-month and 48-month data from its ongoing Phase I/II studies of ifezuntirgene inilparvovec (AMT-130) in Huntington's disease, with a data cutoff of June 30, 2026. The 36-month analysis now includes 15 high-dose and 12 low-dose patients. The 48-month analysis includes 12 patients at each dose. Outcomes were compared with propensity score-matched external controls from an updated ENROLL-HD natural history dataset.
Did the 48-month primary endpoint reach statistical significance?
No. uniQure says cUHDRS is the pre-specified primary endpoint for the 48-month analysis. In 12 high-dose patients it showed 44% slowing of disease progression against the updated external control and did not reach statistical significance (p=0.144). Total Functional Capacity (TFC) showed 61% slowing at 48 months (nominal p=0.008).
Are the 48-month results part of the BLA?
No. uniQure says the FDA gave its view at a June 2026 Type B meeting. It said 36-month data from 12 high-dose patients would be acceptable as the primary basis for a BLA under accelerated approval. The BLA was submitted accordingly and predated the September 29 results, which were not part of the submission.
Why does uniQure say the 48-month effect is understated?
uniQure says missing data in the updated ENROLL-HD matched controls reached 53% at 48 months. Its analysis showed patients who stopped follow-up were progressing materially faster than those who stayed. The company believes this likely understated disease progression in the control, and therefore the treatment effect. In a post-hoc sensitivity analysis using the prior ENROLL-HD external control, it reported 53.5% slowing on cUHDRS (nominal p=0.041) and 68.3% on TFC (nominal p=0.001) at 48 months.
What safety findings were reported?
uniQure says the therapy continues to be generally well tolerated, with the most common adverse events related to the administration procedure, all resolved. As previously disclosed, five high-dose participants (17%) had a treatment-related serious adverse event related to central nervous system inflammation, all of which fully resolved. Since the September 2025 readout, one low-dose patient died by suicide about five years after treatment; the study investigator assessed it as unrelated to treatment.
Sources
- uniQure Announces Additional Data from Ongoing Phase I/II Studies of ifezuntirgene inilparvovec (AMT-130) in Huntington’s Disease Showing Continued Slowing of Disease Progression – uniQure N.V., press release via GlobeNewswire, September 29, 2026.
- uniQure Announces Submission of Biologics License Application for Ifezuntirgene Inilparvovec (AMT-130) in Huntington’s Disease – uniQure N.V., press release via GlobeNewswire, September 2, 2026.
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