Ifezuntirgene Inilparvovec Shows 48-Month Data in Huntington’s Disease

uniQure reported updated clinical data for ifezuntirgene inilparvovec (AMT-130), an investigational gene therapy for Huntington’s disease (HD), showing sustained effects on disease progression through four years after a single administration. At 36 months, the updated analysis in 15 high-dose patients showed an 80% slowing of disease progression based on the composite Unified Huntington’s Disease Rating Scale (cUHDRS) and 67% based on Total Functional Capacity (TFC).

Four-Year Data Show Sustained Functional Benefit

At 48 months, 12 high-dose patients remained evaluable. cUHDRS showed a 44% slowing of disease progression versus the updated propensity score-matched external control, although the difference was not statistically significant (p=0.144). Mean cUHDRS change from baseline was -0.90 in treated patients compared with -1.61 in the external control.

TFC showed a 61% slowing of disease progression at 48 months, with a nominal p-value of 0.008. Mean TFC change from baseline was -0.37 in treated patients versus -0.94 in the external control, corresponding to a favorable treatment difference of 0.57 points.

The 48-month external-control comparison was affected by substantial missing data. Missingness reached 53% in the updated ENROLL-HD matched controls at 48 months. UniQure reported that patients who discontinued follow-up were progressing materially faster than those who remained, potentially causing the remaining control population to underestimate the underlying rate of disease progression and diluting the apparent treatment effect.

A post-hoc sensitivity analysis using the prior ENROLL-HD external control produced larger treatment effects at 48 months, showing 53.5% slowing on cUHDRS (nominal p=0.041) and 68.3% slowing on TFC (nominal p=0.001).

Dose-Dependent Separation at 48 Months

The four-year data also showed separation between the high- and low-dose groups on both functional measures. Mean cUHDRS change from baseline was -0.91 in high-dose patients versus -1.94 in low-dose patients, a difference of 1.03 points. For TFC, mean change was -0.30 versus -0.70, respectively, a difference of 0.40 points. UniQure said these findings were consistent with a dose-dependent treatment effect.

Updated 36-Month Results Strengthen the Development Dataset

The updated 36-month analysis included three additional high-dose patients compared with the September 2025 analysis. cUHDRS showed 80% slowing of disease progression versus the updated external control (nominal p=0.005), while TFC showed 67% slowing (nominal p=0.011).

Mean cUHDRS change from baseline was -0.28 in treated patients versus -1.39 in the external control. For TFC, the corresponding changes were -0.27 and -0.82.

These 36-month data are particularly relevant to the regulatory program. Following a June 2026 Type B meeting, the FDA communicated that 36-month data from 12 high-dose patients could serve as the primary basis for uniQure’s BLA under the accelerated approval pathway. The BLA had already been submitted before the latest topline results and therefore did not include these updated data.

Gene-Silencing Approach Targets Huntingtin

Ifezuntirgene inilparvovec uses uniQure’s miQURE gene-silencing platform and incorporates a microRNA intended to silence the huntingtin (HTT) gene and the potentially toxic exon 1 protein fragment. The therapy is administered as a single treatment through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum, including the caudate and putamen.

Huntington’s disease is an inherited neurodegenerative disorder caused by a CAG repeat expansion in the HTT gene. Progressive motor, cognitive and behavioral impairment leads to declining physical and functional capacity. There are currently no approved therapies that delay disease onset or slow disease progression.

Safety and Biomarker Findings

Ifezuntirgene inilparvovec remained generally well tolerated at both doses. The most common adverse events were related to the administration procedure and had resolved. Five high-dose participants experienced treatment-related serious adverse events involving central nervous system inflammation, all of which resolved. One suicide occurred in a low-dose participant approximately five years after treatment and was assessed by the investigator as unrelated to treatment.

Mean cerebrospinal fluid neurofilament light protein (CSF NfL), a biomarker associated with neuronal injury, was 6% below baseline at 36 months and 4% above baseline at 48 months in the high-dose group.

Regulatory Path and Future Development

UniQure’s Phase I/II program has treated 51 patients across multiple cohorts evaluating safety, tolerability and efficacy, including randomized, open-label and immunosuppression cohorts. Additional development is evaluating the high dose in patients with lower striatal volumes.

Ifezuntirgene inilparvovec has received Breakthrough Therapy, Regenerative Medicine Advanced Therapy (RMAT), and Fast Track designations from the FDA. The updated 36- and 48-month findings extend the clinical dataset supporting the program, while the longer-term results also underscore the importance of accounting for missing data and attrition when interpreting external-control comparisons in progressive neurodegenerative disease.

Reference

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, 29 September 2026