Gene Therapy AMT-130 Slows Huntington Disease Progression in Interim Phase 1/2 Trials


The data, which comes less than a month after the FDA granted RMAT designation, highlighted the impacts of AMT-130 on disease progression in Huntington disease.

Victor Sung, MD, professor of neurology at the University of Alabama at Birmingham (UAB), and director of the UAB Huntington’s Disease Clinic

Victor Sung, MD

A new interim update to the ongoing phase 1/2 trials (NCT0543017; NCT04120493) assessing uniQure’s investigational gene therapy AMT-130 showed that treatment with high doses of the agent resulted in significant slowing of disease progression and lowering of neurofilament light (NfL) in patients with Huntington disease (HD). In the second half of 2024, the company expects to hold a Type B, multi-disciplinary meeting with the FDA to present these updated data and discuss potential expedited clinical development pathways and accelerated approval.1

The interim data update included 21 patients (low-dose: n = 12; high-dose: n = 9) who had 24-month follow-up data as of the March 31, 2024, cut-off date. After 24 months of treatment, those on high-dose AMT-130 demonstrated mean changes of –0.2 on composite Unified Huntington’s Disease Rating Scale (cUHDRS) compared with changes of –1.0 for an expanded, propensity-weighted external control group (n = 154). All told, this represented an 80% slowing of disease progression (P = .007).

For context, the expanded, propensity-weighted external control group was developed in collaboration with the Cure Huntington’s Disease Initiative (CHDI) using data from the TRACK-HD, TRACK-ON, and PREDICT-HD natural history studies. This cohort included patients that met the phase 1/2 clinical trial eligibility criteria, and whose data contributions were statistically weighted using propensity scoring to closely match the baseline characteristics of patients treated with AMT-130.

At 24 months, the mean change in cUDHRS for patients receiving low-dose AMT-130 was –0.7 compared with –1.0 for those in the propensity score-weighted external control, representing a 30% slowing of disease progression (P = .21). In both the high- and low-dose groups, the gene therapy appeared to be generally well-tolerated, with a safety profile that was “manageable” according to the company. Notably, no new serious adverse events related to the study treatment were reported.

"These updated results are exciting and provide compelling evidence of potential therapeutic benefit," Victor Sung, MD, professor of neurology at the University of Alabama at Birmingham (UAB), and director of the UAB Huntington’s Disease Clinic, said in a statement. "The preservation of motor and cognitive function observed through two years, combined with reduced NfL levels below baseline, defy expectations about the natural progression of Huntington’s disease. cUHDRS, in particular, has been shown to be a robust and sensitive measure of disease progression, and offers an opportunity for enhanced clinical trial efficiency relative to individual measurements. These long-term data provide encouraging support of durable disease-modification and offer much needed hope for a community that is in desperate need of therapeutic options."

The multi-center phase 1/2 trials spanned across the U.S. (n = 26) and Europe/UK (n = 13), where patients received either high- (n = 17) or low-dose (n = 12) AMT-130 or imitation surgery (n = 10). Together with the U.S. study, the European study is intended to establish safety, proof of concept, and the optimal dose of AMT-130 to take forward into phase 3 development or into a confirmatory study should an accelerated registration pathway be feasible.

In the latest interim update, both dosed groups on AMT-130 showed mean cerebrospinal fluid NfL levels that were below baseline after 24 months. Overall, treated patients showed a mean NfL reduction of 11% compared with baseline (P = .002). For context, an independent natural history study demonstrated a 26% increase in CSF NfL at 24 months for patients with early manifest HD.

Walid Abi-Saab, MD, chief medical officer at uniQure

Walid Abi-Saab, MD

Less than a month ago, the FDA granted regenerative medicine advanced therapy (RMAT) designation to AMT-130 based on interim data from the European-based phase 1/2 trial and a comparison analysis of the data to a nonconcurrent criteria-matched natural history cohort. In the previously announced interim update, the therapy demonstrated a 0.95-points difference on Total Functional Capacity (TFC) at 30 months in the low-dose group and 0.49-points difference at 18 months in the high-dose (baseline values; low-dose, 11.9; high dose, 12.2). Additionally, patients on active therapy showed a 2.80-point difference in Total Motor Score (TMS) at 30 months in the low-dose and 1.70-point difference in the high-dose at 18 months (baseline values; low-dose, 13.3; high-dose, 12.1).2,3

"We are very pleased with these new data demonstrating a statistically significant, dose-dependent slowing of the progression of Huntington’s disease and lowering of NfL in the CSF at 24 months," Walid Abi-Saab, MD, chief medical officer at uniQure, said in a statement. "We believe this is the first clinical trial of any investigational medicine for Huntington’s disease to show evidence of a potential long-term clinical benefit and reduction of a key marker of neurodegeneration. Moreover, given the one-time administration of AMT-130, we are in a unique position to continue accumulating longer-term patient outcomes from the Phase I/II studies to support the emerging therapeutic benefit. We look forward to holding an initial, multi-disciplinary RMAT meeting with the FDA later this year to discuss the potential for expedited clinical development of AMT-130."1

1. uniQure Announces Positive Interim Data Update Demonstrating Slowing of Disease Progression in Phase I/II Trials of AMT-130 for Huntington’s Disease. News release. July 9, 2024. Accessed July 9, 2024.
2. uniQure Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for Investigational Gene Therapy AMT-130 in Huntington’s Disease. News Release. Published June 3, 2023. Accessed July 9, 2024.
3. uniQure Announces Update on Phase I/II Clinical Trials of AMT-130 Gene Therapy for the Treatment of Huntington’s Disease. News Release. Published December 19, 2023. Accessed July 9, 2024.
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