High-Dose Gene Therapy Slows Huntington Disease Progression


Treated patients had a –0.2 mean change in cUHDRS compared with a –1.0 change in external control data.

Victor Sung, MD, professor of neurology at the University of Alabama at Birmingham

Victor Sung, MD

Credit: UAB Medicine

AMT-130 gene therapy (uniQure) slowed disease progression in patients with Huntington disease (HD) treated in the high-dose cohort of a phase 1/2 clinical trial (NCT05243017).1

“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, uniQure, said in a statement.1 “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.”

uniQure announced updated interim data including up to 24 months of follow-up data from 29 treated patients enrolled in the ongoing United States (n = 26) and European (n = 13) Phase 1/2 clinical trials. These participants included 12 in the low dose cohort, 17 in the high dose cohort, and 10 that received imitation surgery in the control arm. Data were from 24 months of follow-up across both studies with a cutoff date of March 31, 2024.1

The 21 treated patients were compared to 154 propensity-weighted external control patients developed in collaboration with the Cure Huntington’s Disease Initiative (CHDI) from the TRACK-HD, TRACK-ON and PREDICT-HD natural history studies. The high-dose cohort had a mean change of –0.2 in composite Unified Huntington’s Disease Rating Scale (cUHDRS) compared with –1.0 in the external control (P = .007), representing an 80% slowing in disease progression. In the low-dose cohort, patients had a –0.7 change, a not statistically significant, 30% change in disease progression (P = .21).1

READ MORE: Wave Life Sciences' Antisense Oligonucleotide WVE-003 Demonstrates Ability to Lower Mutant Huntingtin in Phase 1b/2a Trial

Investigators observed near-baseline stability of motor and cognitive function in the high dose cohort throughout follow-up. Neurofilament light in cerebrospinal fluid (CSF) was also statistically significantly reduced, with an 11% mean reduction from baseline (P =.02) at 24 months. The therapy remains generally well-tolerated, with no new AMT-130-related serious adverse events reported.1

“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), director, UAB Huntington’s Disease Clinic, codirector, UAB School of Medicine Neuroscience Module, and trustee, National Board of the Huntington’s Disease Society of America, added.1 “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.”

In the second half of 2024, uniQure plans to hold a Type B, multi-disciplinary RMAT meeting with the FDA to present these updated data and discuss potential expedited clinical development pathways and accelerated approval, and to complete enrollment of the third cohort of the study exploring AMT-130 in combination with immunosuppression. The company plans to announce more data from the study in 2025. AMT-130 also recently netted Regenerative Medicine Advanced Therapeutic (RMAT) Designation from the FDA in June 2024.2

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. uniQure. July 9, 2024. https://www.globenewswire.com/en/news-release/2024/07/09/2910220/0/en/uniQure-Announces-Positive-Interim-Data-Update-Demonstrating-Slowing-of-Disease-Progression-in-Phase-I-II-Trials-of-AMT-130-for-Huntington-s-Disease.html#
2. uniQure Receives FDA Regenerative Medicine Advanced Therapy (RMAT) Designation for Investigational Gene Therapy AMT-130 in Huntington’s Disease. News release. June 3, 2024. https://www.globenewswire.com/news-release/2024/06/03/2892124/0/en/uniQure-Receives-FDA-Regenerative-Medicine-Advanced-Therapy-RMAT-Designation-for-Investigational-Gene-Therapy-AMT-130-in-Huntington-s-Disease.html
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