uniQure and FDA Reach Accord on Approval Pathway for Huntington Disease Gene Therapy AMT-130

During a Type B meeting, the FDA and uniQure came into agreement regarding the use of an accelerated approval pathway for AMT-130, the company's adeno-associated virus (AAV) vector-based gene therapy currently being evaluated for the treatment of Huntington disease in 2 phase 1/2 clinical trials (NCT04120493 and NCT05243017).¹

Notably, the agency agreed that data from the ongoing phase 1/2 studies compared to external control natural history data will be sufficient to support a biologics license application (BLA), negating the need to launch another trial before submission. Furthermore, it was determined that for an accelerated approval the composite Unified Huntington’s Disease Rating Scale (cUHDRS) may constitute an intermediate clinical end point and that supportive evidence of clinical benefit can come in the form of data showing cerebrospinal fluid (CSF) neurofilament light chain (NfL) decreases.

“We are very pleased to reach agreement with the FDA on core components of an accelerated approval pathway for AMT-130,” Walid Abi-Saab, MD, the chief medical officer of uniQure, said in a statement.¹ “Our alignment reflects the strength of our data and collaborative discussions with the staff and senior management at FDA’s Center for Biologics Evaluation and Research. This is an important milestone for the Huntington disease community as it puts us on the most rapid and efficient pathway to deliver a potentially life-changing therapy to people living with this devastating neurodegenerative disorder. We have initiated BLA readiness activities and look forward to further engaging with the FDA in the first half of 2025 to discuss our statistical analysis plan and the technical chemistry, manufacturing, and controls requirements.”

In July of this year, uniQure reported updated interim data including up to 24 months of follow-up from 29 patients enrolled in the ongoing United States (n = 26) phase 1/2 trial (NCT04120493) and European (n = 13) phase 1/2 trial (NCT05243017).² The US trial treated 6 patients with a low dose of AMT-130, 10 patients with a high dose, and 10 patient with a sham control surgery. As of December 2024, 4 patients who initially received the sham control later crossed over to receive the gene therapy.² In the European study, which does not include a placebo group, 6 patients received a low dose of AMT-130 and 7 patients received a high dose.

In the July data update, uniQure compared data from patients who had received AMT-130 at that time 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). A statistically significant 11% mean decrease in CSF NfL from baseline was also observed at 24 months posttreatment (P =.02).

“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, said in a July 2024 statement.² “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.”

REFERENCES
1. uniQure Announces Alignment with FDA on Key Elements of Accelerated Approval Pathway for AMT-130 in Huntington’s Disease. News release. uniQure N.V. December 10, 2024. Accessed December 18, 2024. https://www.uniqure.com/investors-media/press-releases
2. 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. Accessed December 18, 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#