Accelerated Approval in Huntington’s disease?

• U.S Food and Drug Administration (FDA) agrees that data from ongoing Phase I/II studies compared to a natural history external control may serve as the primary basis for a Biologics License Application (BLA) for Accelerated Approval
• FDA agrees that the composite Unified Huntington’s Disease Rating Scale (cUHDRS) may serve as an intermediate clinical endpoint for Accelerated Approval

10 December 2024: – uniQure N.V., a gene therapy company advancing therapies for patients with severe medical needs, has announced that the company reached agreement with the U.S Food and Drug Administration (FDA) on key elements of an Accelerated Approval pathway for AMT-130.

“We are very pleased to reach agreement with the FDA on core components of an Accelerated Approval pathway for AMT-130,” said M.D., Chief Medical Officer of uniQure. “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 (CBER). This is an important milestone for the Huntington’s 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 CMC requirements.”

As part of uniQure’s Regenerative Medicine Advanced Therapy (RMAT) Type B meeting held in late November, the FDA agreed that data from the ongoing Phase I/II studies, compared to a natural history external control, may serve as the primary basis for a BLA submission under the Accelerated Approval pathway, avoiding the need for an additional pre-submission study. The FDA also agreed that cUHDRS may be used as an intermediate clinical endpoint and that reductions in neurofilament light chain (NfL) measured in cerebrospinal fluid (CSF) may serve as supportive evidence of therapeutic benefit in the application for accelerated approval.

The FDA granted uniQure RMAT designation for AMT-130 in May 2024, stating that preliminary clinical data from the ongoing Phase I/II studies indicate AMT-130 has the potential to address unmet medical needs for the treatment of Huntington’s disease. In July 2024, uniQure presented interim data at 24 months showing durable, dose-dependent slowing of disease progression based on the cUHDRS of treated patients compared to a propensity-weighted natural history. These data also showed reductions in CSF NfL, a measure of neurodegeneration, in treated patients at 24 months compared to baseline.

About the Phase I/II Clinical Programme of AMT-130
uniQure is conducting two multi-centre, dose-escalating, Phase I/II clinical studies to explore the safety, tolerability, and exploratory efficacy signals of AMT-130 for the treatment of Huntington’s disease. In the U.S. study, a total of 26 patients with early manifest Huntington’s disease were randomised to treatment (n=6 low dose; n=10 high dose) or an imitation (sham) surgical procedure (n=10). Treated patients received a single administration of AMT-130 through MRI-guided, convection-enhanced stereotactic neurosurgical delivery directly into the striatum (caudate and putamen). The study consists of a blinded 12-month core study period followed by unblinded long-term follow-up of treated patients for five years. An additional four control patients crossed over to treatment.

The European open-label Phase Ib/II study of AMT-130 enrolled 13 patients with early manifest Huntington’s disease (n=6 low dose; n=7 high dose). A third cohort is enrolling an additional 12 patients across sites in the U.S. and EU. This cohort is randomised to explore both doses of AMT-130 in combination with immunosuppression, using the current, established stereotactic administration procedure. Additional details are available on http://www.clinicaltrials.gov (NCT0543017, NCT04120493).

AMT-130 was granted the FDA’s Regenerative Medicine Advanced Therapy (RMAT) designation, the first for Huntington’s disease.