FDA Reaches Alignment on Key Elements of Accelerated Approval Pathway for AMT-130 in Huntington Disease

Following uniQure’s recent regenerative medicine advanced therapy (RMAT) Type B meeting with the FDA, the agency has reached agreement with the company on key elements of an accelerated approval pathway for its investigational gene therapy AMT-130 for patients living with Huntington disease (HD).¹

The FDA concurred that data from the ongoing phase 1/2 clinical trials (NCT0543017; NCT04120493) of AMT-130, utilizing a natural history external control as a comparator, could serve as the primary basis for a biologics license application submission under the accelerated approval pathway. Thereby, eliminating the requirement for an additional presubmission study. Furthermore, the agency agreed that the Composite Unified Huntington’s Disease Rating Scale (cUHDRS) could be utilized as an intermediate clinical end point, with reductions in neurofilament light chain (NfL) levels in cerebrospinal fluid (CSF) to provide supportive evidence of therapeutic efficacy for the accelerated approval submission.

“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, 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 (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.”

READ MORE: Huntington Agent SAGE-718 to be Discontinued Following Disappointing Phase 2 DIMENSION Trial Results

Earlier this year, the FDA granted RMAT designation for 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

About a month later, uniQure reported an interim update on the ongoing phase 1/2 trials assessing AMT-130 which showed that treatment with high doses of the agent resulted in significant slowing of disease progression and lowering of NfL in patients with HD. 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 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).⁴

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.

REFERENCES
1. uniQure Announces Alignment with FDA on Key Elements of Accelerated Approval Pathway for AMT-130 in Huntington’s Disease. News Release. Published December 10, 2024. Accessed December 11, 2024. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-alignment-fda-key-elements-accelerated
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 December 11, 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
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 December 11, 2024. https://www.globenewswire.com/news-release/2023/12/19/2798425/0/en/uniQure-Announces-Update-on-Phase-I-II-Clinical-Trials-of-AMT-130-Gene-Therapy-for-the-Treatment-of-Huntington-s-Disease.html
4. 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 December 11, 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