uniQure Makes Progress in Trial for SOD1-ALS Gene Therapy AMT-162

An independent data monitoring committee (IDMC) has given uniQure the green light to begin enrolling patients in the second dose cohort of the phase 1/2 EPISOD1 clinical trial (NCT06100276), which is evaluating AMT-162, an investigational adeno-associated virus (AAV) vector-based gene therapy, for the treatment of amyotrophic lateral sclerosis caused by mutations in superoxide dismutase 1 (SOD1-ALS).¹

The recommendation to proceed with enrollment of the next dose cohort followed a review of 28 days-posttreatment data from patients who received AMT-162 in the first cohort, in which no significant safety concerns were observed.In light of the recommendation, uniQure stated that it anticipates enrollment activities for the second dose cohort will begin before the end of the first quarter of this year.

“We are pleased with the positive outcome of this initial IDMC meeting, which marks a meaningful step in the clinical development of AMT-162 for SOD1-ALS,” Walid Abi-Saab, MD, the chief medical officer of uniQure, said in a statement.¹ “We will continue to advance the study and look forward to proceeding with dose-escalation in the second cohort of patients.”

The first patient in the first cohort of the multicenter, open-label EPISOD1 study, which is taking place in the United States, was dosed in October 2024.² The study is expected to evaluate 3 dose levels in total, before proceeding to a dose expansion portion. The dose expansion portion will evaluate a dose selected from the previously used dose levels in approximately 6 to 8 patients. According to the clinicaltrials.gov page, EPISOD1 includes study centers in California, Florida, Georgia, Illinois, Kansas, Massachusetts, Minnesota, New York, and Pennsylvania.

AMT-162 contains a transgene coding for a microRNA (miRNA) that is intended to silence the expression of the disease-targeted gene, which codes for a misfolded SOD1 protein with neurotoxic properties. The gene therapy is administered intrathecally in a one-time dose, and the transgene is delivered via an AAVrh10 vector.

uniQure is has several other AAV vector-based gene therapy products for neurological indications in development besides AMT-162.³ Among these is AMT-130, which is currently being evaluated for the treatment of Huntington disease in 2 phase 1/2 clinical trials (NCT04120493 and NCT05243017). In December 2024, the FDA and uniQure came into agreement regarding the use of an accelerated approval pathway for AMT-130 in a Type B meeting. 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 may constitute an intermediate clinical end point and that supportive evidence of clinical benefit can come in the form of data showing cerebrospinal fluid neurofilament light chain decreases.

“We are very pleased to reach agreement with the FDA on core components of an accelerated approval pathway for AMT-130,” Abi-Saab said in a December 2024 statement.³ “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.”

REFERENCES
1. uniQure announces favorable recommendation from independent data monitoring committee for its phase I/II EPISOD1 clinical trial of AMT-162 for the treatment of SOD1-ALS. News release. uniQure N.V. January 30, 2025. Accessed January 31, 2025. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-favorable-recommendation-independent-data
2. uniQure announces dosing of first patient in phase I/II clinical trial of AMT-162 for the treatment of SOD1-ALS. News release. October 15, 2024. Accessed January 31, 2025. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-dosing-first-patient-phase-iii-clinical-trial
3. 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 January 31, 2025. https://www.uniqure.com/investors-media/press-releases