Final Results Reported for EPISOD1 Trial of SOD1-ALS Gene Therapy AMT-162

uniQure presented final results from the EPISOD1 trial of AMT-162, an investigational gene therapy for SOD1-associated amyotrophic lateral sclerosis (SOD1-ALS), at the 2026 Northeast ALS Consortium (NEALS) Annual Meeting, held October 27-30, 2026, in Clearwater, Florida. The company halted development of the therapy earlier this year after a dose-limiting safety event in the trial's second dose cohort.¹

Peter M. Andersen, professor and senior consultant neurologist at Umeå University in Sweden, presented the findings. He was joined by coinvestigators James Berry, MD, of Massachusetts General Hospital; Matthew Harms, MD, of Columbia University; and Colin Quinn, MD, of the University of Pennsylvania School of Medicine, along with uniQure staff who contributed to the trial.

AMT-162 is an investigational, one-time gene therapy using an AAVrh10 vector to deliver an engineered microRNA designed to knock down expression of the SOD1 gene, administered by intrathecal injection. SOD1 mutations are thought to cause ALS through a toxic, dose-dependent gain-of-function mechanism, and account for roughly 2% of all ALS cases, or fewer than 500 patients in the US. AMT-162 held FDA Orphan Drug and Fast Track designations.^1,2

EPISOD1 (NCT06100276) was a first-in-human, multicenter, open-label, single ascending-dose Phase 1/2 trial with a planned 5-year safety follow-up. A total of 5 participants were dosed: 3 in the low-dose cohort and 2 in the mid-dose cohort. One Grade 3 serious adverse event of sensory-predominant neuropathy, determined to be a dose-limiting toxicity, occurred in the mid-dose cohort; multiple Grade 2 adverse events of sensory-related symptoms occurred in one low-dose participant.

Cerebrospinal fluid (CSF) neurofilament light chain (NfL) decreased below baseline in 3 of 5 participants after 6 to 12 months, and CSF SOD1 protein decreased below baseline in 4 of 5 participants over the same period. The investigators concluded that AMT-162 showed possible early biomarker changes, including reductions in NfL, but that the serious and other adverse events produced an unfavorable benefit-risk ratio, leading to the decision to stop development. Long-term safety follow-up of the 5 dosed patients is ongoing.

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uniQure dosed the first EPISOD1 patient in October 2024, the company's third gene therapy program to reach the clinic. In a January 2025 update, an independent data monitoring committee reviewed 28-day safety data from the first dose cohort, identified no significant safety concerns, and recommended proceeding to the second dose cohort.^3,4

That recommendation preceded the dose-limiting toxicity later reported in the mid-dose cohort. uniQure disclosed the decision to discontinue AMT-162 as part of its first-quarter 2026 financial results, reporting that the company would continue collecting safety data from the 5 dosed patients consistent with regulatory requirements. The disclosure did not detail the timing of the discontinuation decision relative to when the dose-limiting toxicity occurred.²

Other SOD1-ALS therapies in development

Tofersen (Qalsody), an antisense oligonucleotide that reduces SOD1 protein synthesis by targeting SOD1 messenger RNA, received FDA accelerated approval for SOD1-ALS in 2023 based on reductions in plasma NfL, administered by periodic intrathecal injection rather than as a one-time gene therapy.⁵

Among AAV-based gene therapy approaches targeting SOD1, Avrion Therapeutics, working with researchers at the Swiss Federal Institute of Technology Lausanne (EPFL), is developing AVR-001, an AAV9-based candidate designed to reduce SOD1 production in motor neurons and astrocytes. The program remains in advanced preclinical testing, with a first-in-human trial expected in 2028.⁶

REFERENCES
1. Andersen PM, Berry J, Harms M, et al. EPISOD1: a phase 1/2, multicenter study to evaluate the safety, tolerability, and exploratory efficacy of intrathecally administered gene therapy AMT-162 in patients with SOD1 amyotrophic lateral sclerosis (SOD1-ALS). Presented at: 2026 Northeast ALS Consortium (NEALS) Annual Meeting; October 27-30, 2026; Clearwater, FL.
2. uniQure announces first quarter 2026 financial results and provides recent company updates. News release. uniQure. Published May 5, 2026. Accessed November 3, 2026. https://uniqure.gcs-web.com/news-releases/news-release-details/uniqure-announces-first-quarter-2026-financial-results-and
3. uniQure announces dosing of first patient in Phase I/II clinical trial of AMT-162 for the treatment of SOD1-ALS. News release. uniQure. Published October 15, 2024. Accessed November 3, 2026. https://www.sec.gov/Archives/edgar/data/1590560/000155837024013276/qure-20241015xex99d1.htm
4. 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. Published January 30, 2025. Accessed November 3, 2026. https://www.globenewswire.com/news-release/2025/01/30/3017944/0/en/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.html
5. FDA approves treatment for amyotrophic lateral sclerosis associated with a mutation in the SOD1 gene. FDA. Published April 25, 2023. Accessed November 3, 2026. https://www.fda.gov/drugs/news-events-human-drugs/fda-approves-treatment-amyotrophic-lateral-sclerosis-associated-mutation-sod1-gene
6. Avrion Therapeutics: gene therapy enters amyotrophic lateral sclerosis pipeline. News release. Swiss Biotech Association. Published August 27, 2026. Accessed November 3, 2026. https://www.swissbiotech.org/?p=84450