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Phase 1/2 EPISOD1 Trial of SOD1 Agent AMT-162 to Proceed Following Favorable Recommendation
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Key Takeaways
- AMT-162 gene therapy targets SOD1-ALS, aiming to reduce mutated SOD1 protein levels and slow disease progression.
- The EPISOD1 trial's positive review allows progression to the second cohort, focusing on safety and exploratory efficacy.
The initial cohort of the EPISOD1 trial demonstrated no significant safety concerns for AMT-162, enabling progression to the next dose-escalation phase.
Walid Abi-Saab, MD
According to a new announcement, an independent data monitoring committee (IDMC) has given a positive review for uniQure’s EPISOD1 trial, a phase 1/2 study (NCT) testing the company’s investigational therapy AMT-162 as a potential treatment for amyotrophic lateral sclerosis (ALS) caused by mutations in the superoxide dismutase 1 (SOD1) gene. All told, the 28-day safety data from the study’s first cohort showed no significant safety concerns and may proceed with enrollment in the second cohort.1
AMT-162 is a one-time investigational gene therapy targeting SOD1-ALS. Using AAVrh10, it delivers a miRNA to reduce mutated SOD1 protein levels. Misfolded SOD1 protein contributes to motor neuron damage in SOD1-ALS, leading to muscle weakness, loss of function, and eventual death. Administered intrathecally, AMT-162 aims to slow or stop disease progression.
The phase 1/2 study is a multi-center, single-ascending dose trial featuring patients with confirmed clinical and genetic diagnosis of SOD1-ALS, exhibiting signs of lower motor neuron dysfunction, such as weakness, atrophy, cramps, or fasciculations, with or without upper motor neuron symptoms like spasticity or brisk reflexes. At screening, participants must demonstrate an ALS Functional Rating Scale-Revised (ALSFR) score of 25 or higher and a slow vital capacity (SVC) of at least 50% of the predicted normal value. Additionally, candidates must be able to provide informed consent, be medically fit for lumbar puncture, and have a caregiver available to assist with all clinic visits and trial procedures.
"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, chief medical officer at 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."
EPISOD1, an open-label trial, consists of up to 4 cohorts with up to 4 patients receiving a short course of immunosuppression prior to and after an intrathecal infusion of AMT-162. The trial will explore the safety and tolerability of AMT-162 and will assess exploratory signs of efficacy by measuring neurofilament light chain, a biomarker of neuronal damage, and SOD1 protein. The first participants were dosed in October 2024, with 4 active sites at the time.
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For the study, individuals are excluded if they carry specific SOD1 pathogenic variants (amino acid regions 43-47) or pathogenic C9orf72 repeat expansions. Prior treatments involving SOD1 suppression using viral microRNA or antisense oligonucleotide mediators like tofersen (unless received over 20 weeks before screening without severe or ongoing adverse effects) are not permitted. However, other ALS medications such as riluzole, edaravone, and AMX0035 (Relyvrio; Amylyx) are acceptable if doses are stable for at least 30 days prior to immunosuppression.
Participants with prior exposure to AAV gene therapy or those unwilling to refrain from new ALS treatments for six months post-infusion are also excluded. After this six-month period, treatment adjustments may be made at the discretion of investigators and participants.
In recent news, the FDA reached an agreement with uniQure on key elements of an accelerated approval pathway for its investigational gene therapy AMT-130 for patients living with Huntington disease (HD). In the decision, the FDA concurred that data from the ongoing phase 1/2 studies (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.2
At the time, the agency also 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. In early 2024, 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).3
