Amlenetug Shows Potential in Slowing MSA Progression Despite Phase 2 Trial Missing Primary Endpoint

Background

Multiple system atrophy (MSA) is a rare, progressive neurodegenerative disorder characterized by the pathological aggregation of α-synuclein, leading to severe motor and autonomic dysfunction. Currently, there are no disease-modifying therapies, creating a significant unmet medical need. The AMULET trial investigated amlenetug, a monoclonal antibody targeting aggregated α-synuclein, as a potential treatment to slow disease progression.

Study Design

This phase 2, randomized, double-blind, multicentre trial enrolled 64 participants with MSA across 18 specialist sites in the USA and Japan. Participants were randomized in a 2:1 ratio to receive intravenous amlenetug or placebo every 4 weeks for 48-72 weeks in a common close design. The primary endpoint was disease progression, assessed using a Bayesian model of longitudinal changes in the Unified MSA Rating Scale (UMSARS) total score up to week 72.

Key Findings

The trial did not meet its primary endpoint, with a Bayesian probability of 89.4% for disease progression slowing, falling short of the predefined 97.5% threshold. The effect parameter of 0.81 (2.5th to 97.5th percentile: 0.56 to 1.13) suggested a non-significant 19% slowing of progression (range: -13% to 44%). Amlenetug was well-tolerated, with comparable rates of adverse events between groups (100% vs 95% for placebo). Common adverse events included COVID-19 infection (28% vs 24%), back pain (15% vs 10%), and headache (13% vs 5%). Two deaths occurred in each group, with only one placebo-group death considered possibly treatment-related.

Expert Commentary

While the primary endpoint was not met, the trial’s findings suggest a potential slowing of MSA progression, supporting further investigation in phase 3. Given the lack of effective treatments for MSA, even modest disease modification could represent a significant clinical advance. The acceptable safety profile of amlenetug further underscores its potential as a disease-modifying therapy.

Conclusion

The AMULET trial provides preliminary evidence supporting the continued evaluation of amlenetug in MSA. Despite not achieving its primary endpoint, the antibody’s potential to slow disease progression, combined with its safety profile, warrants further phase 3 investigation to confirm its clinical utility.

Funding and Clinicaltrials.gov

The trial was funded by H Lundbeck and registered at ClinicalTrials.gov (NCT05104476). The open-label phase is ongoing.