Amlenetug Shows Slowing of Multiple System Atrophy Progression Despite Missing Phase 2 Trial Primary End Point

Data newly published in The Lancet Neurology from the phase 2 AMULET trial (NCT05104476) showed that amlenetug (Lundbeck), an investigational monoclonal antibody targeting aggregated α-synuclein, did not meet its primary end point in slowing disease progression among patients with multiple system atrophy (MSA). However, a numerical but non-significant slowing of clinical progression was observed compared with placebo, and the overall safety profile supported further evaluation in a phase 3 trial.¹

Conducted by senior author Johan Luthman, PhD, executive vice president and head of Research & Development at Lundbeck, and colleagues, treatment with amlenetug led to a Bayesian probability of 89.4% for a true slowing of clinical disease progression, which did not meet the predefined threshold of 97.5%. Despite this, the estimated treatment effect parameter was 0.81 (2.5th to 97.5th percentile, 0.56–1.13), corresponding to a nonstatistically significant 19% slowing of clinical progression (2.5th to 97.5th percentile, −13% to 44%) for amlenetug versus placebo in patients with MSA.

Between November 16, 2021, and October 6, 2022, 91 participants were screened, of whom 64 were randomly assigned and 61 received treatment (amlenetug, n = 40; placebo, n = 21). Among treated participants, the mean age was 60.8 years (SD, 7.7), 32 (52%) were men and 29 (48%) were women. Overall, 48 of 61 participants (79%) completed the double-blind treatment period, with a mean treatment duration of 56 weeks (SD, 13).

For context, AMULET was a randomized, controlled, parallel-group study assessing the safety and ability of amlenetug to slow clinical disease progression in patients with MSA vs placebo. Authors noted that the study was conducted at 18 movement disorder and autonomic dysfunction specialty sites in the United States and Japan. Eligible participants were aged 40 to 75 years and had motor symptom onset in the previous 5 years. In the trial, patients were randomly assigned in a 2:1 ratio to receive intravenous amlenetug or placebo every 4 weeks for 48 to 72 weeks in a common close design.

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All told, the double-blind treatment period concluded after the last randomized participant completed the week 48 visit. The primary end point, disease progression, was assessed through a Bayesian progression model that evaluated longitudinal change from baseline using the Unified Multiple System Atrophy Rating Scale (UMSARS) total score (Parts I and II) through week 72. The data from the safety analyses included all treated participants. Researchers noted that the open-label extension phase of the trial is ongoing.

In terms of safety, amlenetug was generally well tolerated, with similar rates of treatment-emergent adverse events (AEs) reported between groups (100% with amlenetug vs 95% with placebo) and comparable rates of serious treatment-emergent adverse events (30% vs 33%, respectively). The most frequently reported AEs in the amlenetug and placebo groups, respectively, included COVID-19 infection (28% vs 24%), back pain (15% vs 10%), headache (13% vs 5%), urinary tract infection (10% vs 14%), peripheral edema (10% vs 5%), flushing (10% vs 0%), and hypertension (10% vs 0%). Authors reported that 2 deaths occurred in each group; however, only 1 death, occurring in the placebo group, was considered possibly treatment related.

In February 2025, the FDA granted fast track designation to amlenetug, formerly known as Lu AF82422, as a potential treatment for patients with MSA.² The agent is currently being assessed in a phase 3 trial dubbed MASCOT (NCT06706622), which comprises 2 parts: a double-blind period where participants are randomized to either high or low doses of amlenetug, or placebo, for 72 weeks, followed by an open-label extension where all participants are offered the investigational treatment. The study aims to evaluate the efficacy, safety, and tolerability of amlenetug, administered as an intravenous infusion every 4 weeks, in patients with MSA.

REFERENCES
1. Kjærsgaard L, Wiedemann J, Singer W, et al. Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial. Lancet Neurol. 2026;25(6):560-570. doi:10.1016/S1474-4422(26)00100-6
2. Lundbeck's potential treatment amlenetug for Multiple System Atrophy receives Fast Track Designation from the FDA. News release. Lundbeck. February 12, 2025. Accessed May 21, 2026.. https://www.prnewswire.com/news-releases/lundbecks-potential-treatment-amlenetug-for-multiple-system-atrophy-receives-fast-track-designation-from-the-fda-302374577.html