Amlenetug in MSA: AMULET Phase 2 Trial Readout

Key Takeaways

• The primary endpoint was not met, although the numerical progression signal favored amlenetug over placebo.
• Progression was modeled from longitudinal UMSARS total scores in a randomized phase 2 placebo comparison.
• Amlenetug was generally well tolerated, adverse event burden was broadly similar between groups, and the authors concluded the findings supported phase 3 evaluation.

In the AMULET phase 2 trial, amlenetug did not meet the prespecified primary endpoint versus placebo in adults with multiple system atrophy. The Bayesian probability of slowing clinical progression was 89.4%, below the predefined 97.5% threshold for success. Although the numerical trend favored active treatment, the formal efficacy analysis remained negative. The result therefore left a directional signal rather than a definitive efficacy finding.

AMULET was a randomized, controlled, parallel-group phase 2 trial conducted at 18 specialist sites for movement disorders and autonomic dysfunction in the USA and Japan. Eligible participants were adults aged 40-75 years with multiple system atrophy and motor symptom onset within the past 5 years. Participants were randomly assigned 2:1 to intravenous amlenetug or placebo every 4 weeks for 48-72 weeks in a common-close design. Investigators screened 91 unique participants, randomly assigned 64, and treated 61, including 40 in the amlenetug group and 21 in the placebo group. Among treated participants, the mean age was 60.8 years, 52% were male, 48 completed double-blind treatment after a mean of 56 weeks, and progression was assessed with a Bayesian model of longitudinal UMSARS total score change through week 72.

In the efficacy analysis, the effect parameter was 0.81, with a 2.5th to 97.5th percentile range of 0.56 to 1.13. This corresponded to a non-significant 19% slowing of clinical progression with amlenetug versus placebo, with a reported percentile range from -13 to 44. The direction of effect favored amlenetug, but the estimate remained compatible with no clear clinical benefit. Because those percentiles spanned both modest worsening and moderate slowing, the result remained statistically non-significant. The prespecified criterion for trial success was therefore not achieved in this phase 2 comparison.

Safety findings were described as generally well tolerated, and treatment-emergent adverse events occurred in 40 of 40 amlenetug-treated participants and 20 of 21 placebo recipients. Serious treatment-emergent adverse events occurred in 12 of 40 participants given amlenetug and seven of 21 given placebo, which investigators characterized as broadly comparable. Two deaths occurred in each group, and only one death, in the placebo group, was considered possibly treatment related. Common events included COVID-19 infection, back pain, headache, urinary tract infection, peripheral oedema, flushing, and hypertension.

The authors concluded that the combined efficacy signal and safety profile supported further evaluation in a phase 3 trial.