Objective: Assess the efficacy and safety of monthly IV infusions with the anti-alpha synuclein [a-syn] monoclonal antibody Lu AF82422 for the treatment of patients with MSA.

Background: Lu AF82422 targets all major forms of extracellular a-syn, with high affinity for oligomers, and inhibits seeding and spreading of pathological forms of a-syn in preclinical models. It has shown target engagement in plasma and CSF [1].

Method: AMULET is an ongoing Phase 2, randomized, controlled trial with open-label extension (OLE) (NCT05104476) conducted at 21 sites in the USA and Japan. Participants with a diagnosis of possible or probable MSA, with <5 years from onset of motor symptoms, and UMSARS Part I score ≤16 (omitting item 11) were randomized (2:1) to 48-72 months of double-blind treatment with Lu AF82422 or placebo. The primary endpoint was disease progression, assessed using a Bayesian progression model of the longitudinal changes from baseline in the Total-UMSARS (Part I+II) score up to Week 72. Additionally, a post-hoc analysis was performed for patients with less impaired disease using the same methodology.

Results: 61 participants were treated with Lu AF82422 (n=40) or placebo (n=21) and 49 completed the double-blind phase. The primary endpoint showed a 19% slowing of clinical progression in the active arm vs placebo but the treatment difference was non-significant. Analysis of modified UMSARS (key secondary) showed a 27% slowing of clinical progression, and the UMSARS Part I and Part II showed similarly consistent trends (slowing in clinical progression of 22%, and 17%, respectively). Subgroup analysis in a less impaired population (Lu AF82422 n=30; placebo n=12) revealed an overall 37% slowing of clinical progression. Lu AF82422 was generally well tolerated, and 45 patients have opted to continue treatment into the open-label extension phase.

Conclusion: Although the trial did not meet its primary endpoint in the overall population, a potential for Lu AF82422 to slow MSA clinical progression was shown. The signal of efficacy was more pronounced in a less impaired population when a treatment with an a-syn antibody would be expected to be most beneficial. These data support the further investigation of Lu AF82422 in a phase 3 trial designed to confirm its potential effects on clinical progression in MSA.

References: 1. Buur et al. Randomized phase I trial of the α-synuclein antibody Lu AF82422. Mov Disord 2024; in press.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/safety-and-efficacy-of-the-anti-alpha-synuclein-monoclonal-antibody-lu-af82422-for-the-treatment-of-patients-with-msa-results-from-the-phase-2-amulet-trial/