Amlenetug (Lu AF82422): An Investigational Monoclonal Antibody for Multiple System Atrophy

1. Executive Summary

Amlenetug, also identified by its investigational name Lu AF82422, is a human monoclonal antibody currently under development for the treatment of Multiple System Atrophy (MSA), a rare, progressive, and ultimately fatal neurodegenerative disorder for which no disease-modifying therapies are currently approved.[1] Developed by H. Lundbeck A/S in collaboration with Genmab A/S, Amlenetug targets extracellular α-synuclein, a protein centrally implicated in the pathology of MSA and other synucleinopathies.[1] The therapeutic rationale is to inhibit the uptake and aggregation of pathological α-synuclein, thereby slowing disease progression.

The Phase 2 AMULET trial (NCT05104476), while not meeting its primary efficacy endpoint in the overall MSA patient population, demonstrated a 19% slowing of clinical progression on the Unified MSA Rating Scale (UMSARS) in the active treatment arm compared to placebo, and a more pronounced, albeit non-significant, 37% slowing of clinical progression in a pre-specified subgroup of less-impaired patients.[12] Encouraged by these signals and a generally well-tolerated safety profile, Lundbeck has advanced Amlenetug into a global Phase 3 clinical trial, MASCOT (NCT06706622).[1] The development program has received significant regulatory support, including Orphan Drug Designation in the US, EU, and Japan, and Fast Track Designation from the US FDA, underscoring the high unmet medical need in MSA.[6]