Lundbeck's Lu AF82422, an anti-alpha-synuclein (α-syn) antibody, has demonstrated potential in slowing disease progression in patients with multiple system atrophy (MSA), according to results from the Phase 2 AMULET trial (NCT05104476). While the trial did not meet its primary endpoint of statistically significant slowing of disease progression compared to placebo, a notable efficacy signal was observed in a less impaired subgroup of patients with MSA, suggesting a potential disease-modifying effect. The findings, presented at the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS), support further development of Lu AF82422 in a Phase 3 trial.
The AMULET trial was a randomized, double-blind, placebo-controlled study that enrolled 61 patients with MSA, aged 40-75 years. Participants were randomized in a 2:1 ratio to receive either Lu AF82422 (n = 40) at a dose of 4.2 g every 4 weeks (Q4W) or placebo (n = 21) for a double-blind period of 48-72 weeks. All patients received standard of care medications in addition to their assigned treatment. Inclusion criteria included less than 5 years from the onset of motor symptoms, an anticipated survival of more than 3 years, and a Unified MSA Rating Scale – Part I (UMSARS) score of less than 17.
The primary endpoint, assessed using a Bayesian progression model of longitudinal changes in the total UMSARS (Part I+II) score up to week 72, showed a 19% slowing of disease progression with Lu AF82422, which was not statistically significant compared to placebo. However, analysis of a modified UMSARS, a secondary endpoint, revealed a 27% slowing of clinical progression. UMSARS Part 1 and Part II showed consistent trends, with slowing of clinical progression of 22% and 17%, respectively. In a less impaired population (Lu AF82422: n = 30; placebo: n = 12), results showed a 37% slowing of clinical progression with active treatment.
Mechanism of Action
Lu AF82422 is a human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) designed to bind to all major forms of extracellular α-syn, preventing uptake and inhibiting seeding of aggregation. The therapy has an active Fc region, which may enhance immune-mediated clearance of α-syn/mAb complexes through microglia-mediated uptake. According to Wolfgang Singer, MD, an associate professor of neurology at Mayo Clinic Rochester, Lu AF82422 is currently the most advanced therapy in clinical development for MSA with a mechanism of action that may address the underlying pathophysiology.
Safety and Tolerability
Lu AF82422 was considered safe and well-tolerated in the AMULET trial, with 45 patients opting to continue treatment into the open-label extension phase for an additional 48 weeks.
Previous Clinical Data
Earlier phase 1 study (NCT03611569) data, published earlier this year, assessed Lu AF82422 in healthy participants and patients with Parkinson's disease (PD). Single intravenous infusions of Lu AF82422 at doses ranging from 75 to 9000 mg were safe and well-tolerated, with no serious adverse events (AEs) observed. The most frequent AEs were lumbar punctures, headache, and common infections. The phase 1 study also demonstrated that Lu AF82422 concentrations in plasma and cerebrospinal fluid increased in a dose-proportional manner, with a concentration-dependent lowering effect on the plasma concentration of free α-syn and the ratio of free to total α-syn.
