A-Synuclein Antibody Lu AF82422 Shows Disease-Modifying Potential in Phase 2 AMULET Trial of MSA

Author(s):

Lu AF84222 was considered well tolerated, with greater treatment effects observed in a subgroup of patients with less impaired multiple system atrophy.

Wolfgang Singer, MD

In the phase 2 AMULET trial (NCT05104476), an ongoing study of patients with multiple system atrophy (MSA), Lundbeck’s Lu AF82422 did not achieve its primary end point of statistically slowing disease progression against placebo; however, the signal of efficacy was more pronounced in a less impaired population of patients with MSA. Investigators concluded that the totality of evidence supports further development of Lu AF82422, an anti-alpha-synuclein (α-syn) antibody, in a phase 3 trial of MSA.¹

AMULET, a randomized, double-blind, placebo-controlled study, enrolled 61 patients with MSA, aged between 40 and 75 years, who were randomly assigned 2:1 to either Lu AF82422 (n = 40) 4.2 g every 4 weeks (Q4W) or placebo (n = 21) for a double-blind period that lasted between 48-72 weeks. Each group received standard of care medications (SOC) on top of their designated treatment as well. Coming into the study, participants had less than 5 years from time of 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.

Presented at the 2024 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held September 27-October 1, in Philadelphia, Pennsylvania, the study excluded those who’ve undergone past anti-α-syn treatment and those with 2 ore more relatives with MSA. Led by Wolfgang Singer, MD, an associate professor of neurology at Mayo Clinic Rochester, the primary end point of disease progression, assessed using a Bayesian progression model of the longitudinal changes in total UMSARS (Part I+II) score up to week 72, was slowed by 19% through Lu AF82422. This was not statistically significant in comparison with placebo.

An analysis of modified UMSARS, a secondary end point, revealed a 27% slowing of clinical progression, while the UMSARS Part 1 and Part II showed similarly consistent trends (slowing in clinical progression of 22% and 17%, respectively). In a less impaired population (Lu AF82422: n = 30; placebo: n = 12), resulted showed a 37% slowing of clinical progression with active treatment. Lu AF82422, a human immunoglobulin G1 (IgG1) monoclonal antibody (mAb), was considered safe and well tolerated, with 45 patients opting to continue treatment into the open-label extension phase, which continues on for an additional 48 weeks.

An investigational agent, Lu AF82422 binds to all major forms of extracellular α-syn and thereby prevents update and inhibit seeding of aggregation. The therapy has an active Fc region, which may increase immune-mediated clearance of α-syn/mAb complexes through microglia mediated uptake. Lu AF82422 is currently the most advanced therapy in clinical development for MSA, with a mechanism of action that may address underlying pathophysiology.

Earlier this year, investigators published data from a phase 1 study (NCT03611569) assessing Lu AF82422 in a cohort of healthy participants (18-55 years; cohort A) and patients with Parkinson disease (PD; 40-80 years; Hoehn and Yahr stage ≤3; cohort B). Overall, single intravenous infusion of Lu AF82422 at doses of 75, 225, 750, 2250, 4500, and 9000 mg, respectively, were safe and well tolerated, with no serious adverse events (AEs) observed. Among those treated with the active agent, the most frequent AEs observed were lumbar punctures, headache, and common infections.²

Additional data from the phase 1 study showed that Lu AF82422 concentrations, both in plasma and cerebrospinal fluid, increased in a dose-proportional manner with no observable differences between cohorts. Plasma concentrations of Lu AF82422 had an immediate, concentration-dependent lowering effect on the plasma concentration of free α-syn and on the ratio of free to total α-syn in all cohorts and lowered the free-to-total α-syn ratio in CSF in the high-dose PD cohort.

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REFERENCES
1. Singer W, Zanigni S, Kjaersgaard L, et al. 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. Presented at: 2024 MDS Congress; September 27-October 1; Philadelphia, PA. ABSTRACT 20
2. Buur L, Wiedemann J, Larsen F, et al. Randomized phase 1 trial of the a-synuclein antibody Lu AF82422. Mov Disord. 2024;39(6):936-944. doi:10.1002/mds.29784.