FDA Grants Fast Track Designation to Promising Multiple System Atrophy Agent Amlenetug

Johan Luthman

According to a new announcement, the FDA has given fast track designation to Lundbeck’s investigational agent, amlenetug, as a potential treatment for multiple system atrophy (MSA), a disabling movement disorder with no therapies currently approved. Formerly known as Lu AF82422, the anti-alpha-synuclein (α-syn) antibody is currently being evaluated in a phase 3 trial dubbed MASCOT (NCT06706622).¹

Prior to MASCOT, the therapy first showed its promise in the phase 2 AMULET trial (NCT05104476), a randomized, double-blind, placebo-controlled study of 61 patients with MSA. While it did not meet its primary end point of statistically slowing disease progression against placebo, the signal of efficacy was more pronounced in a less impaired population of those with the disease, further supporting the therapy’s development in larger populations.

"We are pleased that amlenetug has received Fast Track Designation for the potential treatment of Multiple System Atrophy," Johan Luthman, executive vice president and head of Research & Development at Lundbeck, said in a statement.¹ "This is a step forward in our commitment to address significant unmet needs in this devastating disease."

In AMULET, patients with MSA aged between 40 and 75 years were randomly assigned 2:1 to either amlenetug (n = 40) 4.2 g every 4 weeks (Q4W) or placebo (n = 21) for a double-blind period that lasted between 48-72 weeks. All told, the primary end point of disease progression, assessed using a Bayesian progression model of the longitudinal changes in total Unified MSA Rating Scale (UMSARS; Part I + II) score up to week 72, was slowed by 19% through amlenetug. In the less impaired population (amlenetug: n = 30; placebo: n = 12), treatment with the agent resulted in a 37% slowing of clinical progression.²

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). Above all, the monoclonal antibody was considered safe and well tolerated, with 45 patients opting to continue treatment into the extension phase, which continued on for an additional 48 weeks.

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MASCOT, which was initiated in November 2024, comprises 2 parts: a double-blind period where participants are randomized to either high or low doses of amlenetug, or placebo, for 72 weeks, followed by an open-label extension where all participants are offered the investigational treatment. The trial aims to evaluate the efficacy, safety, and tolerability of amlenetug, administered as an intravenous infusion every 4 weeks, in patients with MSA.³

MASCOT targets patients with clinically established or probably MSA of the parkinsonian (MSA-P) or cerebellar (MSA-C) subtype, diagnosed per the 2022 Movement Disorders Society (MDS) criteria. Eligible participants must have motor symptom onset within the past five years, an anticipated survival of over three years, suitable venous access for investigational drug administration, and a UMSARS Part I score ≤16 (excluding sexual function). Exclusion criteria include prior exposure to amlenetug, recent use of investigational drugs, a family history of MSA in two or more first-degree relatives, unexplained anosmia in MSA-P, or other conditions impairing CNS function. Those with mimicking movement disorders, such as Parkinson disease or progressive supranuclear palsy, are also excluded, except in cases of prior misdiagnosis.

In early 2024, investigators published findings from a phase 1 study (NCT03611569) evaluating amlenetug in two cohorts: healthy participants aged 18-55 (cohort A) and patients with Parkinson's disease (PD) aged 40-80 with Hoehn and Yahr stage ≤3 (cohort B). Single intravenous infusions of amlenetug at doses ranging from 75 to 9000 mg were generally safe and well tolerated, with no serious adverse events reported. The most common adverse events among those receiving the active treatment included lumbar puncture-related effects, headache, and common infections.⁴

Additional results demonstrated dose-proportional increases in amlenetug concentrations in plasma and cerebrospinal fluid (CSF), with no differences between cohorts. In plasma, amlenetug caused an immediate, concentration-dependent reduction in free α-syn levels and the free-to-total α-syn ratio across all cohorts. In the high-dose PD group, similar reductions in the free-to-total α-syn ratio were also observed in CSF.

REFERENCES
1. Lundbeck's potential treatment amlenetug for Multiple System Atrophy receives Fast Track Designation from the FDA. News release. Lundbeck. February 12, 2025. Accessed February 12, 2025. https://www.prnewswire.com/news-releases/lundbecks-potential-treatment-amlenetug-for-multiple-system-atrophy-receives-fast-track-designation-from-the-fda-302374577.html
2. 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
3. A Trial of Lu AF82422 in Participants With Multiple System Atrophy (MSA) (MASCOT). Clinicaltrials.gov. Updated January 9, 2025. Accessed February 12, 2025. https://clinicaltrials.gov/study/NCT06706622
4. 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.