The main goal of this trial is to evaluate the efficacy and safety of amlenetug for the treatment of participants with Multiple System Atrophy (MSA).

This study will consist of a screening period of 10 days up to 6 weeks, a 72-week placebo-controlled period (PCP), and will include a 72-week optional open-label treatment extension (OLE) period. Participants in the PCP will be randomized to amlenetug or placebo. All participants entering the OLE will receive amlenetug during the OLE. Participants will receive intravenous infusions approximately every 4 weeks during both the PCP and OLE.

Key Inclusion Criteria:

• The participant has a diagnosis of clinically established multiple system atrophy parkinsonian type (MSA-P) or multiple system atrophy cerebellar type (MSA-C), or clinically probable MSA-P or MSA-C, according to the 2022 Movement Disorders Society (MDS) criteria for the diagnosis of MSA at the Screening Visit.
• The participant had onset of motor MSA symptoms (that is, parkinsonian and/or cerebellar) within 5 years prior to the Screening Visit in the judgement of the investigator.
• The participant has an anticipated survival of >3 years, in the opinion of the investigator, at the Screening Visit.
• The participant has suitable peripheral venous access for investigational medicinal product (IMP) administration and blood sampling.
• The participant has an UMSARS Part I score ≤16 (omitting item 11 on sexual function) at the Screening Visit.

Exclusion Criteria:

• The participant has previously been dosed with amlenetug.
• The participant has taken any active IMP within 3 months or 5 half lives of that product, whichever is longer, prior to the first dose of IMP.
• The participant has 2 or more first degree relatives with a history of MSA.
• The participant, if of MSA-P subtype, has unexplained anosmia (not explained by other common causes such as allergic rhinitis or smoking, nasal structural lesions, or nasal surgery) on olfactory testing at the Screening Visit.
• The participant has evidence (clinically or on magnetic resonance imaging (MRI)) and/or history of any clinically significant disease or condition other than MSA, that is, in the investigator's opinion, likely to affect CNS functioning, e.g., serious neurological disorder, other intracranial or systemic disease.
• The participant has a current diagnosis of movement disorders that could mimic MSA, e.g., Parkinson's disease, dementia with Lewy bodies, essential tremor, progressive supranuclear palsy, spinocerebellar ataxia, spastic paraparesis, corticobasal degeneration, or vascular, pharmacological, or post-encephalitic parkinsonism, per investigator discretion. Participants who have previously been incorrectly diagnosed with Parkinson's disease will not be excluded.

Other protocol-defined inclusion and exclusion criteria apply.