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AMULET

Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial

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Year of Publication: 2026

Authors: Kjærsgaard L, Wiedemann J, Singer W, ..., Luthman J; AMULET Trial Group

Journal: The Lancet Neurology

Citation: The Lancet Neurology, Volume 25, Issue 6, June 2026, Pages 560-570

Link: https://doi.org/10.1016/S1474-4422(26)00100-6

Clinical Question

Does the anti-α-synuclein monoclonal antibody amlenetug slow clinical disease progression in patients with multiple system atrophy?

Bottom Line

In this phase 2 trial, amlenetug did not meet its primary endpoint for slowing disease progression in MSA (Bayesian probability 89.4% vs predefined 97.5% threshold), though a non-significant 19% slowing of clinical progression and acceptable safety profile supported advancement to a phase 3 trial.

        Major Points
        Primary endpoint not met: Bayesian probability of 89.4% for true slowing of disease progression did not reach the predefined 97.5% threshold
Effect parameter 0.81 (2.5th-97.5th percentile 0.56-1.13) corresponded to a non-significant 19% slowing of clinical progression (range -13% to 44%) for amlenetug vs placebo
First randomized controlled trial comparing an anti-α-synuclein antibody vs placebo in MSA
Bayesian progression model used to enable feasible sample size in rare, rapidly progressing disease
Amlenetug was generally well tolerated with comparable rates of TEAEs (100% vs 95%) and serious TEAEs (30% vs 33%) vs placebo
Trial design used 2:1 randomization and a common close design with 48–72 weeks of treatment
Despite negative primary endpoint, findings support further evaluation in a phase 3 trial; open-label extension is ongoing

      

Design

Study Type: Phase 2, randomised, double-blind, placebo-controlled, parallel-group, multicentre trial

Randomization: 1

Blinding: Double-blind: participants, study partners, treating investigators, study site personnel, and sponsor were all masked to treatment allocation; independent site personnel prepared trial medication

Allocation: 2:1 (amlenetug:placebo), stratified by region (USA or Japan) and blood NfL concentration (low ≤20 pg/mL, high >20 pg/mL, or missing), block size of three, via interactive web-based response technology

Enrollment Period: Nov 16, 2021 to Oct 6, 2022

Follow-up Duration: 48–72 weeks (common close design ending when last randomised participant completed week 48 visit)

Centers: 18

Countries: USA, Japan

Sample Size: 64

Analyzed: 61

Analysis: Full analysis set (FAS): all participants with valid baseline and ≥1 valid post-baseline UMSARS total score assessment; safety assessed in all treated participants. Bayesian repeated measures model with proportional treatment effect (θ); threshold for statistical significance = 97.5% probability of active treatment slowing progression vs placebo

Power Calculation: Sample size of 60 (2:1 allocation) estimated to provide 75% power to detect 40% slowing of MSA progression at one-sided α=0.05, assuming 20% dropout, ~1 point UMSARS total worsening per month, 50% contributing 60 weeks and 25% contributing 72 weeks of data

Registration: ClinicalTrials.gov NCT05104476

Inclusion Criteria

Male or female aged 40–75 years
Possible or probable MSA of parkinsonian (MSA-P) or cerebellar (MSA-C) subtype
Onset of motor MSA symptoms within 5 years before screening
UMSARS part I score ≤16 (omitting item 11 on sexual function)
Montreal Cognitive Assessment (MoCA) score ≥22
Anticipated survival ≥3 years
Care partner with ≥3 h weekly contact able to accompany participant to trial visits
Maximum 25% recruited from Japan

Exclusion Criteria

Evidence (clinical or MRI) or history of any other serious neurological disorder, including movement disorders that could mimic MSA
Other intracranial or systemic conditions leading to a diagnosis other than MSA
Family history of MSA (≥2 blood relatives)
Attempted suicide within past 6 months or significant suicide risk
Receipt of any investigational products within 30 days before screening
Previous treatment with antibodies targeting α-synuclein
Contraindications to MRI

Baseline Characteristics

Treated participants (total): 61

Mean age (years): 60.8 (SD 7.7)

Male: 32 (52%)

Female: 29 (48%)

Arms

Field	Amlenetug	Control
N	40	21
Intervention	Intravenous amlenetug 4.2 g (80 mL) infusion over 30 min every 4 weeks (±3 days)	Intravenous matched placebo infusion over 30 min every 4 weeks (±3 days)
Duration	48–72 weeks (common close design)	48–72 weeks (common close design)

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Disease progression assessed using a Bayesian progression model of longitudinal change from baseline in UMSARS total (parts I and II) score during the double-blind treatment phase	Primary	Reference (placebo)	Effect parameter 0.81 corresponding to 19% slowing of clinical progression vs placebo	19% slowing of clinical progression (2.5th to 97.5th percentile: -13% to 44%); effect parameter 0.81 (2.5th-97.5th percentile 0.56-1.13)	Bayesian probability of 89.4% for true slowing (did not meet predefined 97.5% threshold; primary endpoint NOT met)
Change from baseline in modified UMSARS part I (mUMSARS, scores 0 and 1 collapsed to 1) — key secondary endpoint	Secondary	Statistically non-significant efficacy signal (specific values not provided in available text)
Change from baseline in UMSARS part I	Secondary	Statistically non-significant efficacy signal (specific values not provided in available text)
Change from baseline in UMSARS part II	Secondary	Statistically non-significant efficacy signal (specific values not provided in available text)
MRI-derived volume changes from baseline to week 48 in prespecified brain regions (primary ROIs: pons, cerebellum white matter, cerebellum grey matter; secondary ROIs: caudate, putamen, brainstem, total grey matter)	Secondary	Non-significant biomarker signals reported (specific values not in available text)
Change in plasma neurofilament light chain (NfL) concentration	Secondary	Non-significant biomarker signal (specific values not in available text)
Change from baseline to week 48 in UMSARS part IV (global disability) and Schwab and England Activities of Daily Living (SE-ADL) score	Secondary	Specific values not provided in available text
Clinician, Patient, and Observer Global Impression of Severity (CGI-S, PGI-S, OGI-S, 5-point scales)	Secondary	Specific values not provided in available text
Quality of life (EQ-5D-5L) and prespecified disease milestones (speech, swallowing, falls, walking) from UMSARS part I	Secondary	Specific values not provided in available text
Amlenetug plasma concentrations, CSF concentrations, and CSF-to-plasma ratio at week 48	Secondary	Evidence of target engagement reported; specific PK values not provided in available text
Any treatment-emergent adverse event (TEAE)	Safety	Amlenetug: 40 (100%) · Placebo: 20 (95%)
Serious treatment-emergent adverse event	Safety	Amlenetug: 12 (30%) · Placebo: 7 (33%)
Deaths	Safety	Amlenetug: 2 · Placebo: 2 (only 1 considered possibly treatment-related, in placebo group)
Completion of double-blind treatment	Safety	48/61 (79%) completed; mean 56 weeks (SD 13) treatment
COVID-19 infection	Adverse	Amlenetug 11 (28%) vs Placebo 5 (24%)
Back pain	Adverse	Amlenetug 6 (15%) vs Placebo 2 (10%)
Headache	Adverse	Amlenetug 5 (13%) vs Placebo 1 (5%)
Urinary tract infection	Adverse	Amlenetug 4 (10%) vs Placebo 3 (14%)
Peripheral oedema	Adverse	Amlenetug 4 (10%) vs Placebo 1 (5%)
Flushing	Adverse	Amlenetug 4 (10%) vs Placebo 0
Hypertension	Adverse	Amlenetug 4 (10%) vs Placebo 0

Subgroup Analysis

Post-hoc analysis of primary and secondary UMSARS outcomes was conducted in participants with baseline UMSARS total score <40, hypothesizing greater treatment effect in earlier-stage MSA; specific results not provided in available text

Criticisms

Small sample size (n=61 treated) limited statistical power, particularly for placebo group (n=21)
Primary endpoint not met by predefined Bayesian threshold (89.4% vs 97.5% required)
Wide credible interval (-13% to 44% slowing) reflects substantial uncertainty about true effect
Protocol amendment removed exclusion criteria for advanced disease features after trial initiation
Trial limited to USA and Japan, limiting generalizability
Sponsor-funded trial (H Lundbeck) with multiple sponsor-affiliated authors

Funding

H Lundbeck

Based on: AMULET (The Lancet Neurology, 2026)

Authors: Kjærsgaard L, Wiedemann J, Singer W, ..., Luthman J; AMULET Trial Group

Citation: The Lancet Neurology, Volume 25, Issue 6, June 2026, Pages 560-570

Content summarized and formatted by NeuroTrials.ai.

AMULET

(2026)

Objective

To assess the efficacy and safety of amlenetug, a monoclonal antibody targeting aggregated α-synuclein, versus placebo in slowing clinical disease progression in patients with multiple system atrophy (MSA).

Study Summary

• Primary endpoint NOT met: Bayesian probability of 89.4% for true slowing of progression did not reach predefined 97.5% threshold
• Non-significant 19% slowing of clinical progression (effect parameter 0.81, 2.5th-97.5th percentile 0.56-1.13, range -13% to 44%) with amlenetug vs placebo
• Generally well tolerated: TEAEs in 100% (amlenetug) vs 95% (placebo); serious TEAEs in 30% vs 33%
• Two deaths in each group; only one (placebo) considered possibly treatment-related
• Findings supported further evaluation in a phase 3 trial

Intervention

Intravenous amlenetug 4.2 g (80 mL) every 4 weeks for 48–72 weeks vs matched placebo

Inclusion Criteria

Adults aged 40–75 years with possible or probable MSA (parkinsonian or cerebellar subtype), motor symptom onset within 5 years, UMSARS part I score ≤16, MoCA ≥22, anticipated survival ≥3 years, and a care partner with ≥3 h weekly contact.

Study Design

Arms: Amlenetug 4.2 g IV every 4 weeks (n=40) vs Placebo IV every 4 weeks (n=21)

Patients per Arm: Amlenetug n=40; Placebo n=21

Outcome

• Primary endpoint not met: Bayesian probability 89.4% (threshold 97.5%)
• Effect parameter 0.81 (95% CrI 0.56-1.13) = 19% slowing (95% CrI -13% to 44%)
• TEAEs: 100% amlenetug vs 95% placebo; serious TEAEs: 30% vs 33%
• Most common TEAEs: COVID-19 (28% vs 24%), back pain (15% vs 10%), headache (13% vs 5%)
• 2 deaths in each group; only 1 placebo death possibly treatment-related

Bottom Line

Major Points

Primary endpoint not met: Bayesian probability of 89.4% for true slowing of disease progression did not reach the predefined 97.5% threshold
Effect parameter 0.81 (2.5th-97.5th percentile 0.56-1.13) corresponded to a non-significant 19% slowing of clinical progression (range -13% to 44%) for amlenetug vs placebo
First randomized controlled trial comparing an anti-α-synuclein antibody vs placebo in MSA
Bayesian progression model used to enable feasible sample size in rare, rapidly progressing disease
Amlenetug was generally well tolerated with comparable rates of TEAEs (100% vs 95%) and serious TEAEs (30% vs 33%) vs placebo
Trial design used 2:1 randomization and a common close design with 48–72 weeks of treatment
Despite negative primary endpoint, findings support further evaluation in a phase 3 trial; open-label extension is ongoing

Study Design

Study Type: Phase 2, randomised, double-blind, placebo-controlled, parallel-group, multicentre trial
Randomization: Yes
Blinding: Double-blind: participants, study partners, treating investigators, study site personnel, and sponsor were all masked to treatment allocation; independent site personnel prepared trial medication
Sample Size: 64
Follow-up: 48–72 weeks (common close design ending when last randomised participant completed week 48 visit)
Centers: 18
Countries: USA, Japan

Primary Outcome

Definition: Disease progression assessed using a Bayesian progression model of longitudinal change from baseline in UMSARS total (parts I and II) score during the double-blind treatment phase

Control	Intervention	HR/OR	P-value
Reference (placebo)	Effect parameter 0.81 corresponding to 19% slowing of clinical progression vs placebo	- (Effect parameter credible interval 0.56 to 1.13 (2.5th-97.5th percentile))	Bayesian probability of 89.4% for true slowing (did not meet predefined 97.5% threshold; primary endpoint NOT met)

Limitations & Criticisms

Small sample size (n=61 treated) limited statistical power, particularly for placebo group (n=21)
Primary endpoint not met by predefined Bayesian threshold (89.4% vs 97.5% required)
Wide credible interval (-13% to 44% slowing) reflects substantial uncertainty about true effect
Protocol amendment removed exclusion criteria for advanced disease features after trial initiation
Trial limited to USA and Japan, limiting generalizability
Sponsor-funded trial (H Lundbeck) with multiple sponsor-affiliated authors

Citation

The Lancet Neurology, Volume 25, Issue 6, June 2026, Pages 560-570

View Original Publication →

AMULET

Safety and efficacy of the anti-α-synuclein monoclonal antibody amlenetug for the treatment of patients with multiple system atrophy (AMULET): a phase 2, randomised, double-blind, multicentre trial

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Subgroup Analysis

Criticisms

Funding

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