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
Does the anti-α-synuclein monoclonal antibody amlenetug slow clinical disease progression in patients with multiple system atrophy?
Study Overview
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; 2.5th-97.5th percentile of % slowing -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
Patients per Arm
Amlenetug n=40; Placebo n=21
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 (2.5th-97.5th percentile -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; recruitment capped at 25% from Japan
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
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
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); MMRM 48-week progression 13.93 (SE 3.42) UMSARS total points | MMRM 48-week progression 13.32 (SE 2.86) UMSARS total points; Bayesian effect parameter 0.81 = 19% slowing vs placebo | Bayesian: 19% slowing of clinical progression (2.5th-97.5th percentile -13% to 44%); effect parameter 0.81 (2.5th-97.5th percentile 0.56-1.13); Bayesian probability of true slowing 89.4% (predefined significance threshold 97.5% — NOT met) | |
| Change from baseline in modified UMSARS (mUMSARS, part I scores 0/1 collapsed to 1) — key secondary endpoint | Secondary | 27% slower progression (Bayesian probability 97.0%); MMRM change 6.48 (SE 1.33) amlenetug vs 7.07 (SE 1.62) placebo; treatment effect -0.59 (95% CI -3.56 to 2.38) | |||
| Change from baseline in UMSARS part I | Secondary | 22% slower progression (Bayesian probability 91.6%); MMRM change 6.98 (SE 1.59) vs 7.64 (SE 1.92); treatment effect -0.66 (95% CI -4.09 to 2.77) | |||
| Change from baseline in UMSARS part II | Secondary | 17% slower progression (Bayesian probability 84.4%); MMRM change 6.76 (SE 1.83) vs 7.16 (SE 2.15); treatment effect -0.40 (95% CI -4.04 to 3.24) | |||
| MRI-derived percentage volume change from baseline to week 48 (MMRM treatment effect, amlenetug minus placebo) | Secondary | Primary ROIs: pons 1.95 (95% CI -0.42 to 4.32), cerebellar white matter 2.61 (-1.57 to 6.79), cerebellar grey matter -1.41 (-3.27 to 0.46). Secondary ROIs: caudate 0.71 (-1.10 to 2.52), putamen -0.25 (-2.31 to 1.80), brainstem 1.82 (0.09 to 3.56), total grey matter 0.60 (-0.34 to 1.55). Non-significant signals of less volume loss in pons, cerebellar white matter, and brainstem | |||
| Change in plasma neurofilament light chain (NfL) concentration | Secondary | No relevant changes from baseline in either group | |||
| Change from baseline to week 48 in UMSARS part IV (global disability) and Schwab and England Activities of Daily Living (SE-ADL) score (MMRM) | Secondary | UMSARS IV: 1.13 (SE 0.30) vs 1.35 (SE 0.35); treatment effect -0.22 (95% CI -0.76 to 0.32). SE-ADL: -20.82 (SE 6.52) vs -23.56 (SE 7.40); treatment effect 2.74 (95% CI -7.90 to 13.38) | |||
| Clinician, Patient, and Observer Global Impression of Severity (CGI-S, PGI-S, OGI-S, 5-point scales) MMRM treatment effects | Secondary | CGI-S -0.24 (95% CI -0.52 to 0.04) favouring amlenetug; PGI-S 0.25 (-0.11 to 0.61) favouring placebo; OGI-S -0.16 (-0.68 to 0.37) favouring amlenetug | |||
| Quality of life (EQ-5D-5L VAS) and prespecified disease milestones (speech, swallowing, walking, falls) from UMSARS part I (MMRM treatment effects) | Secondary | EQ-5D-5L VAS -0.64 (95% CI -10.87 to 9.58); speech -0.42 (-0.86 to 0.02); swallowing 0.34 (-0.18 to 0.85, favouring placebo); walking -0.17 (-0.60 to 0.26); falls -0.14 (-0.83 to 0.55) | |||
| Amlenetug plasma and CSF concentrations at week 48; CSF-to-plasma ratio; free CSF α-synuclein change (target engagement) | Secondary | Plasma amlenetug: mean 390,751 ng/mL, median 356,000 ng/mL. CSF amlenetug: mean 1531 ng/mL, median 1350 ng/mL. CSF-to-plasma ratio 0.4%. Free (unbound) CSF α-synuclein reduced 33.0% from baseline (25th-75th percentile -43.8 to -23.5), indicating central target engagement | |||
| Any treatment-emergent adverse event (TEAE) | Safety | Amlenetug: 40 (100%; 95% CI 91–100) · Placebo: 20 (95%; 95% CI 77–99) | |||
| Serious treatment-emergent adverse event | Safety | Amlenetug: 12 (30%; 95% CI 18–45) · Placebo: 7 (33%; 95% CI 17–55) | |||
| Drug-related TEAEs | Safety | Amlenetug: 25 (63%; 95% CI 47–76) · Placebo: 8 (38%; 95% CI 21–59) | |||
| TEAEs potentially related to hypersensitivity | Safety | Amlenetug: 4 (10%; 95% CI 4–23) · Placebo: 1 (5%; 95% CI 1–23) | |||
| TEAEs leading to discontinuation | Safety | Amlenetug: 3 (8%; 95% CI 3–20) · Placebo: 2 (10%; 95% CI 3–29) | |||
| Deaths (adverse events leading to death) | Safety | Amlenetug: 2 (5%; 95% CI 1–17) — cardiopulmonary failure, asphyxia due to foreign body · Placebo: 2 (10%; 95% CI 3–29) — cardiorespiratory arrest (only death assessed as possibly drug-related), sepsis | |||
| 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
Prespecified post-hoc analysis in participants with baseline UMSARS total score <40 (n=42, 69% of FAS): mean 48-week UMSARS total progression 12.21 (SE 3.08) amlenetug vs 18.61 (SE 4.16) placebo. Bayesian effect parameter 0.63 (2.5th-97.5th percentile 0.41-0.94) equated to 37% slower clinical progression (2.5th-97.5th percentile 6 to 59%) with Bayesian probability 98.9% (nominal significance). Domain-specific slowing: mUMSARS 42% (13 to 64), probability 99.6%; UMSARS part I 42% (10 to 65), probability 99.3%; UMSARS part II 30% (-6 to 56), probability 95.5%
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 (2.5th-97.5th percentile -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
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