amlenetug (Lu AF82422) / Lundbeck, Genmab - LARVOL DELTA

Immunotherapy in Early Parkinson's Disease: A Biomarker-Driven Trial Framework for Secondary Prevention. (PubMed, Cureus) - "Although primary efficacy endpoints have not yet been achieved overall, prasinezumab has indicated exploratory slowing in faster progressors and digital measures. MEDI1341 has demonstrated Phase 1 target engagement with acceptable safety, and Lu AF82422 has shown Phase 1 target engagement, along with promising subgroup trends in MSA, and scheduled Phase 3. Meanwhile, cinpanemab was negative...We emphasize biomarkers that verify α-synuclein pathology during the asymptomatic phase and argue for a secondary-prevention model that treats the underlying biology before symptoms to maximize disease-modifying potential. We also propose a practical, biomarker-guided trial blueprint for secondary prevention, with explicit screening funnels and endpoint hierarchies."

Biomarker • IO biomarker • Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

Incorporating Patient and Care Partner Feedback on the Protocol for a Clinical Trial Assessing Progression in MSA (MDS Congress 2025) - P3 | "The phase 3 MASCOT study (NCT06706622) which will assess the efficacy and safety of the alpha-synuclein antibody, amlenetug in MSA was designed considering patient and care partner feedback... Incorporating feedback from PwMSA and their care partners on trial design is aimed to reduce trial burden, make trial participation easier, and improve the overall trial experience for PwMSA and their care partners."

Clinical • CNS Disorders

A Randomized, Double-blind Phase 3 Trial of Amlenetug Versus Placebo in Patients with MSA: The MASCOT Trial (MDS Congress 2025) - P3 | "MASCOT will be the first prospective phase 3 trial to evaluate the efficacy and safety of amlenetug versus placebo in MSA. A total of 360 participants will be recruited from sites experienced in the management of people with MSA."

Clinical • P3 data • CNS Disorders • Movement Disorders • Parkinson's Disease

AMULET: A Study of Lu AF82422 in Participants With Multiple System Atrophy (clinicaltrials.gov) - P2 | N=64 | Active, not recruiting | Sponsor: H. Lundbeck A/S | Trial completion date: May 2026 ➔ Mar 2028

Trial completion date • CNS Disorders • Movement Disorders • Multiple System Atrophy

Lundbeck to showcase amlenetug Phase 3 MASCOT trial design in Multiple System Atrophy at the International Congress of Parkinson's Disease and Movement Disorders 2025 (The Manila Times) - "At the congress, Lundbeck will share Insights into the design of the Phase 3 MASCOT trial and its use of innovative Bayesian progression modeling methods...Lundbeck will also showcase valuable insights from patients and caregivers who participated in the Phase 2 AMULET trial."

Clinical protocol • Trial status • Multiple System Atrophy

MASCOT: A randomized, placebocontrolled phase 3 trial of amlenetug in patients with multiple system atrophy (EAN 2025) - No abstract available

Clinical • P3 data • CNS Disorders • Movement Disorders • Multiple System Atrophy

Comparative assessment of binding and functional differences of clinical antibodies targeting α-synuclein in cellular models of Parkinson's disease. (PubMed, Biomed Pharmacother) - "Except cinpanemab, which binds the N-terminus of α-syn, all other clinical α-syn antibodies bind C-terminal epitopes...Our evaluation shows the impact of epitope, affinity, selectivity, and assay format on PFF uptake, and PFF-seed induced aggregation and S129 phosphorylation of endogenous α-syn in cellular models of PD. The comparative assessment provides new insights into the properties of α-syn antibodies and should aid in the design of next generation therapeutics for the treatment of PD and other synucleinopathies."

Journal • CNS Disorders • Movement Disorders • Parkinson's Disease

Rational selection of the monoclonal α-synuclein antibody amlenetug (Lu AF82422) for the treatment of α-synucleinopathies. (PubMed, NPJ Parkinsons Dis) - "The epitope of amlenetug was mapped to amino acids 112-117 and further characterized by crystallographic structure analysis. Based on our data, we hypothesize that targeting α-synuclein will potentially slow further disease progression by inhibiting further pathology development but be without impact on established pathology and symptoms."

Journal • CNS Disorders • Movement Disorders • Multiple System Atrophy

Lundbeck to share pipeline data and key insights into the progression of rare disease, Multiple System Atrophy, at International MSA Congress in Boston (PRNewswire) - "H. Lundbeck A/S (Lundbeck) will present key pipeline data and patient perspectives from the phase II AMULET trial, investigating amlenetug as a potential new treatment option targeting the rare neurological disorder, multiple system atrophy (MSA)...The data includes results from the AMULET phase II trial, coupled with patient perspectives from the trial, and new insights from the MSA natural history study, TALISMAN....The TALISMAN study will help to better understand how the disease develops over time, particularly in the early MSA population, and support phase III drug development....The data comes as Lundbeck is gearing up for the Phase III trial, MASCOT, involving the investigational treatment, amlenetug, a monoclonal antibody targeting α-synuclein for the potential treatment of MSA."

Observational data • P2 data • P3 data • Multiple System Atrophy

Lundbeck's potential treatment for Multiple System Atrophy granted Orphan Drug Designation in Japan (PRNewswire) - "The Ministry of Health, Labor, and Welfare (MHLW) in Japan has granted Orphan Drug Designation (ODD) to Lundbeck's investigational drug, amlenetug, a potential new treatment option targeting Multiple System Atrophy (MSA)."

Orphan drug • Multiple System Atrophy

Lundbeck’s potential treatment amlenetug for Multiple System Atrophy receives Fast Track Designation from the FDA (PRNewswire) - "H. Lundbeck A/S (Lundbeck) today announced that amlenetug has received Fast Track designation from the United States (US) Food and Drug Administration (FDA)....This designation is based on the outcome of AMULET..."

Fast track • Multiple System Atrophy

An update on immune-based alpha-synuclein trials in Parkinson's disease. (PubMed, J Neurol) - "Specifically, UB-312, AFFITOPE PD01A, PD03A and ACI-7104.056 are designed to provoke an immune response against α-syn (active immunisation), while Prasinezumab and Cinpanemab, MEDI1341 and Lu AF82422 focus on directly targeting α-syn aggregates (passive immunisation). Despite some promising results, challenges such as variable efficacy and trial discontinuations persist. Future research must address these challenges to advance disease-modifying therapies for PD around this therapeutic target."

Journal • Review • CNS Disorders • Movement Disorders • Parkinson's Disease

MASCOT: A Trial of Lu AF82422 in Participants With Multiple System Atrophy (MSA) (clinicaltrials.gov) - P3 | N=360 | Recruiting | Sponsor: H. Lundbeck A/S | Not yet recruiting ➔ Recruiting

Enrollment open • CNS Disorders • Movement Disorders • Multiple System Atrophy

MASCOT: A Trial of Lu AF82422 in Participants With Multiple System Atrophy (MSA) (clinicaltrials.gov) - P3 | N=360 | Not yet recruiting | Sponsor: H. Lundbeck A/S

New P3 trial • CNS Disorders • Movement Disorders • Multiple System Atrophy

Lundbeck initiates a phase III trial with amlenetug for the treatment of Multiple System Atrophy (Lundbeck Press Release) - "H. Lundbeck A/S (Lundbeck) today announced the advancement of the clinical development of amlenetug (Lu AF82422) for the treatment of MSA with the initiation of MASCOT, a randomized, double-blind, phase III trial."

Trial status • CNS Disorders • Multiple System Atrophy

A Trial Investigating Lu AF82422 in Healthy Chinese and Caucasian Adults (clinicaltrials.gov) - P1 | N=24 | Completed | Sponsor: H. Lundbeck A/S | Active, not recruiting ➔ Completed

Trial completion

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 (MDS Congress 2024) - P2 | "Although the trial did not meet its primary endpoint in the overall population, a potential for Lu AF82422 to slow MSA clinical progression was shown. The signal of efficacy was more pronounced in a less impaired population when a treatment with an a-syn antibody would be expected to be most beneficial. These data support the further investigation of Lu AF82422 in a phase 3 trial designed to confirm its potential effects on clinical progression in MSA."

Clinical • P2 data • CNS Disorders • Multiple System Atrophy • Parkinson's Disease

AMULET: A Study of Lu AF82422 in Participants With Multiple System Atrophy (clinicaltrials.gov) - P2 | N=64 | Active, not recruiting | Sponsor: H. Lundbeck A/S | Trial completion date: Feb 2025 ➔ May 2026

Trial completion date • CNS Disorders • Movement Disorders • Multiple System Atrophy

A Trial Investigating Lu AF82422 in Healthy Chinese and Caucasian Adults (clinicaltrials.gov) - P1 | N=24 | Active, not recruiting | Sponsor: H. Lundbeck A/S | Recruiting ➔ Active, not recruiting

Enrollment closed

A Trial Investigating Lu AF82422 in Healthy Chinese and Caucasian Adults (clinicaltrials.gov) - P1 | N=24 | Recruiting | Sponsor: H. Lundbeck A/S | Not yet recruiting ➔ Recruiting

Enrollment open

Randomized Phase I Trial of the α-Synuclein Antibody Lu AF82422. (PubMed, Mov Disord) - P1 | "The safety and pharmacokinetic profile of Lu AF82422 were appropriate for further clinical development, and results indicated peripheral target engagement. The central target engagement observed in participants with PD indicates that the doses of Lu AF82422 tested may provide CSF concentrations sufficient to target aggregated forms of α-syn."

Journal • P1 data • CNS Disorders • Infectious Disease • Movement Disorders • Pain • Parkinson's Disease

SUPPORTIVE RESULTS FROM THE AMULET PHASE 2, DOUBLE-BLIND, RANDOMIZED EXPLORATORY TRIAL OF LU AF82422 IN MULTIPLE SYSTEM ATROPHY (ADPD 2024) - No abstract available

Clinical • P2 data • CNS Disorders • Movement Disorders • Multiple System Atrophy

A Trial Investigating Lu AF82422 in Healthy Chinese and Caucasian Adults (clinicaltrials.gov) - P1 | N=24 | Not yet recruiting | Sponsor: H. Lundbeck A/S

New P1 trial

AMULET: A Study of Lu AF82422 in Participants With Multiple System Atrophy (clinicaltrials.gov) - P2 | N=64 | Active, not recruiting | Sponsor: H. Lundbeck A/S | Trial completion date: Mar 2024 ➔ Feb 2025

Trial completion date • CNS Disorders • Movement Disorders • Multiple System Atrophy

Baseline characteristics for patients with multiple system atrophy entering a randomized, controlled study of the anti-α-synuclein monoclonal antibody Lu AF82422 (MDS Congress 2023) - P2 | "Study randomization is complete and baseline characteristics are consistent with a population of patients with MSA who are still relatively early in their disease course, and who might be good candidates to assess the slowing of clinical progression with a therapy preventing α-syn accumulation."

Clinical • CNS Disorders • Multiple System Atrophy • Parkinson's Disease