H. Lundbeck A/S announced it will showcase the innovative design of its Phase 3 MASCOT trial investigating amlenetug for Multiple System Atrophy (MSA) at the 2025 International Congress of Parkinson's Disease and Movement Disorders in Honolulu, Hawaii. The presentation highlights a novel approach to addressing one of neurology's most challenging rare diseases, for which no approved treatments currently exist.
Targeting α-Synuclein Pathology
Amlenetug represents a potential first-in-class therapy as a human monoclonal antibody that binds to pathological aggregations of the protein α-synuclein in the brain, thereby inhibiting its spreading to nearby brain cells. This mechanism targets the underlying biology believed responsible for MSA's devastating progression.
"MSA is a neurodegenerative disease with no currently available treatments to slow its relentless progression," said Johan Luthman, EVP and Head of Research and Development at Lundbeck. "Amlenetug seeks to address this unmet need by targeting the underlying biology of MSA and delaying disease progression."
Innovative Trial Methodology
The MASCOT trial employs Bayesian progression modeling methods to overcome unique challenges faced in rare disease drug development. This dynamic approach utilizes all available data over a long treatment period, enabling assessment of potential slowing of clinical disease progression overall, contrasting with traditional clinical trial designs that focus on isolated time points.
The Phase 3 MASCOT trial (NCT06706622) is a randomized, double-blind, parallel-group, placebo-controlled study being conducted across North America, Europe, Asia, and Australia. The trial comprises two parts: a 72-week double-blind period where participants receive either high or low doses of amlenetug or placebo, followed by an open-label extension period offering all participants treatment with amlenetug. The drug is administered as an intravenous infusion every four weeks.
Regulatory Recognition and Patient Insights
Amlenetug has received significant regulatory recognition, including Orphan Drug Designation from both the US FDA and European Medicines Agency, plus SAKIGAKE designation in Japan. The Bayesian progression modeling framework has been discussed with regulatory authorities in support of marketing registration across these regions.
The trial design has been informed by valuable insights from patients and caregivers who participated in the Phase 2 AMULET trial. These perspectives, captured through embedded patient experience interviews, have been instrumental in informing the Phase 3 design and highlighting the substantial burden the disease places on patients and their families.
Disease Burden and Unmet Need
MSA is a rapidly progressing rare condition that causes damage to nerve cells in the brain, placing a high disease burden on patients. Symptoms typically begin between ages 55 and 60, with patients generally living 6 to 9 years after symptom onset. The abnormal build-up of α-synuclein protein damages brain areas controlling balance, movement, and normal body functions.
Symptoms are wide-ranging and include muscle control problems similar to Parkinson's disease. Many body functions can be affected, with urinary incontinence, frequent falling, and unintelligible speech occurring within 3 years of disease onset, accompanied by reduced capacity for independent living. Death often results from respiratory problems.
Development Partnership
Amlenetug is being developed by Lundbeck under a joint research and licensing agreement with Genmab A/S. The compound recognizes and binds to all major forms of extracellular α-synuclein, intended to prevent uptake and inhibit seeding of aggregation. As an investigational compound not approved by any regulatory authority worldwide, the efficacy and safety of amlenetug have not yet been established.
The AMULET Phase 2 trial randomized MSA patients 2:1 to either amlenetug or placebo, with treatment periods between 48 to 72 weeks, followed by an ongoing 192-week open-label extension. The primary objective evaluated efficacy on clinical progression with a 5% significance level, alongside safety and tolerability assessments.
