Amylyx Pharmaceuticals has published encouraging data from its Phase 2 PEGASUS trial showing that AMX0035, an investigational oral combination therapy, demonstrated favorable effects on cerebrospinal fluid biomarkers associated with Alzheimer's disease pathology and neurodegeneration. The exploratory analyses, published in Alzheimer's & Dementia: Translational Research & Clinical Interventions, suggest the drug engages multiple pathological pathways implicated in neurodegenerative diseases.
Key Biomarker Findings
The study analyzed cerebrospinal fluid samples from 67 participants out of the 95-person intent-to-treat cohort who had samples available at baseline and Week 24. AMX0035 treatment resulted in significant reductions across multiple biomarker categories compared to placebo.
Most notably, AMX0035 reduced levels of phosphorylated tau181 (p-tau181) and total tau, which are core biomarkers of Alzheimer's disease pathology. The drug also decreased levels of synaptic and neuronal degeneration biomarkers, specifically neurogranin and fatty acid binding protein-3 (FABP3).
Additionally, AMX0035 treatment reduced YKL-40 (chitinase 3-like protein 1), a biomarker associated with gliosis that has been shown to correlate with cortical volume loss and rate of cognitive decline. Previous research published in 2023 demonstrated that AMX0035 also reduced YKL-40 levels in amyotrophic lateral sclerosis patients.
Expert Commentary on Mechanism
"Alzheimer's disease is defined by amyloid plaques and tau tangles, but it's now understood that these pathologies are accompanied by alterations in multiple cell and molecular pathways, including neuronal dysfunction, neurodegeneration, and oxidative stress, driving the progression of this relentless disease," said Steven E. Arnold, MD, Professor of Neurology at Harvard Medical School and Translational Neurology Head at Massachusetts General Hospital.
Arnold noted that "the results from this exploratory analysis suggest that AMX0035 engages important pathways implicated in the pathogenesis of Alzheimer's disease and other neurodegenerative diseases."
Drug Mechanism and Development
AMX0035 is an investigational, oral, fixed-dose combination of sodium phenylbutyrate and taurursodiol (also known as ursodoxicoltaurine outside the U.S.). The drug is designed to slow or mitigate neurodegeneration by targeting endoplasmic reticulum stress and mitochondrial dysfunction, two connected central pathways that lead to cell death and neurodegeneration.
Preclinical studies have provided evidence that AMX0035 may reduce cell death and improve cellular function, with data supporting a synergistic effect of the combination compared to individual compounds.
Implications for Progressive Supranuclear Palsy
The biomarker findings have particular relevance for Amylyx's ongoing development of AMX0035 in progressive supranuclear palsy (PSP), a rare neurodegenerative disorder characterized by abnormal tau inclusions.
"These data lend further support to the preclinical and clinical evidence that AMX0035 has the potential to treat neurodegenerative diseases associated with tau dysfunction and tau aggregation. One such disease is progressive supranuclear palsy, also known as PSP," commented Camille L. Bedrosian, MD, Chief Medical Officer at Amylyx.
The company is currently conducting the ORION trial, a global, randomized, double-blind, placebo-controlled Phase 2b/3 clinical trial designed to assess the efficacy, safety, and tolerability of AMX0035 in people living with PSP.
Disease Context and Unmet Need
Progressive supranuclear palsy affects approximately seven in 100,000 people worldwide and typically begins in late-middle age, rapidly progressing over time. People living with PSP have a life expectancy of six to eight years after initial diagnosis, with epidemiology similar to amyotrophic lateral sclerosis.
The disease affects walking and balance, eye movement, swallowing, and speech. Currently, there are no disease-modifying therapies approved for PSP treatment, representing a significant unmet medical need.
"There is a pressing unmet need for new and effective treatments in PSP, and we are encouraged by our findings that further support the potential of AMX0035," Bedrosian noted.
Trial Design and Methodology
The PEGASUS trial was a randomized, double-blind, multi-center, placebo-controlled study evaluating the safety, tolerability and activity of AMX0035 in 95 adults with mild cognitive impairment or mild to moderate dementia due to Alzheimer's disease over 24 weeks of treatment.
The biomarker analysis examined multiple pathophysiological processes in Alzheimer's disease, including core AD biomarkers such as amyloid beta 42/40 ratio, phosphorylated tau181, and total tau. Additional markers assessed synaptic and neuronal degeneration, gliosis, oxidative stress, and neurodegeneration, inflammation, and metabolism pathways.
The ORION trial studying AMX0035 in PSP was designed and planned in collaboration with key global academic leaders, people living with PSP and their caregivers, and industry advocacy organizations.
