Amylyx: AMX0035 Shows Promising Effects on Alzheimer's Biomarkers in Cerebrospinal Fluid

Amylyx Pharmaceuticals, Inc. has announced findings from exploratory analyses of cerebrospinal fluid (CSF) biomarkers in participants with Alzheimer's disease (AD) from their Phase 2 PEGASUS trial. These analyses indicate that treatment with AMX0035, a combination of sodium phenylbutyrate (PB) and taurursodiol (TURSO), resulted in consistent changes in CSF biomarkers associated with AD and neurodegeneration across a range of disease severities. The results were published in the medical journal *Alzheimer’s & Dementia: Translational Research & Clinical Interventions*.

Alzheimer’s disease, characterized by amyloid plaques and tau tangles, involves various cellular and molecular pathways including neuronal dysfunction and oxidative stress. According to Steven E. Arnold, MD, from Harvard Medical School and Massachusetts General Hospital, the exploratory analysis suggests that AMX0035 engages key pathways implicated in the pathogenesis of Alzheimer's and other neurodegenerative diseases.

The PEGASUS trial involved 95 participants, with 67 providing CSF samples at the start and at Week 24. The analysis focused on biomarkers for different AD pathophysiological processes, such as amyloid beta (Aβ42/40 ratio), phosphorylated tau181 (p-tau181), total tau, biomarkers for synaptic and neuronal degeneration (neurogranin and FABP3), gliosis (YKL-40), oxidative stress (8-OHdG), and other neurodegeneration and inflammation markers.

Compared to placebo, AMX0035 reduced levels of p-tau181 and total tau in the CSF. It also lowered biomarkers for synaptic and neuronal degeneration, specifically neurogranin and FABP3, and YKL-40, which correlates with cortical volume loss and cognitive decline. A 2023 study showed that AMX0035 also reduced YKL-40 levels in ALS.

Camille L. Bedrosian, MD, Chief Medical Officer at Amylyx, emphasized that these data provide further support for the potential of AMX0035 to treat neurodegenerative diseases involving tau dysfunction, such as progressive supranuclear palsy (PSP). The ongoing ORION trial is studying AMX0035 in PSP.

AMX0035 is an oral, fixed-dose combination of PB and TURSO, designed to slow neurodegeneration by targeting endoplasmic reticulum stress and mitochondrial dysfunction. Preclinical studies suggest that AMX0035 may reduce cell death and improve cellular function, demonstrating a synergistic effect compared to the individual compounds. AMX0035 is being investigated as a treatment for various neurodegenerative diseases, including Wolfram syndrome and PSP.

The PEGASUS trial (NCT03533257) was a randomized, double-blind, placebo-controlled study evaluating the safety, tolerability, and activity of AMX0035 in adults with mild cognitive impairment or mild to moderate AD over 24 weeks. The study assessed the effects of PB and TURSO on disease biology in a diverse group of AD patients.

The ORION trial (NCT06122662) is a global, randomized, double-blind, placebo-controlled Phase 2b/3 clinical trial evaluating the efficacy, safety, and tolerability of AMX0035 in individuals with PSP. The trial was designed in collaboration with global academic leaders, PSP patients, caregivers, and industry organizations.

PSP is a rare, adult-onset neurodegenerative disorder that affects walking, balance, eye movement, swallowing, and speech, leading to a life expectancy of six to eight years after diagnosis. It affects approximately seven in 100,000 people worldwide and currently has no approved disease-modifying therapies. The disease is characterized by abnormal tau inclusions and involves multiple contributing factors, including genetic mutations and mitochondrial dysfunction.

Amylyx Pharmaceuticals is dedicated to discovering and developing new treatments for serious and fatal diseases, especially neurodegenerative, neuroendocrine, and endocrine diseases. The company focuses on addressing unmet medical needs through scientific research, with a commitment to patient communities. Amylyx is based in Cambridge, Massachusetts.

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