Year: 2024
Type: article
Abstract: INTRODUCTION: Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS: The first-in-indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS: = 33), reductions were observed in core AD biomarkers phosphorylated tau-181 (p-tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein-3 (FABP3); and gliosis biomarker chitinase 3-like protein 1 (YKL-40), while the oxidative stress marker 8-hydroxy-2-deoxyguanosine (8-OHdG) increased. Between-group differences were observed for the Aβ42/40 ratio, p-tau181, total tau, neurogranin, FABP3, YKL-40, interleukin-15, and 8-OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION: While between-group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights: Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD).Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms.The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets.PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration.Supports further clinical development of PB and TURSO in neurodegenerative diseases.
DOI: 10.1002/trc2.12487
Authors: Steven E. Arnold, Suzanne Hendrix, Jessie Nicodemus‐Johnson, Newman Knowlton, Victoria J. Williams, Jeffrey M. Burns, Monica Crane, Alison J. McManus, Sanjeev N. Vaishnavi, Zoe Arvanitakis, Judith Neugroschl, Karen Bell, Bianca A. Trombetta, Becky C. Carlyle, Pia Kivisäkk, Hiroko H. Dodge, Rudolph E. Tanzi, Patrick D. Yeramian, Kent Leslie
Institutions: Harvard University, Massachusetts General Hospital, University of Wisconsin–Madison, University of Kansas, University of Pennsylvania, Rush University Medical Center, Icahn School of Medicine at Mount Sinai, Columbia University, University of Oxford, Amylyx Pharmaceuticals, Inc. (United States), California Institute of Technology
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,310
OpenAlex ID: W4401462193