Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes.
Document Type
Article
Abstract
INTRODUCTION/AIMS: Biomarkers have shown promise in amyotrophic lateral sclerosis (ALS) research, but the quest for reliable biomarkers remains active. This study evaluates the effect of debamestrocel on cerebrospinal fluid (CSF) biomarkers, an exploratory endpoint.
METHODS: A total of 196 participants randomly received debamestrocel or placebo. Seven CSF samples were to be collected from all participants. Forty-five biomarkers were analyzed in the overall study and by two subgroups characterized by the ALS Functional Rating Scale-Revised (ALSFRS-R). A prespecified model was employed to predict clinical outcomes leveraging biomarkers and disease characteristics. Causal inference was used to analyze relationships between neurofilament light chain (NfL) and ALSFRS-R.
RESULTS: We observed significant changes with debamestrocel in 64% of the biomarkers studied, spanning pathways implicated in ALS pathology (63% neuroinflammation, 50% neurodegeneration, and 89% neuroprotection). Biomarker changes with debamestrocel show biological activity in trial participants, including those with advanced ALS. CSF biomarkers were predictive of clinical outcomes in debamestrocel-treated participants (baseline NfL, baseline latency-associated peptide/transforming growth factor beta1 [LAP/TGFβ1], change galectin-1, all p < .01), with baseline NfL and LAP/TGFβ1 remaining (p < .05) when disease characteristics (p < .005) were incorporated. Change from baseline to the last measurement showed debamestrocel-driven reductions in NfL were associated with less decline in ALSFRS-R. Debamestrocel significantly reduced NfL from baseline compared with placebo (11% vs. 1.6%, p = .037).
DISCUSSION: Following debamestrocel treatment, many biomarkers showed increases (anti-inflammatory/neuroprotective) or decreases (inflammatory/neurodegenerative) suggesting a possible treatment effect. Neuroinflammatory and neuroprotective biomarkers were predictive of clinical response, suggesting a potential multimodal mechanism of action. These results offer preliminary insights that need to be confirmed.
Keywords
Adult, Aged, Female, Humans, Male, Middle Aged, Amyotrophic Lateral Sclerosis, Biomarkers, Double-Blind Method, Neurofilament Proteins, Treatment Outcome
Medical Subject Headings
Adult; Aged; Female; Humans; Male; Middle Aged; Amyotrophic Lateral Sclerosis; Biomarkers; Double-Blind Method; Neurofilament Proteins; Treatment Outcome
Publication Date
6-1-2024
Publication Title
Muscle & nerve
ISSN
1097-4598
Volume
69
Issue
6
First Page
719
Last Page
729
PubMed ID
38593477
Digital Object Identifier (DOI)
10.1002/mus.28093
Recommended Citation
Lindborg, Stacy R; Goyal, Namita A; Katz, Jonathan; Burford, Matthew; Li, Jenny; Kaspi, Haggai; Abramov, Natalie; Boulanger, Bruno; Berry, James D; Nicholson, Katharine; Mozaffar, Tahseen; Miller, Robert; Jenkins, Liberty; Baloh, Robert H; Lewis, Richard; Staff, Nathan P; Owegi, Margaret Ayo; Dagher, Bob; Blondheim-Shraga, Netta R; Gothelf, Yael; Levy, Yossef S; Kern, Ralph; Aricha, Revital; Windebank, Anthony J; Bowser, Robert; Brown, Robert H; and Cudkowicz, Merit E, "Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes." (2024). Translational Neuroscience. 2378.
https://scholar.barrowneuro.org/neurobiology/2378