Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes

Stacy R. Lindborg, Namita A. Goyal, Jonathan Katz, Matthew Burford, Jenny Li, Haggai Kaspi, Natalie Abramov, Bruno Boulanger, James D. Berry, Katharine Nicholson, Tahseen Mozaffar, Robert Miller, Liberty Jenkins, Robert H. Baloh, Richard Lewis, Nathan P. Staff, Margaret Ayo Owegi, Bob Dagher, Netta R. Blondheim-Shraga, Yael GothelfYossef S. Levy, Ralph Kern, Revital Aricha, Anthony J. Windebank, Robert Bowser, Robert H. Brown, Merit E. Cudkowicz

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)719-729
Number of pages11
JournalMuscle and Nerve
Volume69
Issue number6
Early online date9 Apr 2024
DOIs
StatePublished - Jun 2024
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2024 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.

Keywords

  • amyotrophic lateral sclerosis
  • biomarker
  • cellular therapy

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