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 Gothelf; Yossef S. Levy; Ralph Kern; Revital Aricha; Anthony J. Windebank; Robert Bowser; Robert H. Brown; Merit E. Cudkowicz

doi:10.1002/mus.28093

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

Neurology

Research output: Contribution to journal › Article › peer-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 language	English (US)
Pages (from-to)	719-729
Number of pages	11
Journal	Muscle and Nerve
Volume	69
Issue number	6
DOIs	https://doi.org/10.1002/mus.28093
State	Published - Jun 2024

Keywords

amyotrophic lateral sclerosis
biomarker
cellular therapy

ASJC Scopus subject areas

Physiology
Clinical Neurology
Cellular and Molecular Neuroscience
Physiology (medical)

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10.1002/mus.28093

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Lindborg, S. R., Goyal, N. A., Katz, J., Burford, M., Li, J., Kaspi, H., Abramov, N., Boulanger, B., Berry, J. D., Nicholson, K., Mozaffar, T., Miller, R., Jenkins, L., Baloh, R. H., Lewis, R., Staff, N. P., Owegi, M. A., Dagher, B., Blondheim-Shraga, N. R., ... Cudkowicz, M. E. (2024). Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes. Muscle and Nerve, 69(6), 719-729. https://doi.org/10.1002/mus.28093

Lindborg, SR, Goyal, NA, Katz, J, Burford, M, Li, J, Kaspi, H, Abramov, N, Boulanger, B, Berry, JD, Nicholson, K, Mozaffar, T, Miller, R, Jenkins, L, Baloh, RH, Lewis, R, Staff, NP, Owegi, MA, Dagher, B, Blondheim-Shraga, NR, Gothelf, Y, Levy, YS, Kern, R, Aricha, R, Windebank, AJ, Bowser, R, Brown, RH & Cudkowicz, ME 2024, 'Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes', Muscle and Nerve, vol. 69, no. 6, pp. 719-729. https://doi.org/10.1002/mus.28093

@article{359e4c7561364fcdbe99c0ca4f125f95,

title = "Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes",

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 = "amyotrophic lateral sclerosis, biomarker, cellular therapy",

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

note = "Publisher Copyright: {\textcopyright} 2024 The Authors. Muscle & Nerve published by Wiley Periodicals LLC.",

year = "2024",

month = jun,

doi = "10.1002/mus.28093",

language = "English (US)",

volume = "69",

pages = "719--729",

journal = "Muscle and Nerve",

issn = "0148-639X",

publisher = "John Wiley and Sons Inc.",

number = "6",

}

TY - JOUR

T1 - Debamestrocel multimodal effects on biomarker pathways in amyotrophic lateral sclerosis are linked to clinical outcomes

AU - Lindborg, Stacy R.

AU - Goyal, Namita A.

AU - Katz, Jonathan

AU - Burford, Matthew

AU - Li, Jenny

AU - Kaspi, Haggai

AU - Abramov, Natalie

AU - Boulanger, Bruno

AU - Berry, James D.

AU - Nicholson, Katharine

AU - Mozaffar, Tahseen

AU - Miller, Robert

AU - Jenkins, Liberty

AU - Baloh, Robert H.

AU - Lewis, Richard

AU - Staff, Nathan P.

AU - Owegi, Margaret Ayo

AU - Dagher, Bob

AU - Blondheim-Shraga, Netta R.

AU - Gothelf, Yael

AU - Levy, Yossef S.

AU - Kern, Ralph

AU - Aricha, Revital

AU - Windebank, Anthony J.

AU - Bowser, Robert

AU - Brown, Robert H.

AU - Cudkowicz, Merit E.

PY - 2024/6

Y1 - 2024/6

N2 - 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.

AB - 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.

KW - amyotrophic lateral sclerosis

KW - biomarker

KW - cellular therapy

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ER -

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

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