Effect of sodium phenylbutyrate and taurursodiol on plasma concentrations of neuroinflammatory biomarkers in amyotrophic lateral sclerosis: results from the CENTAUR trial.

BACKGROUND

An oral sodium phenylbutyrate and taurursodiol combination (PB and TURSO) significantly reduced functional decline in people living with amyotrophic lateral sclerosis (ALS) in the CENTAUR trial. Biomarkers linking clinical therapeutic effect with biological changes are of high interest in ALS. We performed analyses of neuroinflammatory biomarkers associated with ALS in the literature, including YKL-40 (also known as chitinase-3-like protein 1), chitinase 1 (CHIT1) and C reactive protein (CRP), in plasma samples collected in CENTAUR.

METHODS

Log10-transformed plasma biomarker measurements were analysed using a linear mixed-effects model. Correlation between paired biomarker concentrations and ALS Functional Rating Scale-Revised (ALSFRS-R) total scores was assessed via Pearson correlation coefficients.

RESULTS

By week 24, geometric least squares mean YKL-40 plasma concentration decreased by approximately 20% (p=0.008) and CRP by 30% (p=0.048) in the PB and TURSO versus placebo group. YKL-40 (r of -0.21; p<0.0001) and CRP (r of -0.19; p=0.0002) concentration correlated with ALSFRS-R total score. CHIT1 levels were not significantly different between groups.

CONCLUSIONS

YKL-40 and CRP plasma levels were significantly reduced in participants with ALS receiving PB and TURSO in CENTAUR and correlated with disease progression. These findings suggest YKL-40 and CRP could be treatment-sensitive biomarkers in ALS, pending further confirmatory studies.

TRIAL REGISTRATION NUMBER

https://clinicaltrials.gov/study/NCT03127514.

Informations de copyright

© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Déclaration de conflit d'intérêts

Competing interests: RB reports receiving laboratory supplies from nVector for the biomarker assays used in these analyses; consulting fees from MT Pharma, RRD International, BrainStorm and Cell Therapeutics unrelated to this manuscript; consulting fees from Amylyx Pharmaceuticals, Inc., related to this manuscript; a pending patent with nVector; and stock options in nVector, AcuraStem and Aural Analytics. JA reports stock options in nVector. LM, JC and JT are full-time employees of and have stock option ownership in Amylyx. MC reports consulting fees from Lilly, Immunity Pharm Ltd, Orion, Cytokinetics, Wave Life Sciences, Takeda, Avexis, Biogen, Helixsmith, Sunovian Pharmaceuticals Inc., Disarm, ALSpharma, RRD International, Transposon, QurAlis, Regeneron Pharmaceuticals, AB Science, Locust Walk, NeuroSense Therapeutics, Faze Medicines, Arrowhead Pharmaceuticals, VectorY Therapeutics, Servier, Eledon Pharmaceuticals, Pasithea Therapeutics and Denali Therapeutics and stock in Praxis. SP reports research grants from Amylyx related to this manuscript; research grants from the National Institutes of Health, Alector Therapeutics, Biohaven, Cytokinetics, Anelixis Pharmaceuticals, Revalesio Corporation, UCB, Clene, Prilenia, Seelos Therapeutics, Calico and Denali Therapeutics unrelated to this manuscript; consulting fees from Frequency Therapeutics, SOLA Pharmaceuticals, Stealth BioTherapeutics, Orion, Roche, Janssen, Arrowhead and Amylyx; honoraria from Medscape; and board membership in the Association of Academic Physiatrists.