Abstract
There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10–6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.
Highlights
Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disorder and the commonest neurodegenerative condition in young adults
As the samples were randomly selected from the entire clinical trial cohort, no differences were observed between Group O and Group P, or between these groups and the
Our findings provide compelling proof of concept that pharmacometabolomic approaches add important insights in drug trials of ALS
Summary
Amyotrophic Lateral Sclerosis (ALS) is the most common motor neuron disorder and the commonest neurodegenerative condition in young adults. Olesoxime is a small molecular weight chemical compound with neuroprotective and neurodegenerative properties [4, 5] This cholesterol-like molecule is likely to affect mitochondrial permeability, and has shown promising results in cell cultures and rodent models of neurodegenerative conditions [5]. Based on these preliminary findings, a Phase III clinical trial was undertaken in Europe to evaluate the efficacy of olesoxime in ALS. A post-hoc analysis has been performed using a state-of-the-art pharmaco-metabolomics approach with three specific goals: (1) to establish whether the combination of olesoxime and riluzole led to specific metabolic changes compared to riluzole therapy alone (2) to evaluate the relationship between metabolic patterns and clinical progression and (3) to evaluate if the prognostic value of early blood metabolomic profiles
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