Meta-analysis of pharmacogenetic interactions in amyotrophic lateral sclerosis clinical trials.

Abstract:

OBJECTIVE:To assess whether genetic subgroups in recent amyotrophic lateral sclerosis (ALS) trials responded to treatment with lithium carbonate, but that the treatment effect was lost in a large cohort of nonresponders. METHODS:Individual participant data were obtained from 3 randomized trials investigating the efficacy of lithium carbonate. We matched clinical data with data regarding the UNC13A and C9orf72 genotype. Our primary outcome was survival at 12 months. On an exploratory basis, we assessed whether the effect of lithium depended on the genotype. RESULTS:Clinical data were available for 518 of the 606 participants. Overall, treatment with lithium carbonate did not improve 12-month survival (hazard ratio [HR] 1.0, 95% confidence interval [CI] 0.7-1.4; p = 0.96). Both the UNC13A and C9orf72 genotype were independent predictors of survival (HR 2.4, 95% CI 1.3-4.3; p = 0.006 and HR 2.5, 95% CI 1.1-5.2; p = 0.032, respectively). The effect of lithium was different for UNC13A carriers (p = 0.027), but not for C9orf72 carriers (p = 0.22). The 12-month survival probability for UNC13A carriers treated with lithium carbonate improved from 40.1% (95% CI 23.2-69.1) to 69.7% (95% CI 50.4-96.3). CONCLUSIONS:This study incorporated genetic data into past ALS trials to determine treatment effects in a genetic post hoc analysis. Our results suggest that we should reorient our strategies toward finding treatments for ALS, start focusing on genotype-targeted treatments, and standardize genotyping in order to optimize randomization and analysis for future clinical trials.

journal_name

Neurology

journal_title

Neurology

authors

van Eijk RPA,Jones AR,Sproviero W,Shatunov A,Shaw PJ,Leigh PN,Young CA,Shaw CE,Mora G,Mandrioli J,Borghero G,Volanti P,Diekstra FP,van Rheenen W,Verstraete E,Eijkemans MJC,Veldink JH,Chio A,Al-Chalabi A,van den Berg

doi

10.1212/WNL.0000000000004606

subject

Has Abstract

pub_date

2017-10-31 00:00:00

pages

1915-1922

issue

18

eissn

0028-3878

issn

1526-632X

pii

WNL.0000000000004606

journal_volume

89

pub_type

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