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

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posted on 2023-06-09, 11:44 authored by Ruben P A van Eijk, Ashley R Jones, William Sproviero, Aleksey Shatunov, Pamela J Shaw, Nigel LeighNigel Leigh, Carolyn A Young, Christopher E Shaw, Gabriele Mora, Jessica Mandrioli, Giuseppe Borghero, Paolo Volanti, Frank P Diekstra, Wouter van Rheenen, Esther Verstraete, Marinus J C Eijkemans, Jan H Veldink, Adriano Chio, Ammar Al-Chalabi, Leonard H van den Berg, Michael A van Es
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Neurology

ISSN

1526-632X

Publisher

American Academy of Neurology

Issue

18

Volume

89

Page range

1915-1922

Department affiliated with

  • BSMS Neuroscience Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-01-23

First Open Access (FOA) Date

2018-01-23

First Compliant Deposit (FCD) Date

2018-01-23

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