Riluzole and spinocerebellar ataxia type 2: the ATRIL trial

The search for neuroprotective therapies for the spinocerebellar ataxias remains challenging because of the huge clinical and genetic heterogeneity and low prevalence of these disorders, as well as the absence of objective biomarkers for disease progression. However, efforts persist in the clinical development of gene therapies, in the search for novel drugs, and in the repurposing of neuroprotective agents already approved for neurodegenerative diseases with overlapping pathophysiology. 1 Buijsen RAM Toonen LJA Gardiner SL van Roon-Mom WMC Genetics, mechanisms, and therapeutic progress in polyglutamine spinocerebellar ataxias. Neurotherapeutics. 2019; 16: 263-286 Google Scholar This is the case for riluzole, a glutamate release inhibitor and activator of calcium-activated potassium channels that has shown evidence of efficacy in targeting glutamatergic excitotoxicity and modulating potassium channel activity in spinocerebellar ataxias. Two previous phase 2 clinical trials in mixed cohorts of patients with different cerebellar ataxias provided promising evidence of a beneficial effect of riluzole on motor impairment, 2 Ristori G Romano S Visconti A et al. Riluzole in cerebellar ataxia: a randomized, double-blind, placebo-controlled pilot trial. Neurology. 2010; 74: 839-845 Google Scholar , 3 Romano S Coarelli G Marcotulli C et al. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2015; 14: 985-991 Google Scholar but the evidence from animal models has been inconsistent. 4 Schmidt J Schmidt T Golla M et al. In vivo assessment of riluzole as a potential therapeutic drug for spinocerebellar ataxia type 3. J Neurochem. 2016; 138: 150-162 Google Scholar , 5 Nag N Tarlac V Storey E Assessing the efficacy of specific cerebellomodulatory drugs for use as therapy for spinocerebellar ataxia type 1. Cerebellum. 2013; 12: 74-82 Google Scholar Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trialWe were able to recruit 45 patients moderately affected by spinocerebellar ataxia type 2 for this trial. Riluzole did not improve clinical or radiological outcomes in these patients. However, our findings provide data on progression of spinocerebellar ataxia type 2 that might prove to be valuable for the design of other clinical trials. Full-Text PDF