SMA valiant trial: A prospective, double‐blind, placebo‐controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy

Abstract

Introduction An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. Methods There were 33 subjects, aged 20–55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10–20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. Results Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. Conclusions VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.

Strength Testing in Motor Neuron Diseases

“…A small, open-label trial of valproic acid in patients with SMA types III/IV of ages 17 and older showed an increase in strength as measured by HHD in an open-label setting [39]. However, a placebo-controlled trial in adults with SMA also showed no effect, though quantitative strength testing was found to be reliable and reproducible in a trial of valproic acid in SMA [40]; results suggested no benefit but the properties of the strength assessment suggested that it would be a good measure in future trials. Similarly, a trial of type II/III SMA enrolled patients aged 6 to 36 years in a crossover study of growth hormone; HHD was again found to be reliable and reproducible, although the results suggested no effect [41].…”

Drosophila as an In Vivo Model for Human Neurodegenerative Disease

“…The use of HDAC inhibitors has been well advanced in the field of cancer, with many tested in clinical trials, and three approved for cancer therapy (reviewed in Mottamal et al 2015). Phase II clinical trials for the use of HDAC inhibitors for the treatment of the motor neuron disease, spinal muscular atrophy (SMA), yielded initial encouraging results, although these were not confirmed or extended by later studies (Mercuri et al 2004(Mercuri et al , 2007Swoboda et al 2010;Kissel et al 2011Kissel et al , 2014. More research on the specific targets of acetylation, the specific enzymes involved, and the development of more directed compounds are likely required.…”

Investigational therapies for the treatment of spinal muscular atrophy

“…About one-third of SMA patients are positive-responders [89]. Unfortunately, most patients do not show improvements in muscle strength or function [91]; therefore, the need for new drugs for SMA therapy effective in most patients is still urgent.…”

“…Previously drug candidates very often failed to reproduce in SMA patients the positive effect observed in vitro or in vivo [91]. One measure to improve the preclinical studies of potential candidates was to develop more robust assays to assess the compound efficiency [113].…”