Phase II open label study of valproic acid in spinal muscular atrophy

PLoS One. 2009;4(5):e5268. doi: 10.1371/journal.pone.0005268. Epub 2009 May 14.

Abstract

Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2-3 years, 29 SMA type II ages 2-14 years and 11 type III ages 2-31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p<or=0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Delta7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p<or=0.0036) and maximum ulnar CMAP scores (p<or=0.0001) increased significantly.

Conclusions: While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects.

Trial registration: ClinicalTrials.gov.

Trial registration: ClinicalTrials.gov NCT00374075.

Publication types

  • Clinical Trial, Phase II
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Absorptiometry, Photon
  • Adolescent
  • Adult
  • Analysis of Variance
  • Body Composition / drug effects
  • Bone Density / drug effects
  • Child
  • Child, Preschool
  • Electrophysiology
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Humans
  • Muscular Atrophy, Spinal / drug therapy*
  • Muscular Atrophy, Spinal / genetics
  • Muscular Atrophy, Spinal / pathology
  • Neurologic Examination
  • Respiratory Function Tests
  • Survival of Motor Neuron 2 Protein / genetics
  • Treatment Outcome
  • Valproic Acid / administration & dosage
  • Valproic Acid / adverse effects
  • Valproic Acid / pharmacology
  • Valproic Acid / therapeutic use*
  • Young Adult

Substances

  • Enzyme Inhibitors
  • SMN2 protein, human
  • Survival of Motor Neuron 2 Protein
  • Valproic Acid

Associated data

  • ClinicalTrials.gov/NCT00374075