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


BACKGROUND
ClinicalTrials.gov.
Departments of Neurology, Pediatrics, Neonatology and General Clinical Research Center, University of Utah School of Medicine, Salt Lake City, Utah, United States of America.
Kathryn J
KJ
Swoboda
Charles B
CB
Scott
Sandra P
SP
Reyna
Thomas W
TW
Prior
Bernard
B
LaSalle
Susan L
SL
Sorenson
Janine
J
Wood
Gyula
G
Acsadi
Thomas O
TO
Crawford
John T
JT
Kissel
Kristin J
KJ
Krosschell
Guy
G
D'Anjou
Mark B
MB
Bromberg
Mary K
MK
Schroth
Gary M
GM
Chan
Bakri
B
Elsheikh
Louise R
LR
Simard
D015502:Absorptiometry, Photon; D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001823:Body Composition / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D009134:Muscular Atrophy, Spinal / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009460:Neurologic Examination; D012129:Respiratory Function Tests; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D016896:Treatment Outcome; D014635:Valproic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D055815:Young Adult
D004791:Enzyme Inhibitors; C526477:SMN2 protein, human; D055540:Survival of Motor Neuron 2 Protein; D014635:Valproic Acid