A Prospective, Randomized Controlled Trial of Valproic Acid in Ambulant Adults with SMA: The VALIANT Trial (S25.002)

Abstract

Objective: To report the results of a randomized, double-blind, placebo-controlled trial of valproic acid (VPA) in ambulatory adults with spinal muscular atrophy (SMA). Background Much evidence suggests that VPA, a histone deacetylase inhibitor, might benefit patients with SMA by modulating SMN2 splicing to increase production of full-length SMN transcript from SMN2 . Five open-label human trials of VPA in SMA showed a benefit in strength and function. Design/Methods: This was a prospective, randomized, double blind, 12 month study in SMA adults over 18 years old. After two baseline assessments, subjects were randomized to VPA or placebo and then crossed over to the other group at six months. Patients were evaluated at 3, 6, and 12 months. Primary outcome was the six-month strength change by maximum voluntary isometric contraction testing. Secondary outcomes included adverse events and changes in ulnar compound motor action potential amplitude and motor unit number estimation, strength by handheld dynamometry, 6 minute walk test, pulmonary function, functional rating scale (SMAFRS), and quality of life assessment. Results: Thirty-three subjects (20 M, 13 F; mean age 37.1) were enrolled; 16 patients were initially on VPA and 17 on placebo. Three patients did not complete the study; two due to adverse events not related to VPA and one withdrew. There were no significant adverse events. There was no significant change in the primary or secondary outcome after six months of treatment. Conclusions: VPA at doses used in this study did not improve strength or function in ambulatory SMA adults, and is compatible with earlier published negative CARNI-VAL studies in SMA children. The Project Cure-SMA group is currently analyzing data from open label studies in infants with Type 1 that should provide additional important information on VPA and its effect on biomarkers. Supported by: This study was entirely funded by FSMA through the Project Cure Investigators Network, and NIH CCTS funding at Ohio State. Disclosure: Dr. Elsheikh has nothing to disclose. Dr. Kolb has nothing to disclose. Dr. King has nothing to disclose. Dr. Chelnick has nothing to disclose. Dr. Scott has nothing to disclose. Dr. LaSalle has nothing to disclose. Dr. Krosschell has nothing to disclose. Dr. Reyna has nothing to disclose. Dr. Swoboda has received research support from BioMarin Pharmaceuticals and Orphamed, Dr. Kissel has nothing to disclose.