A placebo-controlled study to evaluate the safety, tolerability, and preliminary efficacy of BVS857 in patients with spinal and bulbar muscular atrophy (S13.003)

Objective: To evaluate the safety, tolerability, and preliminary efficacy of BVS857 in spinal and bulbar muscular atrophy (SBMA). Background: SBMA is an X-linked neuromuscular disease caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene. SBMA is characterized by progressive muscle weakness, atrophy, and fasciculations. Preclinical studies have shown amelioration of disease manifestations with activation of the insulin-like growth factor 1 (IGF-1) pathway. BVS857 is an IGF-1 mimetic; IGF-1 was modified to improve its pharmacological properties. Design/Methods: This study was a double-blind, placebo-controlled study of IGF-1 pathway activation with BVS857 in patients with genetically-confirmed SBMA. Safety and tolerability was first evaluated in Part A with 8 SBMA patients. In Part B, BVS857 was administered as weekly intravenous administration for 12 weeks with a 2:1 drug to placebo randomization in 27 patients. The primary outcome measures included safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) by magnetic resonance imaging (MRI). Secondary and exploratory outcome measurements included measures of muscle strength and function, pharmacokinetic measures, lean body mass (LBM) by dual-energy x-ray absorptiometry (DXA) scan, and pharmacodynamic biomarkers in blood and muscle biopsy samples. Results: BVS857 exposure in SBMA patients was as predicted from pharmacokinetic data in healthy subjects. BVS857 was well tolerated overall with no serious adverse events. However, immunogenicity was detected in 11 of 18 patients treated with BVS857, including cross-reacting antibodies with neutralizing capacity to native IGF-1 in 5 patients. There was no impact on BVS857 and IGF-1 serum profiles and no apparent clinical consequences could be linked to immunogenicity. A significant difference in TMV and a trend in LBM were observed in the interventional arm versus placebo, with a decrease in TMV from baseline to week 13 in placebo but not BVS857 treated patients. BVS857 did not improve study measures of strength or function. Conclusions: TMV remained stable in BVS857 treated SBMA patients after 12 weeks of dosing. The intervention, while well-tolerated, showed a propensity for immunogenicity, and did not improve muscle strength or function. Additional studies may be needed to evaluate the therapeutic efficacy of IGF-1 pathway modulation in this disease. Disclosure: Dr. Grunseich has nothing to disclose. Dr. Miller has received personal compensation for activities with Novartis as an employee. Dr. Swan has received personal compensation from Novartis as an employee. Dr. Glass has received personal compensation for activities with Novartis as an employee. Dr. El Mouelhi has received personal compensation for activities with Novartis Pharmaceuticals as an employee. Dr. Fornaro has received personal compensation for activities with Novartis as an employee. Dr. Petricoul has received personal compensation for activities with Novartis as an employee. Dr. Vositiar has received personal compensation for activities with Novartis as an employee. Dr. Roubenoff has received personal compensation for activities with Novartis as an employee. Dr. Meriggioli has received personal compensation for activities with Novartis. Dr. Vissing has received personal compensation for activities with Alexion Pharmaceuticals and Ultragenyx as an advisory board member. Dr. Soraru has nothing to disclose. Dr. Mozaffar has received personal compensation for activities with Sanofi Genzyme, Grifols, Amicus, Biomarin, Idera Pharmaceuticals and Ultragenyx. Dr. Mozaffar has received research support from Cytokinetics, Alexion, Amicus, Biomarin, Grifols, GlaxoSmithKline, Ultragenyx, and Novartis. Dr. Ludolph has nothing to disclose. Dr. Kissel has received personal compensation for activities with AveXis, Inc. Dr. Fischbeck has nothing to disclose.