Grunseich, Christopher, Miller, Ram, Swan, Therese, Glass, David, El Mouelhi, Mohamed, Fornaro, Mara, Petricoul, Olivier, Vostiar, Igor, Roubenoff, Ronenn, Meriggioli, Matthew, Kokkinis, Angela, Guber, Robert D., Budron, Maher S. , Vissing, John, Soraru, Gianni, Mozaffar, Tahseen, Ludolph, Albert, Kissel, John T and Fischbeck, Kenneth H. (2018) A placebo-controlled study to evaluate the safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy. Lancet Neurology.

Abstract

Background Spinal and bulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor (AR) gene. We assessed safety, tolerability, and preliminary efficacy of BVS857, an insulin like growth factor-1 (IGF-1) mimetic, in SBMA patients. SBMA patients have low IGF-1 levels, and studies of IGF-1 showed benefit in a transgenic model of SBMA. A study of BVS857 in healthy volunteers showed it to be well tolerated.
Methods This study was double-blind, and placebo-controlled. Following a safety and tolerability evaluation with 8 SBMA patients, BVS857 was administered weekly for 12 weeks to 27 patients, with 2:1 drug to placebo randomization. Primary outcome measures included safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) by magnetic resonance imaging. Secondary and exploratory outcome measurements included pharmacokinetics, muscle strength and function, lean body mass by dual-energy x-ray absorptiometry scan, and pharmacodynamic biomarkers in blood and muscle biopsy samples.
Findings BVS857 was generally safe with no serious adverse events. A significant difference in TMV was observed in the interventional arm versus placebo, with a decrease in TMV from baseline to week 13 in placebo but not in BVS857 treated patients. There was no difference in study measures of muscle strength or function. Immunogenicity was detected in 11 of 18 patients treated with BVS857, including cross-reacting antibodies with neutralizing capacity to endogenous IGF-1 in 5 patients.
Interpretation TMV remained stable in BVS857 treated SBMA patients after 12 weeks of dosing. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Treatment with BVS857 for 12 weeks did not demonstrate benefit in SBMA. Additional studies may be needed to evaluate the efficacy of activating the IGF-1 pathway.

Item Type:	Article
Date Deposited:	30 Oct 2018 00:45
Last Modified:	30 Oct 2018 00:45
URI:	https://oak.novartis.com/id/eprint/35285