Studies Of Hereditary Neurological Disease: Clinical Trials

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The purpose of this research program is to develop safe and effective treatments for hereditary neurological disorders. Specific research accomplishments in the past year include the following: (1) We assessed safety, tolerability, and preliminary efficacy of BVS857, an 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. This was a randomized, double-blind, and placebo-controlled study in SBMA patients recruited at neuromuscular centers in Denmark, Germany, Italy, and three sites within the US. Eligible patients were age 18 years or older with a confirmed genetic diagnosis of SBMA, ambulatory, with symptomatic weakness, and serum IGF-1 levels of 170 ng/mL. 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 by a number scheme. Patients, investigators, and study personnel were masked to treatment assignment. Primary outcome measures included safety, tolerability, and the effects of BVS857 on thigh muscle volume (TMV) by magnetic resonance imaging. For the primary outcome measure of TMV, the ratio of post-baseline to baseline at week 13 was analyzed by analysis of covariance per protocol. 27 patients were randomly assigned to treatment groups and 25 were included in the preliminary efficacy analysis. BVS857 was generally safe with no serious adverse events. A significant difference in TMV was observed in the interventional arm versus placebo with a geometric-mean ratio of 104, and a decrease in TMV from baseline to week 13 in placebo but not in BVS857 treated patients, respectively. There were no significant differences in reported adverse events between the BVS857 and placebo groups. There were also no differences in measures of muscle strength and 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. 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. Additional studies may help to further evaluate the efficacy of activating the IGF-1 pathway in SBMA. (2) The effects of spinal bulbar muscular atrophy (SBMA) on quality of life (QoL) are not well understood. Our study described symptoms from the patient's perspective and the impact these symptoms have on QoL. We conducted open-ended interviews with 21 adult men with genetically confirmed SBMA. Using a qualitative framework technique, we coded and analyzed interviews to identify symptoms and resulting themes. From these interviews, 729 quotations were extracted. We identified 200 SBMA-specific symptoms and 20 symptomatic themes. Weakness was mentioned by all interviewees. Symptoms within the domain of mental health and the specific themes of emotional issues and psychological impact were also frequently mentioned. Numerous symptoms affect QoL for patients with SBMA. We identified previously unrecognized symptoms that are important to address in enhancing clinical care for patients with SBMA and in developing tools to evaluate efficacy in future clinical trials.