Vamorolone trial in Becker muscular dystrophy

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Abstract Becker dystrophy is caused by partial loss of function of the dystrophin protein in muscle tissues and some non-muscle cells, with progressive dysfunction of skeletal and cardiac muscle. Mutations of the DMD gene cause both Becker dystrophy and Duchenne muscular dystrophy (DMD); DMD is complete loss of dystrophin, whereas Becker dystrophy patients retain partly functional dystrophin in muscle that reduces the severity of the progressive disease. Therapeutic efforts for DMD have significantly advanced over the last decade, with 4 drugs now approved by FDA for DMD. Clinical research in Becker dystrophy is under-represented relative to DMD, with no drugs approved, and few drug development efforts. This discordance in therapeutic efforts is likely partly due to somewhat lower prevalence of Becker dystrophy vs. DMD in the USA (Becker dystrophy 0.36/10,000; DMD 1.02/10,000), and the very variable clinical phenotype of Becker dystrophy (complicating interpretation of outcomes in clinical trials). Corticosteroids (prednisone and Emflaza) are considered standard of care for DMD, but not Becker dystrophy, as patients and their physicians generally feel that the poor safety profile of chronic corticosteroid use outweighs benefits in strength and mobility. Here, we seek to initiate clinical development of vamorolone (a partial dissociative agonist of the glucocorticoid receptor, and antagonist of the mineralocorticoid receptor) for Becker dystrophy. Vamorolone shows unique structure/activity relationships compared to the corticosteroid class and has shown preliminary data in DMD suggestive of retention of efficacy but loss of safety concerns of the corticosteroid class of drugs. Vamorolone may show improved efficacy in Becker dystrophy compared to DMD, as vamorolone has been shown to inhibit dystrophin mRNA- targeting microRNAs, and thus is anticipated to increase dystrophin levels in Becker dystrophy patient muscle. Thus, vamorolone may have multiple mechanisms of action of efficacy in Becker dystrophy: 1. Inhibition of pro- inflammatory NF-κB pathways; 2. Increase in dystrophin content of muscle via dystrophin-targeting microRNA inhibition; 3. Cardiac benefit via mineralocorticoid antagonism. Aim 1 of the proposed research is to evaluate safety, tolerability, and efficacy of 6mg/kg/day vamorolone for 24 weeks treatment of patients with Becker dystrophy. Aim 2 is to evaluate treatment responsiveness of serum biomarkers over 24 weeks vamorolone treatment of patients with Becker dystrophy. Aim 3 is to use open-label functional outcome data (NSAA, TTRW), carry out sample size calculations to adequately power and design a registration trial of vamorolone in Becker dystrophy.