Clinical Trial Readiness for Monitoring Muscle Inflammation in Duchenne Muscular Dystrophy

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Abstract Duchenne muscular dystrophy (DMD) is caused by mutations of the X-linked DMD gene, with the majority of mutations now occurring as de novo events due to the high mutation rate. The DMD gene is also one of the largest in the human genome, with 79 exons covering 2.3Mb of Xp21. Carrier screening is problematic due to high mutation rate and large gene size, and the incidence of DMD has not declined significantly over the last decade, remaining at about 1/5,000 live born males. The disease is progressive, with onset of skeletal muscle pathology (inflammation, degeneration/regeneration) present from birth, but clinical symptoms of proximal muscle weakness typically not recognized until early school age (~4 to 6 years). DMD boys typically lose ambulation in the second decade and succumb to respiratory or cardiac failure in 3rd decade unless ventilated. Clinical trials in DMD have expanded dramatically over the last decade, and 5 drugs have been approved. However, 4 of these approvals were based on accelerated approval with dystrophin expression in skeletal muscle as the primary outcome (surrogate biomarker) and clinical efficacy has not yet been demonstrated. Indeed, the approvals of exon skipping drugs have been highly controversial within FDA and clinical research community. The only drug approved on clinical outcomes is deflazacort, with approval based on an academic trial done decades earlier, and this approval was also controversial. Thus, there are no drugs approved based on clinical outcomes in contemporary trials, with many more recent clinical trials using clinical outcomes measures failing to show efficacy based on motor outcomes. A challenge with DMD clinical trials is the progressive nature of the disease with appropriate motor outcomes changing as function of patient age, and the lack of blood biomarkers able to monitor drug effect on muscle inflammation or fibrosis, and/or predict later changes in motor outcomes. In this application for clinical trial readiness in DMD, we propose the study of two serum biomarkers of inflammation, MDC and CD23, that we have previously shown to be responsive to corticosteroid anti-inflammatory treatment in 4 disease states (pediatric DMD, pediatric inflammatory bowel disease, juvenile dermatomyositis, and adult vasculitis). These biomarkers were also shown to be dose- responsive to vamorolone, a novel dissociative steroidal drug under development in DMD, within 2-weeks of treatment, and aided in dose-selection for the recently completed confirmatory, pivotal trial (VBP15-004) in 121 DMD boys. The proposed aims are to determine the extent to which drug-related reductions in MDC and/or CD23 at 3 months treatment anticipate clinical improvement of motor outcomes at 6 months and 12 months treatment. The double-blind VBP15-004 trial randomized DMD boys into 4 arms (placebo, vamorolone 2.0 mg/kg/day, vamorolone 6.0 mg/kg/day, prednisone 0.75 mg/kg/day), and included a cross-over of placebo and prednisone to vamorolone at study midpoint. The VBP15-004 demonstrated efficacy of both 2.0 and 6.0 mg/kg/day vamorolone groups vs. placebo (met primary and 4 sequential secondary outcomes) and showed improved safety vs. prednisone (no stunting of growth, no deleterious changes in bone biomarkers). The anticipated result is that MDC and/or CD23 predict later motor outcomes and can then be routinely integrated into DMD clinical trial designs to monitor systemic and/or muscle inflammatory state.