Abstract ReveraGen BioPharma is a clinical stage drug development company that is developing vamorolone (VBP15), a first-in-class dissociative steroidal drug. The initial indication being tested is Duchenne muscular dystrophy (DMD), where vamorolone holds promise for retaining or increasing efficacy of glucocorticoids, while reducing adverse effects (bone fragility, stunting of growth, weight gain, insulin resistance). ReveraGen received a NINDS SBIR Phase II grant in support of the Phase 2a studies in 4 to <7 year old DMD boys in 2016 (protocols VBP15-002; VBP15-003) (R44NS095423). The original trial was planned for four dose groups, with 2-6 boys per dose group (up to 24 patients). After award of the grant, the size of the trial was increased to 48 DMD boys (12 per dose group; n=48). Despite the narrow age range in a rare disease, the trial was fully enrolled within 15 months, and the Phase 2a study completed in November 2017, within the time frame of the SBIR Phase II grant (15 February 2016-31 January 2018). All doses were well-tolerated (0.25 mg/k/gday ? 6.0 mg/kg/day; or to 10-times the typical prednisone dose in DMD boys). Pharmacokinetics showed a well- behaved drug, with PK similar to corticosteroids (short half-life of 2-3 hrs, and no drug accumulation between doses). There was no significant change in body mass index (primary clinical safety outcome relative to prednisone). Pharmacodynamic biomarker results showed improved safety compared to corticosteroids, with no evidence of insulin resistance at any dose, and a >10 fold improved safety margin for bone turnover and adrenal suppression. Here, we request partial support for the pivotal double blind Phase 2b study of 120 DMD boys, ages 4 to <7 years. The Phase 2b study (VBP15-004) includes four groups with six months treatment (placebo, prednisone, low dose vamorolone, high dose vamorolone), followed by an additional 6 months treatment with two dose levels of vamorolone. Co-funding for the Phase 2b study is from the European Commission ($7M Horizons 2020 grant awarded in 2016), venture philanthropy support by non-profit foundations, and an option agreement for future sales and marketing. Aim 1 is to test 6 months of treatment of two dose levels of vamorolone, with efficacy (time to stand) vs. placebo, and safety (change in body mass index) vs. prednisone. Aim 2 is to bridge pharmacodynamic biomarkers to clinical outcomes of both safety and efficacy. Anticipated new matching funding during the proposed award period includes a 2nd milestone payment on the option agreement ($15M August 2018). The completion of the proposed Phase IIB SBIR research will lead to discussions with the FDA regarding possible accelerated approval, with Phase III trials in the post-marketing period. The bridging of novel safety and efficacy biomarkers to clinical outcomes will enable the utilization of these biomarkers to expand labeling to younger DMD children (0-4 years), and efficient testing of vamorolone for treatment of new indications (eg. Becker muscular dystrophy, juvenile dermatomyositis), thus providing the potential to significantly augment the treatment options and quality of life for patients with genetic and autoimmune neuromuscular disorders.