AGAMREE (Vamorolone) improves Becker muscular dystrophy and increases dystrophin protein in novel bmx model mice


Pre-Clinical Research

Poster Number: S7


Christopher Heier, PhD, Virginia Commonwealth University, Nikki McCormack, PhD, Children's National Hospital, Alyson Fiorillo, PhD, Virginia Commonwealth University

There is currently no approved therapy for Becker muscular dystrophy (BMD), a genetic muscle disease caused by in-frame deletions of the dystrophin gene. While glucocorticoids are standard of care for the allelic, dystrophin-null disease Duchenne muscular dystrophy (DMD), few BMD patients are prescribed these drugs due to the harsh side effects associated with chronic administration. We previously developed vamorolone (now FDA approved for DMD) as a first-in-class dissociative corticosteroid in DMD model mdx mice, finding it improves disease while bypassing several adverse side effects caused by traditional glucocorticoids. Additionally, we found vamorolone reduces expression of dystrophin-targeting microRNAs (DTMs). These data suggest a hypothesis that vamorolone can provide a therapy for BMD by safely reducing inflammatory signaling in skeletal muscle and through a novel mechanism of increasing dystrophin protein levels by suppressing DTM expression. Here we test this hypothesis in bmx mice, a mouse model of BMD which we generated through deletion of murine exons 45 through 47. This mutation recreates a common BMD genotype which frequently presents clinically with more severe pathology with earlier onset of cardiomyopathy. We find daily oral treatment with vamorolone or prednisolone improves bmx strength through grip strength and hang time assays. Examining histopathology, both drugs normalize fiber size and decrease the percentage of centrally nucleated fibers. Importantly, vamorolone shows improved safety in dystrophic mice by avoiding the induction of bone loss, anxiety behavior and stunted growth, key side effects that are apparent in prednisolone treatment. Intriguingly, we also find vamorolone increases Becker-like dystrophin protein levels in both skeletal muscle and heart in bmx mice. This data indicates vamorolone, recently FDA approved for DMD and now in clinical trials for BMD, shows efficacy and safety in BMD model mice.