VBP15, an Innovative Steroid-like Intervention on DMD: VISION-DMD

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DESCRIPTION (provided by applicant): The most effective drug identified to date for Duchenne muscular dystrophy (DMD) is daily high dose glucocorticoids (prednisone, deflazacort). However, the benefits of the anti-inflammatory pharmacological activities of glucocorticoids may not be realized for a patient with DMD, or indeed with one of a large number of diverse inflammatory conditions, due to unacceptable side effects of the therapy. The balance of efficacy and side effects leads to significant variation in glucocorticoid use for the clinical management of DMD due to side effects of short stature, osteopenia, mood changes, and altered muscle bulk. A novel dissociative steroid, VBP15, was developed with a more optimal risk-benefit ratio for the treatment of youth with DMD. Preclinical research with VBP15 showed that the anti-inflammatory mechanism, due largely to inhibition of NF-κB activation, is further augmented by beneficial modulation of leukocyte extravasation and increased plasma membrane stabilization. Furthermore, VBP15 has significantly less binding to the glucocorticoid response element (GRE) in target gene enhancers and repressors. Preclinical studies demonstrate that reduced GRE binding results in fewer adverse effects and suggests that there will be fewer glucocorticoid-induced side effects in humans treated with VBP15. Extensive preclinical efficacy and toxicology research support the development of VBP15 for first-in-human clinical use. In multiple pre-clinical models of inflammatory disease, including the mdx murine model of DMD, VBP15 reduces side effects, widens therapeutic windows, and retains or enhances efficacy relative to traditional glucocorticoids. In this application, we propose planning activities to support a Phase 2a (safety, tolerability, dose-finding, PK and PD) clinical trial of VBP15. An extension to this Phase 2a study will integrate pharmacodynamics biomarker panels and MRI outcomes to query time-dependent effects on inflammation and membrane stability in young (4-7 yr. old) DMD patients.