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Scientific Articles

Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug

key information

source: Pharmacological Research

year: 2018

authors: Conklinab LS, Damskera JM, Hoffmana EP, Jusko WJ, Mavroudisd PD, Schwartze BD, Mengle-Gawe LJ, Smith EC, Mah JK, Guglieri M, Nevo Y, Kuntz N, McDonald CM, Tulinius M, Ryan MM, Webster R, Castro D, Finkel RS, Smith AL, Morgenroth LP, Arrieta A, Shimony M, Jaros M, Shaler P, McCall JM, Hathout Y, Nagaraju K, van den Anker J, Ward LM, Ahmet A, Cornish MR, Clemens, PR


We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.

organization: ReveraGen Biopharma, LLC, USA; Children’s National Health System, George Washington University, USA; Binghamton University- SUNY, Binghamton, USA; State University of New York-Buffalo, USA; Camden Group, LLC, USA; Duke University, USA; University of Calgary, Alberta Children’s Hospital, Canada; Newcastle University, UK; Schneider Children’s Medical Center of Israel, Tel Aviv University, Israel; Ann & Robert H. Lurie Children’s Hospital, USA; University of California, USA; Queen Silvia Children’s Hospital, Sweden; Royal Children’s Hospital, University of Melbourne, Australia; The Children’s Hospital at Westmead, Australia; University of Texas Southwestern, USA; Nemours Children’s Hospital, USA; TRiNDS LLC, USA; Summit Analytical, USA; Children’s Hospital of Eastern Ontario, Canada; University of Pittsburgh and Department of Veterans Affairs Medical Center, USA

DOI: 10.1016/j.phrs.2018.09.007

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