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

Abstract：

: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.

journal_name

Pharmacol Res

journal_title

Pharmacological research

authors

Conklin LS,Damsker JM,Hoffman EP,Jusko WJ,Mavroudis PD,Schwartz BD,Mengle-Gaw 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

doi

10.1016/j.phrs.2018.09.007

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

140-150

eissn

1043-6618

issn

1096-1186

pii

S1043-6618(18)30975-7

journal_volume

136

pub_type

杂志文章,多中心研究

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