P22\u2005ADME properties of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug

Abstract

Background Vamorolone is a first-in-class dissociative steroidal drug currently in Phase 2b/3 clinical trials in four to seven-year old boys with Duchenne muscular dystrophy (DMD). Recent published findings from a Phase 2a study in DMD boys have demonstrated that vamorolone is well-tolerated through the highest dose tested (6 mg/kg/day; two-weeks treatment) and shows a similar pharmacokinetic profile to prednisolone.1 The objective of the current study was to assess the ADME (absorption, distribution, metabolism, excretion) properties of vamorolone using in vivo quantitative whole-body autoradiography (QWBA) and mass balance experimentation in rats. Methods For the QWBA study, Long Evans (LE) rats were dosed with 14C-labeled vamorolone and sacrificed after a defined time interval (6 groups with n=5 rats per time interval). Each frozen rat carcass was embedded in a carboxymethylcellulose matrix and cyrosectioned. Autoradiography images were acquired, analyzed, and the radioactivity in each tissue was quantified. For the mass balance study, LE rats (n=6) were dosed with 14C-labeled vamorolone. Urine and feces were collected from each animal at defined time intervals. Results The QWBA study demonstrated a widespread distribution of vamorolone amongst body organs with a peak absorption between 2–6 hours for most structures. In gastrointestinal tract organs, the peak absorption fell between the 6 and 24-hour time points. The mass balance study revealed that vamorolone was eliminated to low steady state levels by 5 days post administration in urine and 7 days post administration in feces. Conclusions This study provides crucial information regarding the ADME properties of vamorolone. The results will help guide the design of a human mass balance study scheduled to take place in late 2019 or early 2020. Reference Conklin LS, Damsker JM, Hoffman EP, et al. Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. Pharma Res. 2018; 136: 140–150. Disclosure(s) Jesse M. Damsker and John M. McCall are employees of ReveraGen BioPharma Inc. and have stock options and founder shares, respectively.