Evaluation of the Biodistribution, Efficacy, and Side-Effect Profile of Deflazacort, Prednisolone and Vamorolone in a DMD Mouse Model


Pre-Clinical Research

Poster Number: 245


Grace Liu, PhD, PTC Therapeutics, Inc., Phil Lipari, PTC Therapeutics Inc., Anna Mollin, PTC Therapeutics Inc., Stephen Jung, PTC Therapeutics Inc., Irina Teplova, PTC Therapeutics Inc., Marcia Ma, PTC Therapeutics Inc., Wencheng Li, PTC Therapeutics Inc., Lanqing Ying, PTC Therapeutics Inc., Shirley Yeh, PTC Therapeutics Inc., Jana Narasimhan, PTC Therapeutics Inc., Pannie (Panayiota) Trifillis, PhD, PTC Therapeutics, Inc., Efthimia Leonardi, PhD, PTC Therapeutics Inc., Ellen Welch, PTC Therapeutics Inc., Gregory Voronin, PTC Therapeutics Inc., Karyn Koladicz, MD, PTC Therapeutics, Nicholas Mastrandrea, PhD, PTC Therapeutics, Marla Weetall, PTC Therapeutics

Background: Corticosteroids are the standard of care for patients with Duchenne muscular dystrophy (DMD). In this report, we present the first direct comparison of three corticosteroids: deflazacort, prednisolone and vamorolone in mice.

Objectives: The goal was to compare the biodistribution, efficacy and side-effects of deflazacort, prednisolone and vamorolone in the wild-type adult mice and the mdx-B10 DMD mouse model.

Methods: The pharmacokinetics and biodistribution of deflazacort, prednisolone and vamorolone were evaluated in wild-type adult mice after oral administration. Efficacy was evaluated in adult mdx-B10 DMD mice by measuring grip strength. Side-effects were evaluated by monitoring changes in behavior, bone density, endogenous corticosteroid levels, and blood glucose levels. Changes in gene expression in the brain, liver, and muscle were evaluated using RNA sequencing.

Results: These compounds differed in their biodistribution in the mouse CNS, with deflazacort showing a lower brain:plasma ratio (0.05) than vamorolone (0.55). All three corticosteroids demonstrated efficacy in mdx mice and side-effects at doses associated with efficacy. After 14 days of treatment, prednisolone and vamorolone extensively altered gene expression in the brains of mdx mice, compared with deflazacort. All three corticosteroids induced extensive changes in gene expression in the muscle and the liver. After 28 days, mdx mice treated with deflazacort showed a greater improvement in grip strength than those treated with prednisolone or vamorolone. Vamorolone and prednisolone induced greater depression than deflazacort (1.6-fold longer in time spent immobile for vamorolone- and prednisolone-treated mice, with no increase in time spent immobile for deflazacort-treated mice).

Conclusions: This is the first direct comparison of the dose response of deflazacort, prednisolone and vamorolone in wild-type adult mice and a mouse model of DMD. Deflazacort was the most effective in increasing muscle strength, as measured by the grip test. Furthermore, of the three corticosteroids, deflazacort resulted in the fewest behavioral side-effects.