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Abstract Details

Evaluation of the Biodistribution, Efficacy, and Side-Effect Profile of Deflazacort, Prednisolone and Vamorolone in a DMD Mouse Model
Child Neurology and Developmental Neurology
S34 - Child Neurology and Developmental Neurology 2 (2:48 PM-3:00 PM)
010

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.

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.

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.

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). 

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.

Authors/Disclosures
Grace Liu, PhD (PTC Therapeutics, Inc.)
PRESENTER
Dr. Liu has nothing to disclose.
Philip Lipari (PTC Therapeutics) Mr. Lipari has received personal compensation for serving as an employee of PTC Terapeutics.
Anna Mollin (PTC THERAPEUTICS) Mrs. Mollin has received personal compensation for serving as an employee of PTC Therapeutics. Mrs. Mollin has stock in PTC THERAPEUTICS.
Stephen Patrick Jung (PTC Therapeutics) Mr. Jung has received personal compensation for serving as an employee of PTC Therapeutics. Mr. Jung has stock in AbbVie. Mr. Jung has stock in Agilon Health. Mr. Jung has stock in AmeriSourceBergen. Mr. Jung has stock in Abbott Laboratories. Mr. Jung has stock in Aflac. Mr. Jung has stock in Amgen. Mr. Jung has stock in Axa SA. Mr. Jung has stock in BASF. Mr. Jung has stock in Becton, Dickinson and Co. Mr. Jung has stock in BeiGene. Mr. Jung has stock in Boston Scientific. Mr. Jung has stock in Cardinal Health. Mr. Jung has stock in Cigna. Mr. Jung has stock in CNO Financial Group. Mr. Jung has stock in DexCom. Mr. Jung has stock in Icon plc. Mr. Jung has stock in Medtronic plc. Mr. Jung has stock in Elevance Health. Mr. Jung has stock in EXACT Sciences. Mr. Jung has stock in CVS Health. Mr. Jung has stock in Centene. Mr. Jung has stock in Certara. Mr. Jung has stock in Colgate-Palmolive. Mr. Jung has stock in Danaher. Mr. Jung has stock in DuPont de Nemours. Mr. Jung has stock in Edwards Lifesciences. Mr. Jung has stock in Elekta. Mr. Jung has stock in General Electric. Mr. Jung has stock in Genmab A/S. Mr. Jung has stock in Gilead Sciences. Mr. Jung has stock in HCA Healthcare. Mr. Jung has stock in Hologic. Mr. Jung has stock in Illumina. Mr. Jung has stock in Incyte. Mr. Jung has stock in Intuitive Surgical. Mr. Jung has stock in Iqvia Holdings. Mr. Jung has stock in Kimberly Clark. Mr. Jung has stock in Lifestance Health Group. Mr. Jung has stock in McKesson. Mr. Jung has stock in MetLife. Mr. Jung has stock in Moderna. Mr. Jung has stock in Omega Healthcare Investors. Mr. Jung has stock in Omron. Mr. Jung has stock in Proctor & Gamble. Mr. Jung has stock in Reckitt Benckiser Group plc. Mr. Jung has stock in Regeneron Pharmaceuticals. Mr. Jung has stock in Shockwave Medical. Mr. Jung has stock in Siemens AG. Mr. Jung has stock in Siemens Healthineers ADR. Mr. Jung has stock in Straumann Holding ADR. Mr. Jung has stock in Stryker. Mr. Jung has stock in Terumo. Mr. Jung has stock in Thermo Fisher Scientific. Mr. Jung has stock in 3M. Mr. Jung has stock in Unicharm. Mr. Jung has stock in UnitedHealth Group. Mr. Jung has stock in Vertex Pharmaceuticals. Mr. Jung has stock in Walmart. Mr. Jung has stock in Alnylam Pharmaceuticals.
Irina Teplova, PhD (PTC Therapeutics) Dr. Teplova has nothing to disclose.
Chia Ma, Other (PTC Therapeutics) Ms. Ma has nothing to disclose.
Wencheng Li, PhD (PTC Therapeutics) Dr. LI has received personal compensation for serving as an employee of PTC Therapeutics. Dr. LI has stock in PTC Therapeutics.
Lanqing Ying, PhD (PTC Therapeutics) Ms. Ying has received personal compensation for serving as an employee of PTC Therapeutics.
Shirley Yeh (Ptc Therapeutics) Mrs. Yeh has nothing to disclose.
Jana Narasimhan, PhD (PTC Therapeutics Inc) Dr. Narasimhan has received personal compensation for serving as an employee of PTC Therapeutics Inc. Dr. Narasimhan has stock in PTC Therapeutics Inc. Dr. Narasimhan has received intellectual property interests from a discovery or technology relating to health care.
Panayiota Trifillis Panayiota Trifillis has received personal compensation for serving as an employee of PTC Therapeutics. Panayiota Trifillis has received stock or an ownership interest from PTC Therapeutics, Inc.. Panayiota Trifillis has received intellectual property interests from a discovery or technology relating to health care.
Efthimia Leonardi (PTC Therapeutics, Inc.) Efthimia Leonardi has received personal compensation for serving as an employee of PTC Therapeutics, Inc. Efthimia Leonardi has stock in {TC Therapeutics Inc.
Ellen Welch Ms. Welch has received personal compensation for serving as an employee of PTC Therapeutics. Ms. Welch has stock in PTC Therapeutics.
Greg Voronin, Other (PTC Therapeutics) Dr. Voronin has received personal compensation for serving as an employee of PTC Therapeutics. Dr. Voronin has stock in PTC Therapeutics.
Elaine Dong, Other (PTC Therapeutics) Dr. Dong has nothing to disclose.
Nicholas Mastrandrea (Edgewise Therapeutics) Nick Mastrandrea has received personal compensation for serving as an employee of PTC Therapeutics. Nick Mastrandrea has stock in PTC Therapeutics.
Jonathan Blaize, PhD Dr. Blaize has stock in PTC Therapeutics Inc.
Marla Weetall, PhD (PTC Therapeutics) Dr. Weetall has received personal compensation for serving as an employee of PTC Therapeutics.