Efficacy and Safety of Vamorolone vs Placebo and Prednisone Among Boys With Duchenne Muscular Dystrophy
Authors: Guglieri Michela , Clemens Paula R. , Perlman Seth J. , Smith Edward C. , Horrocks Iain , Finkel Richard S. , Mah Jean K. , Deconinck Nicolas , Goemans Nathalie , Haberlova Jana , Straub Volker , Mengle-Gaw Laurel J. , Schwartz Benjamin D. , Harper Amy D. , Shieh Perry B. , De Waele Liesbeth , Castro Diana , Yang Michelle L. , Ryan Monique M. , McDonald Craig M. , Tulinius Mar , Webster Richard , McMillan Hugh J. , Kuntz Nancy L. , Rao Vashmi K. , Baranello Giovanni , Spinty Stefan , Childs Anne-Marie , Sbrocchi Annie M. , Selby Kathryn A. , Monduy Migvis , Nevo Yoram , Vilchez-Padilla Juan J. , Nascimento-Osorio Andres , Niks Erik H. , de Groot Imelda J.M. , Katsalouli Marina , James Meredith K. , van den Anker Johannes , Damsker Jesse M. , Ahmet Alexandra , Ward Leanne M. , Jaros Mark , Shale Phil , Dang Utkarsh J. , Hoffman Eric P. 
Published: August 2022

Importance

Corticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life.

Objective

To determine if vamorolone, a structurally unique dissociative steroidal anti-inflammatory drug, is able to retain efficacy while reducing safety concerns with use in Duchenne muscular dystrophy (DMD).

Design, Setting, and Participants

Randomized, double-blind, placebo- and prednisone-controlled 24-week clinical trial, conducted from June 29, 2018, to February 24, 2021, with 24 weeks of follow-up. This was a multicenter study (33 referral centers in 11 countries) and included boys 4 to younger than 7 years of age with genetically confirmed DMD not previously treated with corticosteroids.

Interventions

The study included 4 groups: placebo; prednisone, 0.75 mg/kg per day; vamorolone, 2 mg/kg per day; and vamorolone, 6 mg/kg per day.

Main Outcomes and Measures

Study outcomes monitored (1) efficacy, which included motor outcomes (primary: time to stand from supine velocity in the vamorolone, 6 mg/kg per day, group vs placebo; secondary: time to stand from supine velocity [vamorolone, 2 mg/kg per day], 6-minute walk distance, time to run/walk 10 m [vamorolone, 2 and 6 mg/kg per day]; exploratory: NorthStar Ambulatory Assessment, time to climb 4 stairs) and (2) safety, which included growth, bone biomarkers, and a corticotropin (ACTH)–challenge test.

Results

Among the 133 boys with DMD enrolled in the study (mean [SD] age, 5.4 [0.9] years), 121 were randomly assigned to treatment groups, and 114 completed the 24-week treatment period. The trial met the primary end point for change from baseline to week 24 time to stand velocity for vamorolone, 6 mg/kg per day (least-squares mean [SE] velocity, 0.05 [0.01] m/s vs placebo −0.01 [0.01] m/s; 95% CI, 0.02-0.10; P = .002) and the first 4 sequential secondary end points: time to stand velocity, vamorolone, 2 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 6 mg/kg per day, vs placebo; 6-minute walk test, vamorolone, 2 mg/kg per day, vs placebo; and time to run/walk 10 m velocity, vamorolone, 6 mg/kg per day, vs placebo. Height percentile declined in prednisone-treated (not vamorolone-treated) participants (change from baseline [SD]: prednisone, −1.88 [8.81] percentile vs vamorolone, 6 mg/kg per day, +3.86 [6.16] percentile; P = .02). Bone turnover markers declined with prednisone but not with vamorolone. Boys with DMD at baseline showed low ACTH-stimulated cortisol and high incidence of adrenal insufficiency. All 3 treatment groups led to increased adrenal insufficiency.

Conclusions and Relevance

In this pivotal randomized clinical trial, vamorolone was shown to be effective and safe in the treatment of boys with DMD over a 24-week treatment period. Vamorolone may be a safer alternative than prednisone in this disease, in which long-term corticosteroid use is the standard of care.

Trial Registration

ClinicalTrials.gov Identifier: NCT03439670