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

ImportanceCorticosteroidal anti-inflammatory drugs are widely prescribed but long-term use shows adverse effects that detract from patient quality of life.ObjectiveTo 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 ParticipantsRandomized, 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.InterventionsThe 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 MeasuresStudy 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.ResultsAmong 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 RelevanceIn 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 RegistrationClinicalTrials.gov Identifier: NCT03439670