Efficacy and Safety of Vamorolone in Duchenne Muscular Dystrophy: A 30-Month Nonrandomized Controlled Open-Label Extension Trial

Abstract

Importance: Vamorolone is a synthetic steroidal drug with potent anti-inflammatory properties. Initial open-label, multiple ascending dose-finding studies of vamorolone among boys with Duchenne muscular dystrophy (DMD) found significant motor function improvement after 6 months treatment in higher-dose (ie, ≥2.0 mg/kg/d) groups.

Objective: To investigate outcomes after 30 months of open-label vamorolone treatment.

Design, setting, and participants: This nonrandomized controlled trial was conducted by the Cooperative International Neuromuscular Research Group at 11 US and non-US study sites. Participants were 46 boys ages 4.5 to 7.5 years with DMD who completed the 6-month dose-finding study. Data were analyzed from July 2020 through November 2021.

Interventions: Participants were enrolled in a 24-month, long-term extension (LTE) study with vamorolone dose escalated to 2.0 or 6.0 mg/kg/d.

Main outcomes and measures: Change in time-to-stand (TTSTAND) velocity from dose-finding baseline to end of LTE study was the primary outcome. Efficacy assessments included timed function tests, 6-minute walk test, and NorthStar Ambulatory Assessment (NSAA). Participants with DMD treated with glucocorticoids from the Duchenne Natural History Study (DNHS) and NorthStar United Kingdom (NSUK) Network were matched and compared with participants in the LTE study receiving higher doses of vamorolone.

Results: Among 46 boys with DMD who completed the dose-finding study, 41 boys (mean [SD] age, 5.33 [0.96] years) completed the LTE study. Among 21 participants treated with higher-dose (ie, ≥2.0 mg/kg/d) vamorolone consistently throughout the 6-month dose-finding and 24-month LTE studies with data available at 30 months, there was a decrease in mean (SD) TTSTAND velocity from baseline to 30 months (0.206 [0.070] rises/s vs 0.189 (0.124) rises/s), which was not a statistically significant change (-0.011 rises/s; CI, -0.068 to 0.046 rises/s). There were no statistically significant differences between participants receiving higher-dose vamorolone and matched participants in the historical control groups receiving glucocorticoid treatment (75 patients in DNHS and 110 patients in NSUK) over a 2-year period in NSAA total score change (0.22 units vs NSUK; 95% CI, -4.48 to 4.04]; P = .92), body mass index z score change (0.002 vs DNHS SD/mo; 95% CI, -0.006 to 0.010; P = .58), or timed function test change. Vamorolone at doses up to 6.0 mg/kg/d was well tolerated, with 5 of 46 participants discontinuing prematurely and for reasons not associated with study drug. Participants in the DNHS treated with glucocorticoids had significant growth delay in comparison with participants treated with vamorolone who had stable height percentiles (0.37 percentile/mo; 95% CI, 0.23 to 0.52 percentile/mo) over time.

Conclusions and relevance: This study found that vamorolone treatment was not associated with a change in TTSTAND velocity from baseline to 30 months among boys with DMD aged 4 to 7 years at enrollment. Vamorolone was associated with maintenance of muscle strength and function up to 30 months, similar to standard of care glucocorticoid therapy, and improved height velocity compared with growth deceleration associated with glucocorticoid treatment, suggesting that vamorolone may be an attractive candidate for treatment of DMD.

Trial registration: ClinicalTrials.gov Identifier: NCT03038399.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Mah reported receiving grants from ReveraGen BioPharma during the conduct of the study; grants from Pfizer, Italfarmaco, Sarepta, Catabasis, Roche, Biogen, Novartis, NS Pharma, PTC Therapeutics, and Alberta Children's Hospital Foundation; and personal fees from PTC Therapeutics, Biogen, and Roche outside the submitted work. Dr Clemens reported serving as a board member for Therapeutic Research in Neuromuscular Disorders Solutions (TRINDS); receiving grants from the National Institutes of Health (NIH), NS Pharma, Amicus, Sanofi, Spark, and Muscular Dystrophy Association; receiving research support through a donation from the Foundation to Eradicate Duchenne to the University of Pittsburgh; and receiving personal fees from Epirium during the conduct of the study outside the submitted work. Dr Guglieri reported receiving data management support from North Star Network during the conduct of the study; grants from the NIH, European Committee H2020, Duchenne Muscular Dystrophy UK, and Sarepta (funding through Translational Research in Europe: Assessment and Treatment of Neuromuscular Disorders); personal fees from Sarepta; and travel fees from Santhera outside the submitted work and serving as principal or chief investigator or clinical investigator for clinical trials sponsored by Pfizer, Italfarmaco, Summit, Santhera, Roche, and PTC Therapeutics. Dr Smith reported receiving grants for partial salary support from Reveragen BioPharma as principal investigator during the conduct of the study. Dr Finkel reported receiving grants from ReveraGen BioPharma during the conduct of the study and grants from Catabasis and Sarepta outside the submitted work. Dr Webster reported receiving research funding from ReveraGen BioPharma during the conduct of the study. Dr Kuntz reported receiving grants from Astellas Gene Therapies, Biogen, Genentech, Novartis, and Sarepta; personal fees from Biogen, Genentech, Novartis, and Sarepta; and data safety monitoring board services from Sarepta during the conduct of the study. Dr McDonald reported receiving grants from the NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), US Department of Defense, National Institute on Disability Independent Living and Rehabilitation Research, and Parent Project Muscular Dystrophy and personal fees from Astellas, BioMarin, Epirium Bio (formerly Capricor), Catabasis, Entrada Therapeutics, Avidity Therapeutics, Edgewise Therapeutics, FibroGen, Hoffmann La Roche, Marathon, Pfizer, Santhera Pharmaceuticals, Saraepta Therapeutics, and PTC Therapeutics outside the submitted work. Dr Damsker reported being an employee and shareholder of ReveraGen BioPharma. Dr Schwartz reported receiving personal fees from ReveraGen Biopharma during the conduct of the study and personal fees from RegenXBio and TRINDS outside the submitted work. Dr Mengle-Gaw reported receiving personal fees from ReveraGen BioPharma during the conduct of the study and personal fees from RegenXBio outside the submitted work. Dr Baranello reported receiving personal fees from Roche, serving as principal investigator in clinical trials for Pfizer and Reveragen, receiving grants from Sarepta via the Dubowitz Neuromuscular Centre, and serving as an investigator in a clinical trial for NS Pharma outside the submitted work. Dr Manzur reported receiving grants from NorthStar Clinical Network during the conduct of the study and serving as clinical lead for Northstar Clinical Network UK. Dr Muntoni reported receiving grants from Muscular Dystrophy UK North Star Consortium during the conduct of the study; grants from the NIH Research Great Ormond Street Hospital-ICH Biomedical Research Centre, Genethon, and Sarepta; and personal fees from Dyne Therapeutics, Pfizer, and Sarepta outside the submitted work. Dr Gordish-Dressman reported receiving personal fees from TRINDS during the conduct of the study and co-owning TRINDS outside the submitted work. Dr Ward reported receiving grants from ReveraGen BioPharma via the Children's Hospital of Eastern Ontario (CHEO) Research Institute during the conduct of the study and grants from Amgen, Novartis, and PTC Therapeutics via the CHEO Research Institute outside the submitted work. Dr Hoffman reported receiving salary as chief executive officer and owning stock from ReveraGen BioPharma, serving as a board member for TRINDS, receiving grants from the NIH National Institute of Neurological Disorders and Stroke during the conduct of the study; serving as vice president and owning stock for Agada BioSciences outside the submitted work; and owning a patent issued to ReveraGen BioPharma. Dr Dang reported receiving grants from the Foundation to Eradicate Duchenne and personal fees from ReveraGen BioPharma during the conduct of the study and grants from the NIH NIAMS outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Flowchart of Vamorolone Long-term Extension (LTE) Study

VBP indicates vamorolone. aTreating physicians were permitted to up-titrate or down-titrate dose according to clinical judgement. There were 3 participants who ended the study at an intermediate dose of 4.0 mg/kg/d.

Figure 2.. Efficacy of Vamorolone in Motor Function Assessments by High vs Low Starting Dose

6MWT indicates 6-minute walk test; high, a starting dose of 2.0 mg/kg/d or greater; low, a starting dose of less than 2.0 mg/kg/d; points, means; whiskers, standard error of the mean. Mean estimated differences between participants treated at higher dose and low dose, as well as P values, are provided at 6 months (ie, prior to LTE) and 30 months (ie, at conclusion of LTE).

Figure 3.. Outcome Comparisons of Vamorolone Long-term Extension (LTE) and Duchenne Natural History (DNHS) Study Cohorts

BMI indicates body mass index. Trajectories based on model estimates, along with 95% CIs, are plotted for an individual with fixed baseline values.