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

NorthStar UK Network and CINRG DNHS Investigators

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51 Scopus citations

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.

Original languageEnglish (US)
Article numbere2144178
JournalJAMA network open
Volume5
Issue number1
DOIs
StatePublished - Jan 25 2022

Funding

This work was funded by grants R44NS095423 from the National Institutes of Health (NIH) National Institute of Neurological Disorders and Stroke to Drs Hoffman and Clemens, 5U54HD090254 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development to Dr Hoffman, and U34AR068616 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases to Dr Clemens and grant agreement number 667078 from the European Commission Horizons 2020 to Dr Guglieri. Support for the vamorolone development program was provided by the Muscular Dystrophy Association, Foundation to Eradicate Duchenne, Parent Project Muscular Dystrophy, Duchenne UK (formed by Joining Jack and Duchenne Children's Trust), Duchenne Research Fund, Save Our Sons, Michael's Cause, Pietro's Fight, Alex's Wish, Ryan's Quest, and Cure Duchenne. Vamorolone was developed through a partnership with the NIH National Center for Advancing Translational Sciences Therapeutics for Rare and Neglected Diseases program, with support for drug production, formulation, and toxicology studies. The Cooperative International Neuromuscular Research Group Duchenne Natural History Study was supported by grants H133B031118 and H133B090001 from the US Department of Education National Institute on Disability and Rehabilitation Research, W81XWH-12-1-0417 from the US Department of Defense, and R01AR061875 from the NIH NIAMS and Parent Project Muscular Dystrophy. The UK NorthStar Clinical Network for Duchenne Muscular Dystrophy is funded by Muscular Dystrophy UK.

ASJC Scopus subject areas

  • General Medicine

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