TY - JOUR
T1 - Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function
AU - Hoffman, Eric P.
AU - Schwartz, Benjamin D.
AU - Mengle-Gaw, Laurel J.
AU - Smith, Edward C.
AU - Castro, Diana
AU - Mah, Jean K.
AU - Mcdonald, Craig M.
AU - Kuntz, Nancy L.
AU - Finkel, Richard S.
AU - Guglieri, Michela
AU - Bushby, Katharine
AU - Tulinius, Mar
AU - Nevo, Yoram
AU - Ryan, Monique M.
AU - Webster, Richard
AU - Smith, Andrea L.
AU - Morgenroth, Lauren P.
AU - Arrieta, Adrienne
AU - Shimony, Maya
AU - Siener, Catherine
AU - Jaros, Mark
AU - Shale, Phil
AU - Mccall, John M.
AU - Nagaraju, Kanneboyina
AU - Van Den Anker, John
AU - Conklin, Laurie S.
AU - Cnaan, Avital
AU - Gordish-Dressman, Heather
AU - Damsker, Jesse M.
AU - Clemens, Paula R.
N1 - Funding Information:
ReveraGen BioPharma was the drug sponsor and received funds to carry out the described clinical trial from Actelion Pharmaceuticals (option agreement), US and EU governments, and nonprofit foundations. This work was funded by NIH (United States) grants (National Institutes of Neurologic Disorders and Stroke R44NS095423 [E.P.H., P.R.C.], National Institute of Child Health and Human Development 5U54HD090254 [J.v.d.A., E.P.H., L.S.C.], and a European Commission Horizons 2020 (grant agreement 667078; M.G.). Support for the vamorolone development program was provided by the Muscular Dystrophy Association (United States), Foundation to Eradicate Duchenne (United States), Parent Project Muscular Dystrophy (United States), Duch-enneUK (Joining Jack [United Kingdom], Duchenne Children’s Trust [United Kingdom]), Duchenne Research Fund (United Kingdom), Save Our Sons (Australia), Michael’s Cause (United States), Pietro’s Fight (United States), Alex’s Wish (United Kingdom), Ryan’s Quest (United States), and CureDuchenne (United States). 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 CINRG DNHS was supported by US Department of Education/ National Institute on Disability, Independent Living, and Rehabilitation Research (H133B031118, H133B090001); US Department of Defense (W81XWH-12-1-0417); NIH/ National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR061875); and Parent Project Muscular Dystrophy. The authors thank the CINRG and study participants for their role in the CINRG DNHS and Prednisone Clinical Trial used as external comparator data. Patents awarded relevant to the results include WO2017004205 (A1), US2016060289 (A1), US2015011519 (A1), US9649320 (B2), and US2017027959 (A1).
Funding Information:
The Article Processing Charge was funded by NIH National Institutes of Neurologic Disorders and Stroke R44 NS095423.
Publisher Copyright:
© American Academy of Neurology.
PY - 2019/9/24
Y1 - 2019/9/24
N2 - ObjectiveTo study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD).MethodsAn open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity.ResultsOral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy.ConclusionsDaily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study.Classification of evidenceThis study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.
AB - ObjectiveTo study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD).MethodsAn open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity.ResultsOral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy.ConclusionsDaily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study.Classification of evidenceThis study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.
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U2 - 10.1212/WNL.0000000000008168
DO - 10.1212/WNL.0000000000008168
M3 - Article
C2 - 31451516
AN - SCOPUS:85072620057
SN - 0028-3878
VL - 93
SP - E1312-E1323
JO - Neurology
JF - Neurology
IS - 13
ER -