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September 24, 2019; 93 (13) ArticleOpen Access

Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

View ORCID ProfileEric P. Hoffman, Benjamin D. Schwartz, Laurel J. Mengle-Gaw, Edward C. Smith, Diana Castro, Jean K. Mah, Craig M. McDonald, Nancy L. Kuntz, Richard S. Finkel, Michela Guglieri, Katharine Bushby, Mar Tulinius, Yoram Nevo, Monique M. Ryan, Richard Webster, Andrea L. Smith, Lauren P. Morgenroth, Adrienne Arrieta, Maya Shimony, Catherine Siener, Mark Jaros, Phil Shale, John M. McCall, Kanneboyina Nagaraju, John van den Anker, View ORCID ProfileLaurie S. Conklin, Avital Cnaan, Heather Gordish-Dressman, Jesse M. Damsker, Paula R. Clemens, the Cooperative International Neuromuscular Research Group
First published August 26, 2019, DOI: https://doi.org/10.1212/WNL.0000000000008168
Eric P. Hoffman
From ReveraGen Biopharma (E.P.H., J.M.M., K.N., J.v.d.A., L.S.C., J.M.D.), Rockville, MD; Binghamton University–SUNY (E.P.H., K.N.), NY: Camden Group (B.D.S., L.J.M.-G.), LLC, St. Louis, MO; Duke University (E.C.S.), Durham, NC; University of Texas Southwestern (D.C.), Dallas; Alberta Children's Hospital (J.K.M.), Calgary, Canada; University of California Davis (C.M.M.), Sacramento; Ann & Robert H. Lurie Children's Hospital (N.L.K.), Chicago, IL; Nemours Children's Hospital (R.S.F.), Orlando, FL; John Walton Muscular Dystrophy Research Centre (M.G., K.B.), Newcastle University, Newcastle-Upon-Tyne, UK; Queen Silvia Children's Hospital (M.T.), Gothenburg, Sweden; Schneider Children's Medical Center (Y.N.), Tel Aviv University, Israel; Royal Children's Hospital and Murdoch Children's Research Institute (M.M.R.), Melbourne, Australia; The Children's Hospital at Westmead (R.W.), Sydney, Australia; TRiNDS LLC (A.L.S., L.P.M., A.A., M.S., C.S.), Kensington, MD; Summit Analytical (M.J., P.S.), Denver, CO; Children's National Health System (J.v.d.A., L.S.C., A.C., H.G.-D.), Washington, DC; and University of Pittsburgh and Department of Veterans Affairs Medical Center (P.R.C.), PA.
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Benjamin D. Schwartz
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Laurel J. Mengle-Gaw
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Edward C. Smith
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Diana Castro
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Jean K. Mah
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Craig M. McDonald
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Nancy L. Kuntz
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Richard S. Finkel
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Michela Guglieri
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Katharine Bushby
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Mar Tulinius
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Yoram Nevo
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Monique M. Ryan
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Richard Webster
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Andrea L. Smith
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Lauren P. Morgenroth
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Adrienne Arrieta
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Maya Shimony
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Catherine Siener
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Mark Jaros
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Phil Shale
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John M. McCall
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Kanneboyina Nagaraju
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John van den Anker
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Laurie S. Conklin
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Avital Cnaan
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Heather Gordish-Dressman
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Jesse M. Damsker
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Paula R. Clemens
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Citation
Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function
Eric P. Hoffman, Benjamin D. Schwartz, Laurel J. Mengle-Gaw, Edward C. Smith, Diana Castro, Jean K. Mah, Craig M. McDonald, Nancy L. Kuntz, Richard S. Finkel, Michela Guglieri, Katharine Bushby, Mar Tulinius, Yoram Nevo, Monique M. Ryan, Richard Webster, Andrea L. Smith, Lauren P. Morgenroth, Adrienne Arrieta, Maya Shimony, Catherine Siener, Mark Jaros, Phil Shale, John M. McCall, Kanneboyina Nagaraju, John van den Anker, Laurie S. Conklin, Avital Cnaan, Heather Gordish-Dressman, Jesse M. Damsker, Paula R. Clemens, the Cooperative International Neuromuscular Research Group
Neurology Sep 2019, 93 (13) e1312-e1323; DOI: 10.1212/WNL.0000000000008168

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Abstract

Objective To study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD).

Methods An 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.

Results Oral 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.

Conclusions Daily 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 evidence This 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.

Glossary

BMI=
body mass index;
CINRG=
Cooperative International Neuromuscular Research Group;
CTCAE=
Common Terminology Criteria for Adverse Events;
DMD=
Duchenne muscular dystrophy;
DNHS=
Duchenne Natural History Study;
NF-κB=
nuclear factor-κB;
NSAA=
North Star Ambulatory Assessment;
SAE=
serious adverse event;
6MWT=
6-minute walk test;
TEAE=
treatment-emergent adverse event;
TTRW=
time to run/walk 10 m;
TTSTAND=
timed stand from supine

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • The Article Processing Charge was funded by NIH National Institutes of Neurologic Disorders and Stroke R44 NS095423.

  • Class of Evidence: NPub.org/coe

  • Received October 26, 2018.
  • Accepted in final form May 29, 2019.
  • Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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  • Class IV
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  • Muscle disease

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