PMID- 32956407
OWN - NLM
STAT- MEDLINE
DCOM- 20201015
LR  - 20201015
IS  - 1549-1676 (Electronic)
IS  - 1549-1277 (Print)
IS  - 1549-1277 (Linking)
VI  - 17
IP  - 9
DP  - 2020 Sep
TI  - Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month 
      interim analysis of a non-randomized open-label extension study.
PG  - e1003222
LID - 10.1371/journal.pmed.1003222 [doi]
LID - e1003222
AB  - BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular 
      dystrophy (DMD) patients to slow the progression of weakness. However, chronic 
      corticosteroid treatment causes significant morbidities. Vamorolone is a 
      first-in-class anti-inflammatory investigational drug that has shown evidence of 
      efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, 
      open-label efficacy and safety experience of vamorolone was evaluated over a 
      period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A 
      multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term 
      extension (VBP15-LTE) was conducted by the Cooperative International 
      Neuromuscular Research Group (CINRG) and evaluated drug-related effects of 
      vamorolone on motor outcomes and corticosteroid-associated safety concerns. The 
      study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 
      to 2019. This report covers the initial 24-week trial and the first 12 months of 
      the VBP15-LTE trial (total treatment period 18 months). DMD trial participants 
      (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for 
      the full 18-month period (n = 23) showed clinical improvement of all motor 
      outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 
      0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 
      0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 
      event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North 
      Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in 
      vamorolone-treated DMD patients (n = 46) were compared to group-matched 
      participants in the CINRG Duchenne Natural History Study (corticosteroid-naive, n 
      = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to 
      stand was not significantly different between vamorolone-treated and 
      corticosteroid-naive participants (p = 0.088; least squares [LS] mean 0.042 [95% 
      CI -0.007, 0.091]), but vamorolone-treated participants showed significant 
      improvement compared to group-matched corticosteroid-naive participants for 
      run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and 
      climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The 
      vamorolone-related improvements were similar in magnitude to 
      corticosteroid-related improvements. Corticosteroid-treated participants showed 
      stunting of growth, whereas vamorolone-treated trial participants did not (p < 
      0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of 
      adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and 
      behavior change were less for vamorolone than published incidences for prednisone 
      and deflazacort. Key limitations to the study were the open-label design, and use 
      of external comparators. CONCLUSIONS: We observed that vamorolone treatment was 
      associated with improvements in some motor outcomes as compared with 
      corticosteroid-naive individuals over an 18-month treatment period. We found that 
      fewer physician-reported AEs occurred with vamorolone than have been reported for 
      treatment with prednisone and deflazacort, and that vamorolone treatment did not 
      cause the stunting of growth seen with these corticosteroids. This Phase IIa 
      study provides Class III evidence to support benefit of motor function in young 
      boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable 
      safety profile. A Phase III RCT is underway to further investigate safety and 
      efficacy. TRIAL REGISTRATION: Clinical trials were registered at 
      www.clinicaltrials.gov, and the links to each trial are as follows (as provided 
      in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE 
      [NCT03038399].
FAU - Smith, Edward C
AU  - Smith EC
AUID- ORCID: 0000-0003-0073-9377
AD  - Duke University, Durham, North Carolina, United States of America.
FAU - Conklin, Laurie S
AU  - Conklin LS
AD  - ReveraGen Biopharma, Rockville, Maryland, United States of America.
AD  - Children's National Hospital, Washington, District of Columbia, United States of 
      America.
FAU - Hoffman, Eric P
AU  - Hoffman EP
AUID- ORCID: 0000-0001-6470-5139
AD  - ReveraGen Biopharma, Rockville, Maryland, United States of America.
AD  - Binghamton University-SUNY, Binghamton, New York, United States of America.
FAU - Clemens, Paula R
AU  - Clemens PR
AD  - University of Pittsburgh and Department of Veterans Affairs Medical Center, 
      Pittsburgh, Pennsylvania, United States of America.
FAU - Mah, Jean K
AU  - Mah JK
AD  - Alberta Children's Hospital, Calgary, Alberta, Canada.
FAU - Finkel, Richard S
AU  - Finkel RS
AUID- ORCID: 0000-0002-9351-7054
AD  - Nemours Children's Hospital, Orlando, Florida, United States of America.
FAU - Guglieri, Michela
AU  - Guglieri M
AD  - John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle 
      upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
FAU - Tulinius, Mar
AU  - Tulinius M
AD  - Queen Silvia Children's Hospital, Gothenburg, Sweden.
FAU - Nevo, Yoram
AU  - Nevo Y
AD  - Schneider Children's Medical Center, Tel Aviv University, Petah Tikvah, Israel.
FAU - Ryan, Monique M
AU  - Ryan MM
AD  - Royal Children's Hospital and Murdoch Children's Research Institute, Melbourne, 
      Victoria, Australia.
FAU - Webster, Richard
AU  - Webster R
AUID- ORCID: 0000-0002-8198-2207
AD  - The Children's Hospital at Westmead, Sydney, New South Wales, Australia.
FAU - Castro, Diana
AU  - Castro D
AD  - University of Texas Southwestern Medical Center, Dallas, Texas, United States of 
      America.
FAU - Kuntz, Nancy L
AU  - Kuntz NL
AD  - Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United 
      States of America.
FAU - Kerchner, Laurie
AU  - Kerchner L
AUID- ORCID: 0000-0003-0690-5786
AD  - TRiNDS, Pittsburgh, Pennsylvania, United States of America.
FAU - Morgenroth, Lauren P
AU  - Morgenroth LP
AD  - TRiNDS, Pittsburgh, Pennsylvania, United States of America.
FAU - Arrieta, Adrienne
AU  - Arrieta A
AUID- ORCID: 0000-0002-2583-8585
AD  - TRiNDS, Pittsburgh, Pennsylvania, United States of America.
FAU - Shimony, Maya
AU  - Shimony M
AD  - TRiNDS, Pittsburgh, Pennsylvania, United States of America.
FAU - Jaros, Mark
AU  - Jaros M
AD  - Summit Analytical, Denver, Colorado, United States of America.
FAU - Shale, Phil
AU  - Shale P
AUID- ORCID: 0000-0001-6910-1174
AD  - Summit Analytical, Denver, Colorado, United States of America.
FAU - Gordish-Dressman, Heather
AU  - Gordish-Dressman H
AUID- ORCID: 0000-0002-2330-5427
AD  - Children's National Hospital, Washington, District of Columbia, United States of 
      America.
FAU - Hagerty, Laura
AU  - Hagerty L
AUID- ORCID: 0000-0001-6341-0697
AD  - ReveraGen Biopharma, Rockville, Maryland, United States of America.
FAU - Dang, Utkarsh J
AU  - Dang UJ
AUID- ORCID: 0000-0003-4120-2015
AD  - Binghamton University-SUNY, Binghamton, New York, United States of America.
FAU - Damsker, Jesse M
AU  - Damsker JM
AD  - ReveraGen Biopharma, Rockville, Maryland, United States of America.
FAU - Schwartz, Benjamin D
AU  - Schwartz BD
AUID- ORCID: 0000-0003-1163-9478
AD  - Camden Group, St. Louis, Missouri, United States of America.
FAU - Mengle-Gaw, Laurel J
AU  - Mengle-Gaw LJ
AD  - Camden Group, St. Louis, Missouri, United States of America.
FAU - McDonald, Craig M
AU  - McDonald CM
AUID- ORCID: 0000-0002-8779-3220
AD  - University of California, Davis, Davis, California, United States of America.
CN  - CINRG VBP15 and DNHS Investigators
LA  - eng
SI  - ClinicalTrials.gov/NCT02760264
SI  - ClinicalTrials.gov/NCT03038399
SI  - ClinicalTrials.gov/NCT02760277
GR  - R44 NS095423/NS/NINDS NIH HHS/United States
GR  - U54 HD090254/HD/NICHD NIH HHS/United States
GR  - U34 AR068616/AR/NIAMS NIH HHS/United States
PT  - Clinical Trial, Phase II
PT  - Journal Article
PT  - Multicenter Study
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20200921
PL  - United States
TA  - PLoS Med
JT  - PLoS medicine
JID - 101231360
RN  - 0 (Adrenal Cortex Hormones)
RN  - 0 (Glucocorticoids)
RN  - 0 (Pregnadienediols)
RN  - 0 (VBP15 compound)
RN  - VB0R961HZT (Prednisone)
SB  - IM
MH  - Adrenal Cortex Hormones/adverse effects
MH  - Child
MH  - Child, Preschool
MH  - Disease Progression
MH  - Glucocorticoids/adverse effects
MH  - Humans
MH  - Male
MH  - Motor Activity/*drug effects
MH  - Muscular Dystrophy, Duchenne/*drug therapy
MH  - Prednisone/therapeutic use
MH  - Pregnadienediols/metabolism/*therapeutic use
MH  - Treatment Outcome
MH  - Walking/physiology
PMC - PMC7505441
COIS- I have read the journal's policy and the authors of this manuscript have the 
      following competing interests: LSC, JMD, LH and EPH are employees of ReveraGen 
      BioPharma. LSC, JMD, LH own stock options of ReveraGen. UD is a paid consultant 
      for ReveraGen. MJ and PS are employees of Summit Analytical, a biostatistics 
      clinical research organization. BDS and LJM G own Camden Group, LLC, a clinical 
      research organization. EPH and HG-D are co-founders and members of the Board, and 
      ALD'A, LPM, AA, and MS are employees of TRiNDS LLC, a clinical trials management 
      organization. PRC, ECS, JKM, RSF, MG, MT, YN, MMR, RW, DC, NLK, and CMM have 
      received grant funding from ReveraGen for the conduct of clinical trials but they 
      have not received compensation from ReveraGen for other activities. CMM has 
      served as a consultant for clinical trials in Duchenne muscular dystrophy outside 
      the submitted work for Astellas, Biomarin, Capricor Therapeutics, Cardero 
      Therapeutics, Inc., Catabasis Pharmaceuticals, Eli Lilly, FibroGen, Marathon 
      Pharmaceuticals, Pfizer, PTC Therapeutics, Santhera Pharmaceuticals, Sarepta 
      Therapeutics, PTC Therapeutics; serves on external advisory boards related to 
      Duchenne muscular dystrophy for PTC Therapeutics, Eli Lilly, Sarepta 
      Therapeutics, Santhera Pharmaceuticals, and Capricor; and reports grants US Dept. 
      of Education/NIDRR, NIDILRR, US NIH/NIAMS, US Dept. of Defense, and Parent 
      Project Muscular Dystrophy US, during the conduct of the study. Patents awarded 
      relevant to the results include: WO2017004205 (A1), US2016060289 (A1), 
      US2015011519 (A1), US9649320 (B2); US2017027959 (A1). The authors have declared 
      that no other competing interests exist.
EDAT- 2020/09/22 06:00
MHDA- 2020/10/21 06:00
PMCR- 2020/09/21
CRDT- 2020/09/21 17:14
PHST- 2020/02/14 00:00 [received]
PHST- 2020/08/25 00:00 [accepted]
PHST- 2020/09/21 17:14 [entrez]
PHST- 2020/09/22 06:00 [pubmed]
PHST- 2020/10/21 06:00 [medline]
PHST- 2020/09/21 00:00 [pmc-release]
AID - PMEDICINE-D-20-00478 [pii]
AID - 10.1371/journal.pmed.1003222 [doi]
PST - epublish
SO  - PLoS Med. 2020 Sep 21;17(9):e1003222. doi: 10.1371/journal.pmed.1003222. 
      eCollection 2020 Sep.