Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study

Autoři: Edward C. Smith aff001;  Laurie S. Conklin aff002;  Eric P. Hoffman aff002;  Paula R. Clemens aff005;  Jean K. Mah aff006;  Richard S. Finkel aff007;  Michela Guglieri aff008;  Mar Tulinius aff009;  Yoram Nevo aff010;  Monique M. Ryan aff011;  Richard Webster aff012;  Diana Castro aff013;  Nancy L. Kuntz aff014;  Laurie Kerchner aff015;  Lauren P. Morgenroth aff015;  Adrienne Arrieta aff015;  Maya Shimony aff015;  Mark Jaros aff016;  Phil Shale aff016;  Heather Gordish-Dressman aff003;  Laura Hagerty aff002;  Utkarsh J. Dang aff004;  Jesse M. Damsker aff002;  Benjamin D. Schwartz aff017;  Laurel J. Mengle-Gaw aff017;  Craig M. McDonald aff018
Působiště autorů: Duke University, Durham, North Carolina, United States of America aff001;  ReveraGen Biopharma, Rockville, Maryland, United States of America aff002;  Children’s National Hospital, Washington, District of Columbia, United States of America aff003;  Binghamton University–SUNY, Binghamton, New York, United States of America aff004;  University of Pittsburgh and Department of Veterans Affairs Medical Center, Pittsburgh, Pennsylvania, United States of America aff005;  Alberta Children’s Hospital, Calgary, Alberta, Canada aff006;  Nemours Children’s Hospital, Orlando, Florida, United States of America aff007;  John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom aff008;  Queen Silvia Children’s Hospital, Gothenburg, Sweden aff009;  Schneider Children’s Medical Center, Tel Aviv University, Petah Tikvah, Israel aff010;  Royal Children’s Hospital and Murdoch Children’s Research Institute, Melbourne, Victoria, Australia aff011;  The Children’s Hospital at Westmead, Sydney, New South Wales, Australia aff012;  University of Texas Southwestern Medical Center, Dallas, Texas, United States of America aff013;  Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, United States of America aff014;  TRiNDS, Pittsburgh, Pennsylvania, United States of America aff015;  Summit Analytical, Denver, Colorado, United States of America aff016;  Camden Group, St. Louis, Missouri, United States of America aff017;  University of California, Davis, Davis, California, United States of America aff018
Vyšlo v časopise: Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003222
Kategorie: Research Article
doi: 10.1371/journal.pmed.1003222



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-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve 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-naïve 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.


We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve 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].

Klíčová slova:

Adverse events – Comparators – Corticosteroid therapy – Drug therapy – Duchenne muscular dystrophy – Physicians – Walking – Weight gain


1. Liu X, Wang Y, Ortlund EA. First high-resolution crystal structures of the glucocorticoid receptor ligand-binding domain-peroxisome proliferator-activated γ coactivator 1-α complex with endogenous and synthetic glucocorticoids. Mol Pharmacol. 2019;96:408–17. doi: 10.1124/mol.119.116806 31391291

2. Liu A, Wanga Y, Gutierreza JS, Damsker JM, Nagaraju K, Hoffman EP, Ortlunda EA. Disruption of a key ligand-H-bond network drives dissociative properties in vamorolone for Duchenne muscular dystrophy treatment. Proc Natl Acad Sci U S A. In press.

3. Heier CR, Damsker JM, Yu Q, Dillingham BC, Huynh T, Van der Meulen JH, et al. VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects. EMBO Mol Med. 2013;5:1569–85. doi: 10.1002/emmm.201302621 24014378

4. Damsker JM, Cornish MR, Kanneboyina P, Kanneboyina I, Yu Q, Lipson R, et al. Vamorolone, a dissociative steroidal compound, reduces collagen antibody-induced joint damage and inflammation when administered after disease onset. Inflamm Res. 2019;68:969–80. doi: 10.1007/s00011-019-01279-z 31446438

5. Heier CR, Yu Q, Fiorillo AA, Tully CB, Tucker A, Mazala DA, et al. Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy. Life Sci Alliance. 2019;2(1):e201800186. doi: 10.26508/lsa.201800186 30745312

6. Garvin LM, Chen Y, Damsker JM, Rose MC. A novel dissociative steroid VBP15 reduces MUC5AC gene expression in airway epithelial cells but lacks the GRE mediated transcriptional properties of dexamethasone. Pulm Pharmacol Ther. 2016;38:17–26. doi: 10.1016/j.pupt.2016.04.004 27133900

7. Sreetama SC, Chandra G, Van der Meulen JH, Ahmad MM, Suzuki P, Bhuvanendran S, et al. Membrane stabilization by modified steroid offers a potential therapy for muscular dystrophy due to dysferlin deficit. Mol Ther. 2018;26:2231–42. doi: 10.1016/j.ymthe.2018.07.021 30166241

8. Chen YW, Nagaraju K, Bakay M, McIntyre O, Rawat R, Shi R, et al. Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophy. Neurology. 2005;65:826–34. doi: 10.1212/01.wnl.0000173836.09176.c4 16093456

9. Hoffman EP, Riddle V, Siegler MA, Dickerson D, Backonja M, Kramer WG, et al. Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes. Steroids 2018;134:43–52. doi: 10.1016/j.steroids.2018.02.010 29524454

10. Rosenberg AS, Puig M, Nagaraju K, Hoffman EP, Villalta SA, Rao VA, et al. Immune-mediated pathology in Duchenne muscular dystrophy. Sci Transl Med. 2015;7:299rv4. doi: 10.1126/scitranslmed.aaa7322 26246170

11. Conklin LS, Damsker JM, Hoffman EP, Jusko WJ, Mavroudis PD, Schwartz BD, et al. Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug. Pharmacol Res. 2018;136:140–50. doi: 10.1016/j.phrs.2018.09.007 30219580

12. Mavroudis PD, van den Anker J, Conklin LS, Damsker JM, Hoffman EP, Nagaraju K, et al. Population pharmacokinetics of vamorolone (VBP15) in healthy men and boys with Duchenne muscular dystrophy. J Clin Pharmacol. 2019;59:979–88. doi: 10.1002/jcph.1388 30742306

13. Li X, Conklin LS, van den Anker J, Hoffman EP, Clemens PR, Jusko WJ. Exposure-response analysis of vamorolone (VBP15) in boys with Duchenne muscular dystrophy. J Clin Pharmacol. 2020 May 20. doi: 10.1002/jcph.1632 32434278

14. Hoffman EP, Schwartz BD, Mengle-Gaw LJ, Smith EC, Castro D, Mah JK, et al. Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function. Neurology. 2019;93:e1312–23. doi: 10.1212/WNL.0000000000008168 31451516

15. McDonald CM, Henricson EK, Abresch RT, Han JJ, Escolar DM, Florence JM, et al. The CINRG Duchenne Natural History Study—a longitudinal natural history study in the era of glucocorticoid therapy: design of the protocol and methods. Muscle Nerve. 2013;48:32–54. doi: 10.1002/mus.23807 23677550

16. McDonald CM, Henricson EK, Abresch RT, Duong T, Joyce NC, Hu F, et al. Long-term effects of glucocorticoids on function, quality of life, and survival in patients with Duchenne muscular dystrophy: a prospective cohort study. Lancet 2018;391:451–61. doi: 10.1016/S0140-6736(17)32160-8 29174484

17. Escolar DM, Hache LP, Clemens PR, Cnaan A, McDonald CM, Viswanathan V, et al. Randomized, blinded trial of weekend vs daily prednisone in Duchenne muscular dystrophy. Neurology 2011;77:444–52. doi: 10.1212/WNL.0b013e318227b164 21753160

18. Bello L, Gordish-Dressman H, Morgenroth LP, Henricson EK, Duong T, Hoffman EP, et al. Prednisone/prednisolone and deflazacort regimens in the CINRG Duchenne Natural History Study. Neurology. 2015;85:1048–55. doi: 10.1212/WNL.0000000000001950 26311750

19. Dang UJ, Ziemba M, Clemens PR, Hathout Y, Conklin LS, CINRG Vamorolone 002/003 Investigators, et al. Serum biomarkers associated with baseline clinical severity in young steroid-naive Duchenne muscular dystrophy boys. Hum Mol Genet. 2020 Jun 27. doi: 10.1093/hmg/ddaa132 32592467

20. Griggs RC, Miller JP, Greenberg CR, Fehlings DL, Pestronk A, Mendell JR, et al. Efficacy and safety of deflazacort vs prednisone and placebo for Duchenne muscular dystrophy. Neurology. 2016;87:2123–31. doi: 10.1212/WNL.0000000000003217 27566742

21. Dillingham BC, Knoblach SM, Many GM, Harmon BT, Mullen AM, Heier CR, et al. VBP15, a novel anti-inflammatory, is effective at reducing the severity of murine experimental autoimmune encephalomyelitis. Cell Mol Neurobiol. 2015;35:377–87. doi: 10.1007/s10571-014-0133-y 25392236

22. Babadjanova G, Allolio B, Vollmer M, Reincke M, Schulte HM. Comparison of the pharmacodynamic effects of deflazacort and prednisolone in healthy subjects. Eur J Clin Pharmacol. 1996;51:53–7. doi: 10.1007/s002280050160 8880052

23. Saviola G, Abdi Ali L, Shams Eddin S, Coppini A, Cavalieri F, Campostrini L, et al. Compared clinical efficacy and bone metabolic effects of low-dose deflazacort and methyl prednisolone in male inflammatory arthropathies: a 12-month open randomized pilot study. Rheumatology (Oxford). 2007;46:994–8.

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PLOS Medicine

2020 Číslo 9
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