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

Souhrn

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-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.

Conclusions

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


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PLOS Medicine


2020 Číslo 9

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