Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.
Efficacy and safety of vamorolone in Duchenne muscular dystrophy: An 18-month interim analysis of a non-randomized open-label extension study.
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DOI：
10.1371/journal.pmed.1003222
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发表时间：
2020-09
期刊：
影响因子：
15.8
通讯作者：
CINRG VBP15 and DNHS Investigators
中科院分区：
文献类型：
--
作者：
Smith EC;Conklin LS;Hoffman EP;Clemens PR;Mah JK;Finkel RS;Guglieri M;Tulinius M;Nevo Y;Ryan MM;Webster R;Castro D;Kuntz NL;Kerchner L;Morgenroth LP;Arrieta A;Shimony M;Jaros M;Shale P;Gordish-Dressman H;Hagerty L;Dang UJ;Damsker JM;Schwartz BD;Mengle-Gaw LJ;McDonald CM;CINRG VBP15 and DNHS Investigators
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. 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. 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]. In an interim analysis of a multi-center open-label study, Edward Smith and colleagues investigate motor outcomes and adverse events in patients with Duchenne muscular dystrophy treated with the novel anti-inflammatory drug vamorolone. The standard-of-care pharmacological management of Duchenne muscular dystrophy (DMD) is high-dose corticosteroids (prednisone or deflazacort; about 0.5 to 0.9 mg/kg/day), but this treatment is associated with safety concerns. Vamorolone is a first-in-class steroidal drug that aims to retain or improve efficacy of corticosteroids, while decreasing safety concerns. Twenty-four-week treatment of DMD with vamorolone has been reported to show dose-responsive improvements in motor outcomes, but longer-term treatment and comparative safety profiles to corticosteroids have not been previously reported. Participants with DMD completing the 24-week dose-ranging study of vamorolone (VBP15-003; n = 46) were offered transition to standard of care (prednisone or deflazacort) or continued treatment with vamorolone with enrollment into a 2-year long-term extension study (VBP15-LTE). All participants (46/46) opted to continue treatment with vamorolone and enrolled in VBP15-LTE. We report data from the midpoint of the 2-year VBP15-LTE study (total of 18 months of vamorolone treatment in VBP15-003 + VBP15-LTE). All measures of efficacy (5 motor outcome tests) showed significant improvements from baseline to 18 months of vamorolone treatment by paired intragroup analyses. Three motor outcome tests could be compared to group-matched corticosteroid-naïve external comparators, and 2 showed significant vamorolone-associated improvement. Vamorolone treatment did not result in stunting of growth, as seen with prednisone and deflazacort. Vamorolone treatment showed fewer physician-reported adverse events (such as behavior change, hirsutism, and Cushingoid appearance) than these drugs. Vamorolone holds promise as a replacement for corticosteroid standard of care (prednisone and deflazacort) in DMD. Limitations of the study include the open-label design and use of external comparators.
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