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

Abstract

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].

Conflict of interest statement

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.

Figures

Fig 1. Participant-level longitudinal data and aggregated cross-sectional data comparing vamorolone-associated efficacy to CINRG DNHS external comparators.

Left panels show participant-level change from baseline after an 18-month treatment period. Vamorolone group A was treated with 2.0 or 6.0 mg/kg/day for the last 3–9 months of the 18-month period, group B was treated with 2.0 or 6.0 mg/kg/day for the last 9–11 months, and groups C and D with 2.0 or 6.0 mg/kg/day for all 18 months. The specific dose of each participant at the end of the 18-month period is indicated (red = 2.0 mg/kg/day; blue = 6.0 mg/kg/day). Dose groups B, C, and D show mean improvements over baseline compared to matched corticosteroid-naïve participants from CINRG DNHS (n = 19). Right panels show mean group cross-sectional analysis at age 5.5–8.5 years. The baseline mean is shown for each vamorolone-treated group (black line). The corticosteroid-treated natural history group (n = 68) has no baseline shown, as the age at initiation of corticosteroids was variable. This panel shows improvement over baseline in vamorolone-treated groups B, C, and D, with the cross-sectional data suggesting an effect size similar to that of age-group-matched corticosteroid-treated participants in CINRG DNHS. CINRG, Cooperative International Neuromuscular Research Group; DNHS, Duchenne Natural History Study; SEM, standard error of the mean; TTCLIMB, time to climb 4 stairs; TTRW, time to run/walk 10 meters; TTSTAND, time to stand from supine.