The efficacy of vamorolone at a dose of 6 mg/kg/d was maintained over 48 weeks of treatment for all 5 motor outcomes.
Utkarsh Dang, PhD, MSc, BSc
Months after the FDA approved vamorolone (Agamree) as a novel treatment for patients with Duchenne muscular dystrophy (DMD), Santhera, the drug manufacturers, announced the full publication of the phase 3 VISION-DMD trial (NCT03439670), the supportive study for its approval. All told, the study confirms the maintenance of efficacy and benefits in safety and tolerability of treatment with vamorolone over a 48-week period.
To date, vamorolone is the only approved medication in the European Union for treating all patients from age 4 years with DMD, and the first DMD treatment approved across the US, EU, and UK. VISION-DMD, a double-blind, placebo-controlled trial included 121 patients with DMD aged 4 to 7 years old. In the study, patients were randomly assigned to 2 mg/kg/d of vamorolone and 6 mg/kg/d of vamorolone for 48 weeks (period 1: 24 weeks + period 2: 24 weeks and 0.75 mg/kg/d of prednisone and placebo for the first 24 weeks (before crossover).
Efficacy was assessed using 5 motor outcomes: time to stand from supine velocity (TTSTANDV), 6-minute walk test distance (6MWD), time to run/walk 10 m velocity (TTRWV), time to climb 4 stairs velocity (TTCLIMBV), and North Star Ambulatory Assessment (NSAA). Led by Utkarsh Dang, PhD, MSc, BSc, an assistant professor at Carleton University, 92.6% (112 of 121) of patients completed the study through week 48. For the primary outcome, TTSTANDV, the improvement seen with vamorolone 6 mg/kg/d after 24 weeks of treatment was maintained (week 24 least square mean [LSM], 0.052 [SE, 0.0130] rises/s vs week 48 LSM, 0.0446 [SE, 0.0138]).
Assessment of dose dependency of motor outcomes showed a difference between vamorolone at a dose of 2 mg/kg/d vs 6 mg/kg/d for TTSTANDV after 48 weeks of treatment (LSM, 0.0500 [SE, 0.0186] rises/s; 95% CI 0.0126–0.0874; P = 0.010). Similarly, significant differences between 2 vamorolone dose levels at week 48 were seen for 6MWD (LSM, 34.7634 [SE, 17.0194] m; 95% CI 0.4506–69.0761 m; P = 0.047) and TTCLIMBV (LSM, 0.0531 [SE, 0.0238] m; 95% CI 0.0052–0.1010 m; P = 0.031). Findings on TTRWV and NSAA weren’t significantly different between dose groups; however, performance remained better, on average, in the higher dosed group.
Vamorolone continued to show efficacy in those who switched from placebo midway through the study. From week 24, the crossover period, to week 48 assessments, treatment with vamorolone 6 mg/kg/d resulted in greater response on 6MWD (LSM difference, 34.1 m; 95% CI, –4.48 to 72.7 m; P = .082) and TTCLIMBV (LSM difference, 0.066 m; 95% CI, –0.001 to 0.133 m/s; P = .053). Dose-dependent differences in this post-hoc analysis were not statistically significant, which authors noted was possibly because of low power.
Throughout the 48-week trial, the most common adverse events (AEs) for vamorolone-dosed groups included upper respiratory tract infection, vomiting, cough, pyrexia, and diarrhea. There were no deaths during the study and 3 serious AEs reported (perforated appendicitis, asthma, and viral gastroenteritis) that were considered unrelated to the study treatment. Overall, the percentage of participants with at least 1 drug-related AE continued to be lower in the vamorolone 2 mg/kg group vs the 6 mg/kg group in period 2 (17.9% vs 39.3%, respectively).
For those who crossed over from prednisone to vamorolone, there was a 19.3% reduction in all events and a 39.7% reduction in AEs of special interest. Of all the reported AEs of special interest, the largest reductions in annualized rates of AEs/patient/year were seen in behavior problems (prednisone vs vamorolone; 1.08-0.51; 52.8% change) and gastrointestinal symptoms (prednisone vs vamorolone 0.72-0.60; 16.7% change). Within this patient group, prednisone showed slowing of growth velocities in period 1, and crossover to vamorolone 6 mg/kg/d showed reversal of growth trajectories through catch-up growth (period 1 LSM, –0.1001; period 2 LSM, 0.1276; LSM, 0.228; 95% CI, 0.157-0.44; P = .036).
Over the first 24 weeks of treatment, both vamorolone dosed groups and those on prednisone demonstrated increases in body mass index (BMI); however, these stabilized in period 2. For those who crossed over from prednisone to vamorolone 6 mg/kg/d, the weight gain seen in period 1 was stabilized throughout period 2. Those who switched from prednisone to 2 mg/kg/d of vamorolone demonstrated a nonsignificant reduction in BMI (LS mean, 0.181; 95% CI, –0.112 to 0.473; P = .21).
