Adrenal Suppression From Vamorolone and Prednisone in Duchenne Muscular Dystrophy: Results From the Phase 2b Clinical Trial

Abstract

Context: Vamorolone, a novel "dissociative" steroid, demonstrated similar efficacy in muscle function relative to prednisone 0.75 mg/kg/day but improved linear growth and bone turnover markers in a randomized trial of pediatric Duchenne muscular dystrophy (DMD).

Objectives: To determine the frequency of adrenal suppression (AS) induced by vamorolone and prednisone in pediatric DMD and to assess cortisol thresholds using a monoclonal antibody immunoassay.

Methods: Post hoc analysis of cortisol levels was performed on data from a randomized, double-blind, placebo- and prednisone-controlled 24-week trial of vamorolone with a 24-week crossover extension. Morning and ACTH-stimulated cortisol levels were measured using the Elecsys II immunoassay, with AS defined as a stimulated cortisol of <500 nmol/L ("historical threshold") and <400 nmol/L ("revised threshold").

Results: Mean age at enrolment was 5.41 ± 0.86 years (n = 118). At week 24, the proportion of participants with AS using the historical and revised cortisol thresholds, respectively, were as follows: prednisone 0.75 mg/kg/day = 100% (25/25) and 92.0% (23/25); vamorolone 6 mg/kg/day = 95.2% (20/21) and 90.5% (19/21); vamorolone 2 mg/kg/day = 84.2% (16/19) and 47.5% (9/19); and placebo = 20.0% (4/20) and 0% (0/20). Morning and peak ACTH-stimulated cortisol were strongly correlated in steroid-treated boys (Spearman correlation week 48 = 0.83).

Conclusion: AS after vamorolone and prednisone was frequent and vamorolone-associated AS appeared dose-dependent. A lower stimulated cortisol threshold may be appropriate when using a monoclonal assay. We recommend hydrocortisone for glucocorticoid stress dosing in patients receiving vamorolone.

Keywords: Duchenne muscular dystrophy; adrenal insufficiency; adrenal suppression; prednisone; vamorolone.

Figure 1.

Schematic design of the placebo- and prednisone-controlled randomized, double-blinded trial of vamorolone 2 and 6 mg/kg/day study (VBP15-004). Participants assigned to nonvamorolone groups in period 1 crossed over to 1 of 2 vamorolone doses in period 2.

Figure 2.

Change in morning and ACTH peak stimulated cortisol levels over 48 weeks of treatment. (A) The merged treatment groups for period 1 are provided over the first 24 weeks, along with the tapered washout for the prednisone group and period 2 for the vamorolone 0- to 48-week groups. The P-value in green is for the change from week 24 to week 28 in the prednisone group after starting tapering. The P-value in light blue represents the change from week 24 to week 48 in the vamorolone 2 group; similarly, in dark blue, the P-value is for change from week 24 to week 48 in the vamorolone 6 group. (B) Change in peak cortisol after ACTH stimulation was plotted for each of the 6 randomized treatment groups. The crossover groups start as dashed (period 1 assignment) before crossover to vamorolone dose groups (solid).

Figure 3.

Peak cortisol on the 250 mcg ACTH stimulation test after 24 weeks on study drug (24-week visit). Peak concentrations were the maximum concentration between the 30- and 60-minute samples (see Methods section for more details). For each treatment group, cortisol concentrations for each participant (black points) are overlaid over boxplots. Dashed black lines show thresholds of 400 (revised) and 500 (traditional) nmol/L (14.5 and 18.1 ng/dL).