Exposure-Response Analysis of Vamorolone (VBP15) in Boys With Duchenne Muscular Dystrophy

Abstract

Exposure-response relationships of vamorolone, a novel dissociative steroidal anti-inflammatory drug, were investigated in clinical trials in boys with Duchenne muscular dystrophy. Variables were clinical outcome measures, Fridericia-corrected QT (QTcF) duration, and pharmacodynamic (PD) biomarkers. Exposure metrics were area under the plasma concentration time curve (AUC) and maximum plasma concentration (Cmax ), with a sigmoid Emax model applied. Significant improvement in clinical efficacy outcomes was observed after 24 weeks of daily dosing. The primary outcome, time to stand from supine velocity, exhibited the highest sensitivity to vamorolone, with the lowest AUC value providing 50% of maximum effect (E50 = 186 ng·h/mL), followed by time to climb 4 stairs (E50 = 478 ng·h/mL), time to run/walk 10 m (E50 = 1220 ng·h/mL), and 6-minute walk test (E50 = 1770 ng·h/mL). Week 2 changes of proinflammatory PD biomarkers showed exposure-dependent decreases. The E50 was 260 ng·h/mL for insulin-like growth factor-binding protein 2, 1200 ng·h/mL for matrix metalloproteinase 12, 1260 ng·h/mL for lymphotoxin α1/β2, 1340 ng·h/mL for CD23, 1420 ng·h/mL for interleukin-22-binding protein, and 1600 ng·h/mL for macrophage-derived chemokine/C-C motif chemokine 22. No relationship was found between QTcF interval changes from baseline and Cmax in week 2 or 24. This analysis showed that improvements in clinical efficacy end points in week 24 and PD biomarkers in week 2 were achieved at typical vamorolone exposure of 2 mg/kg daily dose with a median AUC dose of 6 mg/kg (3651 ng·h/mL), corresponding to approximately 95% of maximum effects for most response variables.

Trial registration: ClinicalTrials.gov NCT02760264 NCT02760277.

Keywords: Duchenne muscular dystrophy (DMD); children; exposure-response; glucocorticoids; pharmacodynamics; vamorolone.

Conflict of interest statement

Declaration of Conflicting Interests:

Drs. Conklin, van den Anker, and Hoffman are part-time employees and own stock in ReveraGen BioPharma. Dr. Jusko receives contract funds from ReveraGen BioPharma. Dr. Clemens receives NIH grant funding directly and via subcontracts from ReveraGen for support of these studies.

© 2020, The American College of Clinical Pharmacology.

Figures

Figure 1.

Exposure-response relationship between AUC on day 14 and percent changes of clinical efficacy endpoints from baseline at week 24. The dotted line represents the zero change line. Open circles are observed percent change from baseline and solid lines are population model fittings. Horizontal solid lines on the bottom panels are the range of minimum to maximum AUC values for 0.25 (red), 0.75 (purple), 2 (orange) and 6 mg/kg (green) doses of vamorolone.

Figure 2.

Exposure-response relationship between AUC on day 14 and percent changes of exploratory PD biomarkers from baseline at week 2 demonstrated by percent change in Relative Fluorescence Unites (RFU). Graph metrics are the same as in Figure 1.

Figure 3.

The relationship between Cmax on day 14 and QTcF interval change from baseline (ΔQTcF) at weeks 2 and 24. Dots with different colors reflect dose groups: 0.25 (red); 0.75 (purple); 2 (orange); 6 mg/kg (green).