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.

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

“…The first multiple ascending dose (MAD) cohort trial tested pharmacokinetics (PK) and safety for 2 weeks of drug dosing followed by a 2-week washout (VBP15-002) [11]. Vamorolone treatment in this study showed no dose-limiting toxicities, and PK demonstrated a short half-life similar to corticosteroids (~2 hours), no drug accumulation, similar PK on day 1 and day 14, and PK similar to that of healthy adult male volunteers (VBP15-001) [9,[11][12][13]. All DMD participants completed the MAD study and then continued on the same dose for a 24-week dosefinding (efficacy and safety) extension study (VBP15-003).…”

Cardiac therapies for Duchenne muscular dystrophy

“…Vamorolone (previously known as VBP-15) is a novel anti-inflammatory steroid analog that is currently being studied as a replacement for traditional glucocorticoid treatment for DMD. 35 This drug acts in a similar way to other glucocorticoids by binding to the GR but not to GREs. As such, the adverse effects associated with traditional glucocorticoids are expected to be significantly lower with the use of vamorolone.…”

Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

“…Further, when delivered orally to B6AJ mice, it decreased lipid mobility, increased muscle repair, and reduced fatty replacement of myofibers, all of which were made more severe by prednisone treatment [186]. Currently, vamorolone is in clinical trials as an antiinflammatory for DMD/BMD, and preliminary findings reported fewer adverse events and some improved motor function [30,187]. While the data are intriguing, there are no trials in LGMD2B or MM patients currently.…”