Vamorolone trial in Duchenne muscular dystrophy shows dose-related improvement of muscle function

Abstract

ObjectiveTo study vamorolone, a first-in-class steroidal anti-inflammatory drug, in Duchenne muscular dystrophy (DMD). MethodsAn open-label, multiple-ascending-dose study of vamorolone was conducted in 48 boys with DMD (age 4-<7 years, steroid-naive). Dose levels were 0.25, 0.75, 2.0, and 6.0 mg/kg/d in an oral suspension formulation (12 boys per dose level; one-third to 10 times the glucocorticoid dose in DMD). The primary goal was to define optimal doses of vamorolone. The primary outcome for clinical efficacy was time to stand from supine velocity. ResultsOral administration of vamorolone at all doses tested was safe and well tolerated over the 24-week treatment period. The 2.0-mg/kg/d dose group met the primary efficacy outcome of improved muscle function (time to stand; 24 weeks of vamorolone treatment vs natural history controls), without evidence of most adverse effects of glucocorticoids. A biomarker of bone formation, osteocalcin, increased in vamorolone-treated boys, suggesting possible loss of bone morbidities seen with glucocorticoids. Biomarker outcomes for adrenal suppression and insulin resistance were also lower in vamorolone-treated patients with DMD relative to published studies of glucocorticoid therapy. ConclusionsDaily vamorolone treatment suggested efficacy at doses of 2.0 and 6.0 mg/kg/d in an exploratory 24-week open-label study. Classification of evidenceThis study provides Class IV evidence that for boys with DMD, vamorolone demonstrated possible efficacy compared to a natural history cohort of glucocorticoid-naive patients and appeared to be tolerated.

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

“…17 First-in-patient phase 2a clinical trials included a 2-week open-label multipleascending-dose (0.25, 0.75, 2, and 6 mg/kg/day) study in 48 DMD boys (4 to <7 years old, steroid naive; VBP15-002) 16 and a subsequent 24-week extension phase (VBP15-003) at the same doses. 18 The phase 2a studies demonstrated that vamorolone was safe at all doses tested, with decreased steroid-associated safety concerns predicted by biomarker studies. Both doseresponsive improvements in clinical outcomes (eg, time to stand from supine velocity and 6-minute walk test, etc.)…”

“…and decreases in proinflammatory corticosteroidresponsive biomarkers were observed. 16,18 The US Food and Drug Administration (FDA) has a guidance regarding the importance of exploring exposure-response relationships in drug development (https://www.fda.gov/media/71277/download). Although PK provides key data to link drug dosing to blood concentrations, in their guidance the FDA notes, "Far less attention has been paid to establishing the relationship between blood concentrations and pharmacodynamic (PD) responses and possible differences among population subsets in these concentrationresponse (often called PK/PD) relationships."…”

“…Further details for all studies have been published. [16][17][18] A summary of these studies is shown in Table 1.…”

Developmental Pharmacodynamics and Modeling in Pediatric Drug Development

“…These were then used to test the anti‐inflammatory effects of a new drug, vamorolone, in Duchenne muscular dystrophy . Initial dose‐ranging pediatric trials in Duchenne muscular dystrophy studied a 24‐fold dose range (0.25– 6.0 mg/kg/day), in which the serum pharmacodynamics biomarkers helped to establish the likely efficacious doses with only a 2‐week exposure study …”

“…36 Initial dose-ranging pediatric trials in Duchenne muscular dystrophy studied a 24-fold dose range (0.25-6.0 mg/kg/day), in which the serum pharmacodynamics biomarkers helped to establish the likely efficacious doses with only a 2-week exposure study. 36,37 Clinical end points, as the primary outcome for determining PD in children, can be problematic when end points in pediatric trials differ from those measured in adult trials; use of different outcome measures has been found to be a risk factor for trial failure in children. 28 PD biomarkers show that a biological response has occurred in an individual who has been exposed to a medical product or an environmental agent.…”