Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Abstract

Background Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. Purpose Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. Experimental approach We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1–20.0 mg/kg), and multiple ascending doses (1.0–20 mg/kg/day; 14 days treatment). Key results Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. Conclusions and interpretations Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.

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

“…10,12,[14][15][16] The retention of antiinflammatory efficacy and loss of side effects in preclinical models are consistent with vamorolone blocking NF-κBassociated proinflammatory signals as a ligand/receptor monomeric state instead of the traditional molecular models of ligand/receptor dimeric complexes. 17 A phase 1 study of vamorolone in healthy adult men 18 and a 2-week treatment, 2-week washout, 4-week phase 2a study in patients with DMD 19 showed an improved profile of typical glucocorticoid-like safety concerns as measured by serum biomarkers after 2 weeks of treatment. Vamorolone showed pharmacokinetics and metabolism similar to those of corticosteroids and is similarly administered with daily oral dosing.…”

Population Pharmacokinetics of Vamorolone (VBP15) in Healthy Men and Boys With Duchenne Muscular Dystrophy

“…38 The first-in-human safety data obtained for vamorolone in healthy adult men showed no changes in bone-turnover markers, no evidence of drug-induced hyperglycemia, and no loss of blood lymphocytes at any dose tested. 18 Adrenal suppression evaluated by first-in-morning cortisol was only evident in a subset of men on the highest doses of vamorolone. Along with improved safety biomarker profiles compared with glucocorticoids, the phase 2a studies in DMD boys showed good dose-related antiinflammatory effects of vamorolone based on exploratory efficacy biomarkers.…”

“…The phase 1 data were previously published. 18 Institutional review board (IRB) approval for the phase 1 study (VBP15-001) was obtained from the Midlands Independent Review Board. The clinical trial registration number is NCT02415439 -phase 2a study (boys with DMD).…”

“…10,14-17 Phase 1 clinical trials (86 healthy adult men) showed that vamorolone is well tolerated for all tested doses with pharmacokinetic (PK) and metabolic profiles similar to prednisone and lesser adrenal suppression along with fewer traditional glucocorticoids side effects (bone fragility, metabolic disturbance, immune suppression). 18 Furthermore, phase IIa first-in-patient studies (48 DMD boys from 4 to 7 years old) showed improved safety compared with glucocorticoids as shown by reduction in insulin resistance, beneficial changes in bone turnover, and reduction in adrenal suppression. 19 Vamorolone was selected among 20 9,11-derivatives because of its NF-κB inhibition potency, reduced transactivation properties, and good bioavailability.…”

High throughput screening to identify inhibitors of the type I interferon – major histocompatibility complex class I pathway in skeletal muscle

“…The current first-line therapy for dermatomyositis, polymyositis, and necrotizing autoimmune myopathy is prednisone (Dalakas, 2015). However, it has serious side effects including metabolic and endocrine disturbances, osteopenia and bone breaks, psychiatric changes, skeletal muscle atrophy and weakness, hypertension, and renal disturbances (Hoffman et al, 2018). These are especially concerning in children, who can exhibit stunting of growth, delay in puberty, weight gain, mood disturbances, and fragile bones.…”