Abstract
BackgroundGlucocorticoid 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. PurposeVamorolone (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 approachWe 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 resultsVamorolone 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 interpretationsVamorolone 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.
Highlights
The largest class of steroidal hormones are those secreted by the adrenal glands targeting Type 1 nuclear hormone receptors, and include glucocorticoids, sex steroids, and mineralocorticoids
While most physiological responses to steroidal hormones and drugs have been attributed to their broad genomic effects, there is increasing recognition and interest in non-genomic effects where ligand/ receptor complexes interact with other proteins [2]
The initial starting dose for the vamorolone single ascending (SAD) study was chosen based on 10% of the NOAEL in the most sensitive species (0.1 mg/kg)
Summary
The largest class of steroidal hormones are those secreted by the adrenal glands targeting Type 1 nuclear hormone receptors, and include glucocorticoids (cortisol), sex steroids (estrogen, progesterone, testosterone), and mineralocorticoids (aldosterone). These hormones diffuse through cell membranes where they bind cytosolic Type 1 receptors, dimerize, translocate to the nucleus, and regulate gene transcription through binding of target gene regulatory elements. Research into the relative effects of genomic and non-genomic activities of steroidal hormones and drugs have been complicated by variable cross-reaction with multiple Type 1 receptors, the variable expression of receptors in specific cell types, and cell-specific ligand metabolism. 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)
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