AI Article Synopsis

  • - Vamorolone (VBP15) is a new type of glucocorticoid drug that effectively reduces inflammation without many side effects commonly seen with traditional glucocorticoids, like prednisone.
  • - In clinical trials, Vamorolone was shown to be well-tolerated by healthy adults, with a similar metabolism to prednisone but significantly less impact on adrenal function and side effects like bone fragility or immune suppression.
  • - The unique structure of Vamorolone allows it to bind to glucocorticoid and mineralocorticoid receptors differently than existing drugs, which may explain its reduced side effects while retaining anti-inflammatory properties.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136660PMC
http://dx.doi.org/10.1016/j.steroids.2018.02.010DOI Listing

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