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Steroids. 2018 Jun;134:43-52. doi: 10.1016/j.steroids.2018.02.010. Epub 2018 Mar 8.

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

Author information

1
ReveraGen BioPharma, Rockville, MD, USA; Department of Pharmaceutical Sciences, School of Pharmacy, Binghamton University - SUNY, Binghamton, NY, USA. Electronic address: ericphoffman@gmail.com.
2
BioPharmAdvisors LLC, USA.
3
Department of Chemistry, Johns Hopkins University, 3400 N. Charles St., Baltimore, MD 21218 USA.
4
PRA Health Sciences, Lenexa, KS, USA.
5
Kramer Consulting LLC, USA.
6
ReveraGen BioPharma, Rockville, MD, USA; Department of Pharmaceutical Sciences, School of Pharmacy, Binghamton University - SUNY, Binghamton, NY, USA.
7
Children's National Medical Center, Washington, DC, USA.
8
ReveraGen BioPharma, Rockville, MD, USA.

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.

PMID:
29524454
PMCID:
PMC6136660
DOI:
10.1016/j.steroids.2018.02.010
[Indexed for MEDLINE]
Free PMC Article

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