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.

Conflict of interest statement

Competing interests

EPH, KN, JMM are part-time employees of ReveraGen BioPharma and own founder shares. JMD is a full-time employee of ReveraGen BioPharma and owns stock options. DD is an employee of PRA, a clinical trial services provider. Patents awarded relevant to the results include: WO2017004205 (A1), US2016060289 (A1), US2015011519 (A1), US9649320 (B2); US2017027959 (A1).

Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

Fig. 1

Pharmacokinetic analysis of vamorolone single ascending dose trial (SAD). Shown are arithmetic mean ± standard error plasma concentrations of vamorolone after oral administration of single 0.1, 0.3, 1, 3, 8, and 20 mg/kg doses to healthy subjects under fasted conditions — linear (top panel) and semi-logarithmic (bottom panel) axes. The data shows strong dose proportionality, short half-life (~ 3 h), and relatively little interindividual variability.

Fig. 2

Pharmacokinetic analysis of vamorolone for food effect. Shown are arithmetic mean ± standard error plasma concentrations of vamorolone after oral administration of single 8 mg/kg doses to healthy subjects under fed and fasted conditions — linear (top panel) and semi-logarithmic (bottom panel) axes. This shows a significant food effect, with a 250% increase in bioavailability with a 40 g fat meal.

Fig. 3

Pharmacokinetic analysis of multiple ascending dose (MAD) trial. Shown are arithmetic mean ± standard error plasma concentrations of vamorolone on Days 1 and 14 during oral administration of 1, 3, 9, and 20 mg/kg doses once daily for 14 days to healthy subjects under fasted conditions (linear axes [top panel] and semi logarithmic axes [bottom panel]). Day 1 and Day 14 PK data were superimposable for each dose group, showing that there was little or no drug accumulation between daily doses, consistent with the short half-life of vamorolone. Bioavailability was not significantly changed with 14 days of daily dosing.

Fig. 4

First-in-morning serum cortisol shows evidence for adrenal suppression at high doses. First-in-morning cortisol was measured in Phase 1 volunteers as in-patients in the Phase 1 clinical trial unit. Cortisol and glucocorticoid drugs cause rapid suppression of the adrenal axis, with marked reductions in serum cortisol within 8 hrs of the first 0.25 mg/kg dose (5,6). Adrenal suppression is often defined as inability to mount a morning cortisol response (diurnal fluctuations), and a diagnostic threshold for this is when first-in-morning cortisols fall to < 100 nmol/L (< 3.6 µg/dL). Morning cortisol levels of adult volunteers treated with 1.0 and 3.0 mg/kg/day vamorolone showed successful mounting of a morning cortisol response, with patterns similar to placebo. Subjects receiving 9.0 mg/kg/day showed a mild decrease at 24 hrs after the first dose (paired T = 0.0005), with one of six subjects falling 100 nmol/L at 24 h, and three of six (50%) after two weeks of daily dosing. Subjects receiving 20 mg/kg/day showed stronger adrenal suppression, with four of six falling below the 100 nmol/L threshold at 24 h after the first dose, and 100% (five of five) after two weeks of daily dosing. One subject had dosing stopped after 10 days due to mild elevations of liver enzyme (dashed red line). The adrenal function of this subject returned to baseline levels at 5 days after cessation of dosing.

Fig. 5

Vamorolone shows no changes in bone turnover biomarkers. Osteocalcin (biomarker for bone formation), and CTX1 (carboxy-terminal cross-linked telopeptides of type 1 collagen; biomarker for bone resorption). Data is shown for placebo and 20 mg/kg/day dose groups (complete data in Supplemental Tables). Prednisone shows significant decreases in osteocalcin levels at 8 h after a single 0.2 mg/kg dose, and after seven days of daily dosing (Kauh et al. 2012). Vamorolone did not show significant decreases of osteocalcin at any dose. In Kauh et al., a biomarker for bone resorption, NTX (amino-terminal cross-linked telopeptides of type 1 collagen), showed significant increases after seven days of treatment with prednisone at 0.25 mg/kg/day, whereas vamorolone did not shown any changes of CTX1 (a similar biomarker) through the highest dose tested (20 mg/kg/day). This data suggests that vamorolone does show the safety concern of bone fragility, and is consistent with pre-clinical data on vamorolone, consistent with mouse data (Heier et al. 2013).

Fig. 6

Comparison of the experimentally determined crystal structures of vamorolone and glucocorticoids (prednisone, dexamethasone). Panel A. Structure Overlay of Vamorolone (Vam, red) and Prednisone (Pred, blue). Overlay was calculated based on the fit of the 10C atoms marked as *, r.m.s = 0.0627. Panel B. Structure Overlay of Vamorolone (Vam, red) and Dexamethasone (Dex, green). Overlay was calculated based on the fit of the 10C atoms marked as *, r.m.s = 0.0622.