A phase 2 randomized, double-blind, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after an acute coronary syndrome.

Abstract

OBJECTIVE:

Arachidonate 5-lipoxygenase (5-LO) is a key enzyme in the synthesis of leukotrienes. VIA-2291 is a potent 5-LO inhibitor, which has been shown to reduce hsCRP and noncalcified coronary plaque volume following an acute coronary syndrome (ACS). We aim to evaluate the effect of VIA-2291 on vascular inflammation compared to placebo using FDG-PET.

METHODS:

A Phase II, randomized, double-blind, parallel-group study was conducted in 52 patients with recent ACS assigned 1:1 to either 100 mg VIA-2291 or placebo for 24 weeks. The primary outcome was the effect of VIA-2291 relative to placebo on arterial inflammation detected by (18)fluorodeoxyglucose positron emission tomography (FDG-PET) within the index vessel after 24 weeks of daily treatment, compared to baseline.

RESULTS:

VIA-2291 was relatively well tolerated and was associated with a significant inhibition of the potent chemo-attractant LTB4, with a mean inhibition of activity of 92.8% (p<0.0001) at 6 weeks in the VIA-2291 group, without further significant change in inhibition at 24 weeks. However, for VIA-2291 was not associated with significant difference in inflammation (target-to-background ratio) compared to placebo at 24 weeks or 6 weeks of treatment. Further, VIA-2291 was not associated with a significant reduction in hsCRP from baseline after either 6 or 24 weeks of treatment.

CONCLUSIONS:

VIA-2291 is well-tolerated and effectively reduces leukotriene production. However, inhibition of 5-LO with VIA-2291 is not associated with significant reductions in vascular inflammation (by FDG-PET) or in blood inflammatory markers. Accordingly, this study does not provide evidence to support a significant anti-inflammatory effect of VIA-2291 in patients with recent ACS.

• Authors: Juan Gaztanaga, Michael Farkouh, James H F Rudd, Tilmann M Brotz, David Rosenbaum, Venkatesh Mani, Todd C Kerwin, Rebecca Taub, Jean-Claude Tardif, Ahmed Tawakol, Zahi A Fayad
• Journal: Atherosclerosis (Atherosclerosis) Vol. 240 Issue 1 Pg. 53-60 (May 2015) ISSN: 1879-1484 [Electronic] Ireland
• PMID: 25752438 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Lipoxygenase Inhibitors
• atreleuton
• Hydroxyurea

Topics

• Acute Coronary Syndrome (diagnosis, drug therapy, enzymology)
• Aged
• Aortitis (diagnosis, drug therapy, enzymology)
• Aortography (methods)
• Canada
• Carotid Artery Diseases (diagnosis, drug therapy, enzymology)
• Double-Blind Method
• Female
• Humans
• Hydroxyurea (adverse effects, analogs & derivatives, therapeutic use)
• Lipoxygenase Inhibitors (adverse effects, therapeutic use)
• Male
• Middle Aged
• Multidetector Computed Tomography
• Multimodal Imaging (methods)
• Positron-Emission Tomography
• Predictive Value of Tests
• Time Factors
• Treatment Outcome
• United States
• Vasculitis (diagnosis, drug therapy, enzymology)