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.

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 2016;240(1):53-60

PMID: 25752438

Full Text on Elsevier Science View on PubMed

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.

Address: Department of Cardiology, Winthrop University Hospital, Mineola, NY, USA.; Mount Sinai Cardiovascular Institute, New York, NY, USA; Peter Munk Cardiac Centre and Li Ka Shing Knowledge Institute, University of Toronto, Translational and Molecular Imaging Institute and Imaging Science Laboratories, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Division of Cardiovascular Medicine, University of Cambridge, United Kingdom.; VIA Pharmaceuticals, Inc., USA.; Insitute of Cardiology Nutrition and Metabolism, Pitié Salpétrière Hospital, AP-HP, Paris, France.; Department of Radiology and Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Department of Cardiology, New York Hospital Queens, Flushing, NY, USA.; VIA Pharmaceuticals, Fort Washington, PA, USA.; Montreal Heart Institute, Université de Montréal, Canada.; Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Radiology and Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Cardiology, Zena and Michael A. Weiner Cardiovascular Institute and Marie-Josée and Henry R. Kravis Cardiovascular Health Center, Icahn School of Medicine at Mount, New York, NY, USA. Electronic address: [email protected].

DOI: 10.1016/j.atherosclerosis.2015.02.027

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MeSH Terms: Acute Coronary Syndrome, Aged, Aortitis, Aortography, Canada, Carotid Artery Diseases, Double-Blind Method, Female, Humans, Hydroxyurea, Lipoxygenase Inhibitors, Male, Middle Aged, Multidetector Computed Tomography, Multimodal Imaging, Positron-Emission Tomography, Predictive Value of Tests, Time Factors, Treatment Outcome, United States, Vasculitis