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.
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.
Department of Cardiology, Winthrop University Hospital, Mineola, NY, USA.
Juan
J
Gaztanaga
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.
Michael
M
Farkouh
Division of Cardiovascular Medicine, University of Cambridge, United Kingdom.
James H F
JH
Rudd
VIA Pharmaceuticals, Inc., USA.
Tilmann M
TM
Brotz
Insitute of Cardiology Nutrition and Metabolism, Pitié Salpétrière Hospital, AP-HP, Paris, France.
David
D
Rosenbaum
Department of Radiology and Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Venkatesh
V
Mani
Department of Cardiology, New York Hospital Queens, Flushing, NY, USA.
Todd C
TC
Kerwin
VIA Pharmaceuticals, Fort Washington, PA, USA.
Rebecca
R
Taub
Montreal Heart Institute, Université de Montréal, Canada.
Jean-Claude
JC
Tardif
Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Ahmed
A
Tawakol
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: zahi.fayad@mssm.edu.
Zahi A
ZA
Fayad
D054058:Acute Coronary Syndrome / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D000368:Aged; D001025:Aortitis / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D001027:Aortography / Q000379:methods; D002170:Canada; D002340:Carotid Artery Diseases / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D006918:Hydroxyurea / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016859:Lipoxygenase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D061330:Multidetector Computed Tomography; D064847:Multimodal Imaging / Q000379:methods; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D013997:Time Factors; D016896:Treatment Outcome; D014481:United States; D014657:Vasculitis / Q000175:diagnosis / Q000188:drug therapy* / Q000201:enzymology
D016859:Lipoxygenase Inhibitors; C096921:atreleuton; D006918:Hydroxyurea
(18)Fluorodeoxyglucose positron emission tomography; Acute coronary syndrome; Arachidonate 5-lipoxygenase inhibitor; Inflammation