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

作者：Gaztanaga Juan; Farkouh Michael; Rudd James H F; Brotz Tilmann M; Rosenbaum David; Mani Venkatesh; Kerwin Todd C; Taub Rebecca; Tardif Jean Claude; Tawakol Ahmed; Fayad Zahi A^*

来源：Atherosclerosis, 2015, 240(1): 53-60.

DOI：10.1016/j.atherosclerosis.2015.02.027

• Arachidonate 5-lipoxygenase inhibitor
• Acute coronary syndrome
• (18)Fluorodeoxyglucose positron emission tomography
• Inflammation

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.

• 出版日期2015-5