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

Gaztañaga, Juan; Farkouh, Michael E.; Rudd, James H.F.; Brotz, Tilmann M.; Rosenbaum, David; Mani, Venkatesh; Kerwin, Todd; Taub, Rebecca; Tardif, Jean‐Claude; Tawakol, Ahmed; Fayad, Zahi A.

doi:10.1016/j.atherosclerosis.2015.02.027

Cited by 56 publications

(28 citation statements)

References 45 publications

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“…However, this enzyme is also involved in the synthesis of lipoxins and resolvins (above). Phase II studies conducted in patients with acute coronary syndromes demonstrated that while leukotriene production was decreased in patients given atreleuton, vascular inflammation within the ascending aorta and carotids as measured by fludeoxyglucose (FDG) PET did not show any significant change (118,119). This lack of efficacy in this early attempt at resolution-targeting therapy may have been due to the dual role of this enzyme in SPM synthesis.…”

Section: Antiinflammation Versus Resolution Therapy In Atherosclerosismentioning

confidence: 94%

The role of non-resolving inflammation in atherosclerosis

Kasikara¹,

Doran²,

Cai³

et al. 2018

Journal of Clinical Investigation

216

166

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Non-resolving inflammation drives the development of clinically dangerous atherosclerotic lesions by promoting sustained plaque inflammation, large necrotic cores, thin fibrous caps, and thrombosis. Resolution of inflammation is not merely a passive return to homeostasis, but rather an active process mediated by specific molecules, including fatty acid-derived specialized pro-resolving mediators (SPMs). In advanced atherosclerosis, there is an imbalance between levels of SPMs and proinflammatory lipid mediators, which results in sustained leukocyte influx into lesions, inflammatory macrophage polarization, and impaired efferocytosis. In animal models of advanced atherosclerosis, restoration of SPMs limits plaque progression by suppressing inflammation, enhancing efferocytosis, and promoting an increase in collagen cap thickness. This Review discusses the roles of non-resolving inflammation in atherosclerosis and highlights the unique therapeutic potential of SPMs in blocking the progression of clinically dangerous plaques.

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Section: Antiinflammation Versus Resolution Therapy In Atherosclerosismentioning

confidence: 94%

The role of non-resolving inflammation in atherosclerosis

Kasikara¹,

Doran²,

Cai³

et al. 2018

Journal of Clinical Investigation

216

166

View full text Add to dashboard Cite

show abstract

“…Because many treatments exist for ACS, our study participants were on various medications before and after study enrollment. A recent study investigated the effect of VIA‐2291 on vascular inflammation using fluorodeoxyglucose–positron emission tomography and did not show a significant anti‐inflammatory effect of VIA‐2291 . This may be due to severe arterial inflammation after ACS, but the authors could not exclude the potential effect of anti‐inflammatory changes of statin therapy.…”

Section: Discussionmentioning

confidence: 98%

Effect of treatment with 5‐lipoxygenase inhibitor VIA‐2291 (atreleuton) on coronary plaque progression: a serial CT angiography study

Matsumoto

Ibrahim

Grégoire

et al. 2016

Clinical Cardiology

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Background Inflammation has a key role in the process of atherosclerosis. Production of leukotrienes by 5‐lipoxygenase has been linked to atherosclerotic plaques and cardiovascular events. Hypothesis In this study, a selective 5‐LO inhibitor will slow plaque progression using serial cardiac computed tomographic angiography (CCTA). Methods Patients with recent acute coronary syndrome (ACS) were prospectively assigned to one of 3 VIA‐2291 doses (25 mg, 50 mg, 100 mg) or placebo by oral administration. All groups underwent CCTA at baseline and at 6 months’ follow‐up. Plaque types such as low‐attenuation plaque (LAP), fibro‐fatty tissue (FF), fibro‐calcified plaque (FC), and dense calcium plaque (DC) were measured based upon predefined density threshold, and changes from baseline CCTA were analyzed. Results The final analysis included 54 patients (age, 56 ± 9 years; 85.1% male) with CCTA at baseline and 24 weeks. Evaluating on treatment VIA‐2291 (all 3 doses, n = 37) demonstrated significant reductions in plaque progression compared with placebo (n = 17). VIA‐2291 significantly reduced LAP (5.9 ± 20.7 mm3 vs −9.7 ± 33.3 mm3), FF (11.1 mm3 ± 13.3 mm3 vs −0.9 ± 2.7 mm3), and FC (−0.1 ± 6.22 mm3 vs −14.3 ± 6.2 mm3; all P < 0.05) and retarded the progression of DC (3.9 ± 3.2 mm3 vs 0.2 ± 0.4 mm3) compared with placebo. Conclusions VIA‐2291 resulted in slowed plaque progression compared with placebo across different plaque subtypes in patients with recent ACS (http://ClinicalTrials.gov NCT00358826).

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“…Several studies either pharmacologically or genetically targeting components of the 5-LOX pathway, such as ALOX5 and ALOX5AP, have indicated both beneficial and neutral effects on atherosclerosis development in animal models [30-31, 47-49]. Importantly, a recent phase II randomized, placebo-controlled study of the effect of VIA-2291, a 5-lipoxygenase inhibitor, on vascular inflammation in patients after acute coronary syndrome did not provide evidence to support a significant anti-inflammatory effect of 5-lipoxygenase inhibition [50]. The complexity of the inflammation cascade may explain the controversy.…”

Section: Discussionmentioning

confidence: 99%

Genetic Variations of Oxidative Stress Related Genes ALOX5, ALOX5AP and MPO Modulate Ischemic Stroke Susceptibility Through Main Effects and Epistatic Interactions in a Chinese Population

Liu

Song

et al. 2017

Cell Physiol Biochem

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Background/Aims: To investigate the roles of the oxidative stress related-genes ALOX5, ALOX5AP and MPO in ischemic stroke susceptibility in the Han Chinese population. Methods: A total of 351 ischemic stroke patients and 417 controls were recruited. The ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 gene polymorphisms were genotyped. Results: We identified that rs2107545 of MPO gene was significantly associated with ischemic stroke susceptibility after adjusting for covariates. Furthermore, we also considered the likely complexity of oxidative stress and inflammatory process in stroke by assessing the combined effects of multiple genes. Generalized multifactor dimensionality reduction (GMDR) analysis revealed that the combination of ALOX5 rs10900213, ALOX5AP rs4293222 and MPO rs2107545 was significantly associated with increased risk of ischemic stroke (P=0.0040, OR (95% CI) =1.991 (1.241 to 3.195)). Additionally, the MPO rs2107545 genotype was significantly associated with clinical outcomes at 6 months after discharge from the hospital. Conclusion: Our study revealed that epistatic interaction among the ALOX5, ALOX5AP and MPO genes played a significant role in vulnerability to ischemic stroke. Furthermore, these results also suggest that the rs2107545 of MPO gene can be used as a biomarker for the susceptibility and prognosis of ischemic stroke patients.

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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

Cited by 56 publications

References 45 publications

The role of non-resolving inflammation in atherosclerosis

The role of non-resolving inflammation in atherosclerosis

Effect of treatment with 5‐lipoxygenase inhibitor VIA‐2291 (atreleuton) on coronary plaque progression: a serial CT angiography study

Genetic Variations of Oxidative Stress Related Genes ALOX5, ALOX5AP and MPO Modulate Ischemic Stroke Susceptibility Through Main Effects and Epistatic Interactions in a Chinese Population

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