The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: A multicenter FDG-PET trial

Objectives: This study evaluated the effect of p38 mitogen-activated protein kinase (p38MAPK) inhibitor, BMS-582949, on atherosclerotic plaque inflammation, using (18)FDG-PET imaging. p38MAPK is an important element of inflammatory pathways in atherothrombosis and its inhibition may lead to reduced inflammation within atherosclerotic plaques. Methods: Subjects with documented atherosclerosis (n = 72) on stable low-dose statin therapy and having at least one lesion with active atherosclerotic plaque inflammation in either aorta or carotid arteries were randomized to BMS-582949 (100 mg once daily), placebo, or atorvastatin (80 mg once daily), for 12 weeks. Arterial inflammation was assessed using (18)FDG-PET/CT imaging of the carotid arteries and aorta. Uptake of arterial (18)FDG was assessed as target-to-background ratio (TBR): 1) as a mean of all slices of the index vessel, and 2) within active slices of all vessels (AS: which includes only slices with significant inflammation (TBR >= 1.6) at the baseline). Results: Treatment with BMS-582949 did not reduce arterial inflammation relative to placebo, (DTBR index: 0.10 [ 95% CI: -0.11, 0.30], p = 0.34; DTBR AS: -0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %Delta CRP [ IQR]: 33.83% [ 153.91] vs. 16.71% [ 133.45], p = 0.61). In contrast, relative to placebo, statin intensification was associated with significant reduction of hs-CRP (%DCRP [ IQR]: -17.44% [ 54.68] vs. 16.71% [ 133.45], p = 0.04) and arterial inflammation in active slices (Delta TBRAS - -0.24 [ 95% CI: - 0.46, -0.01], p - 0.04). Conclusions: The findings of this study demonstrates that in stable atherosclerosis, 12 weeks of treatment with BMS-582949 did not reduce arterial inflammation or hs-CRP compared to placebo, whereas intensification of statin therapy significantly decreased arterial inflammation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.