The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: A multicenter FDG-PET trial
Introduction
Cardiovascular disease (CVD) is the leading cause of mortality worldwide [1]. Atherothrombosis is the primary cause of ischemic CVD and is caused by the accumulation of inflammatory cells, which culminates in the development of complex atherosclerotic plaques, precursors of acute coronary syndromes [2]. Currently, the mainstay for the preventive treatment of atherothrombosis is lipid lowering, mainly using statins, whereby anti-inflammatory effects are believed to contribute to their mechanism of action [3], [4]. Statin usage in secondary prevention trials has been shown to produce about a 30% reduction in events, which leaves approximately 70% of the events unattenuated [5]. Novel treatments are therefore needed to address the residual risk.
Inflammation is a critical component in the pathogenesis of atherothrombosis [6] and represents an attractive therapeutic target [7]. Novel anti-inflammatory therapeutics have been developed targeting specific intracellular protein kinases to suppress key mediators of inflammation. One approach is targeted towards the inhibition of the p38 mitogen-activated protein kinases (P38 MAPKs) [8]. P38 MAPKs are members of a key signaling pathway responsible for the cellular response to various extracellular stresses, which function to orchestrate a broader cellular response [9]. Activation of P38 MAPKs is linked to increased production of inflammatory mediators such as proinflammatory cytokines, prostaglandins/prostacyclins and matrix metalloproteinases [9]. In humans, the inhibition of p38 MAPK has been demonstrated to improve nitric oxide mediated vasodilation accompanied by a reduction in systemic inflammation [10], and a decrease in neointima formation and systemic inflammatory markers, after percutaneous coronary intervention [11].
Quantification of inflammation in atherosclerotic plaques with 18FDG-PET is based on the metabolic activity of plaque macrophages, which avidly take up 18F-fluordeoxyglucose (18FDG). 18F-fluordeoxyglucose then becomes metabolically trapped and can be detected non-invasively with positron emission tomography (PET) [12], [13]. This technique has been demonstrated as a reproducible imaging modality for the evaluation of inflammation in atherosclerotic plaques in both animal and human studies and allows for non-invasive efficacy assessment of therapeutic interventions [14], [15], [16], [17], [18].
Recently, the dual αβ subtype, p38 MAPK inhibitor, losmapimod (7.5 mg once daily for 12 weeks), was associated with a modest reduction in arterial inflammation in stable atherosclerosis subjects, as measured by 18FDG-PET/CT [19]. Furthermore, a significant reduction of inflammation in visceral fat and a persistent reduction in high sensitivity C-reactive peptide (hsCRP) was observed. In contrast to losmapimod, BMS-582949 is a novel highly selective p38α MAPK inhibitor [20]. In the current study, we sought to evaluate the effect of BMS-582949 on arterial inflammation in subjects with stable atherosclerosis, and to compare this potential anti-inflammatory action to the effect of statin intensification (using high-dose atorvastatin in subjects already on low-dose statins at baseline).
Section snippets
Methods
This 12 week, randomized, partially double-blinded study (double-blind for BMS-582949 and placebo, open label administration of atorvastatin 80 mg) was conducted at 17 US Centers in compliance with the principles of the Declaration of Helsinki and according to Good Clinical Practice guidelines (www.clinicaltrails.gov, NCT00570752). The protocol was reviewed and approved by each center's institutional review board and all participants provided written informed consent prior to any study
Subject data
Subject demographics and characteristics at baseline were generally comparable across treatment groups as shown in Table 1. A total of 72 subjects were randomized. Ten subjects discontinued early due to adverse effects, withdrawal of consent, protocol derivation, or other reason and 53 subjects provided evaluable imaging data at 12 weeks (Fig. 1).
Effects on atherosclerotic plaque activity
Results of various image analysis endpoints are summarized in Table 2. The analysis evaluating the change from baseline TBR within all slices of the
Discussion
The present study demonstrates that p38 MAPK inhibitor, BMS-582949, is safe and well-tolerated in subjects with stable atherosclerotic disease receiving statin therapy. However, it is not associated with attenuation of atherosclerotic inflammation and, though in a relatively small number of subjects and short treatment duration, it was not associated with a reduction in systemic inflammatory biomarkers.
In the previously mentioned 18FDG-PET/CT trial evaluating another p38 MAPK inhibitor,
Funding
This study is sponsored by Bristol-Myers Squibb.
Acknowledgments
We thank all of the BMS-582949 investigators, their staff personnel, and subjects that participated in this trial. The statistical analysis was conducted with consult from Harvard Catalyst which is supported by National Center for Research Resources and the National Center for Advancing Translational Sciences (NIH Award UL1 TR001102).
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Contributed equally to this work.