The effect of BMS-582949, a P38 mitogen-activated protein kinase (P38 MAPK) inhibitor on arterial inflammation: a multicenter FDG-PET trial.
OBJECTIVE
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, (ΔTBR index: 0.10 [95% CI: -0.11, 0.30], p = 0.34; ΔTBR AS: -0.01 [-0.31, 0.28], p = 0.93) or hs-CRP (median %ΔCRP [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 (%ΔCRP [IQR]: -17.44% [54.68] vs. 16.71% [133.45], p = 0.04) and arterial inflammation in active slices (ΔTBRAS = -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.
Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Hamed
H
Emami
Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Esad
E
Vucic
Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Sharath
S
Subramanian
Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Amr
A
Abdelbaky
Translational and Molecular Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Zahi A
ZA
Fayad
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Shuyan
S
Du
Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Eli
E
Roth
Division of Atherosclerosis and Vascular Medicine, Baylor College of Medicine and Houston Methdodist DeBakey Heart and Vascular Center, Houston, TX, USA.
Christie M
CM
Ballantyne
Hospital of the University of Pennsylvania, Philadelphia, PA, USA.
Emile R
ER
Mohler
Peter Munk Cardiac Centre and the Heart and Stroke Richard Lewar Centre of Excellence, The University of Toronto, ON, Canada.
Michael E
ME
Farkouh
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Joonyoung
J
Kim
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Matthew
M
Farmer
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Li
L
Li
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Alexander
A
Ehlgen
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Thomas H
TH
Langenickel
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Linda
L
Velasquez
Exploratory Clinical & Translational Research, Bristol-Myers Squibb, Princeton, NJ, USA.
Wendy
W
Hayes
Cardiac MR PET CT Program, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA; Cardiology Division, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: atawakol@partners.org.
Ahmed
A
Tawakol
D000368:Aged; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D001018:Aortic Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D050197:Atherosclerosis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D000069059:Atorvastatin / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D002340:Carotid Artery Diseases / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D004311:Double-Blind Method; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use; D007249:Inflammation / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000201:enzymology; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D058226:Plaque, Atherosclerotic; D049268:Positron-Emission Tomography; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D019275:Radiopharmaceuticals; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014227:Triazines / Q000009:adverse effects / Q000627:therapeutic use*; D014481:United States; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
C552704:4-(5-(cyclopropylcarbamoyl)-2-methylphenylamino)-5-methyl-N-propylpyrrolo(1,2-f)(1,2,4)triazine-6-carboxamide; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D019275:Radiopharmaceuticals; D014227:Triazines; D019788:Fluorodeoxyglucose F18; D002097:C-Reactive Protein; D000069059:Atorvastatin; D048051:p38 Mitogen-Activated Protein Kinases
Atherosclerosis; FDG; Imaging; Inflammation; MAPK