title: Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.
abstract: BACKGROUND
  p38 MAPK inhibition has potential myocardial protective effects. We assessed losmapimod, a potent oral p38 MAPK inhibitor, in patients with non-ST-segment elevation myocardial infarction (NSTEMI) in a double-blind, randomised, placebo-controlled trial.
  
  
  METHODS
  From October, 2009, to November, 2011, NSTEMI patients were assigned oral losmapimod (7·5 mg or 15·0 mg loading dose followed by 7·5 mg twice daily) or matching placebo in a 3:3:2 ratio. Safety outcomes were serious adverse events and alanine aminotransferase (ALT) concentrations over 12 weeks, and cardiac events (death, myocardial infarction, recurrent ischaemia, stroke, and heart failure) at 90 days. Efficacy outcomes were high-sensitivity C-reactive protein (hsCRP) and B-type natriuretic peptide (BNP) concentrations at 72 h and 12 weeks, and troponin I area under the curve (AUC) over 72 h. The losmapimod groups were pooled for analysis. This trial is registered with ClinicalTrials.gov, number NCT00910962.
  
  
  RESULTS
  Of 535 patients enrolled, 526 (98%) received at least one dose of study treatment (losmapimod n=388 and placebo n=138). Safety outcomes did not differ between groups. HsCRP concentrations at 72 h were lower in the losmapimod group than in the placebo group (geometric mean 64·1 nmol/L, 95% CI 53·0-77·6 vs 110·8 nmol/L, 83·1-147·7; p=0·0009) but were similar at 12 weeks. Early geometric mean BNP concentrations were similar at 72 h but significantly lower in the losmapimod group at 12 weeks (37·2 ng/L, 95% CI 32·3-42·9 vs 49·4 ng/L, 38·7-63·0; p=0·04). Mean troponin I AUC values did not differ.
  
  
  CONCLUSIONS
  p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes.
  
  
  BACKGROUND
  GlaxoSmithKline.
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA. Electronic address: kristin.newby@duke.edu.
authors.forename: L Kristin
authors.initials: LK
authors.lastname: Newby
authors.affiliation: King's College London BHF Centre, Cardiovascular Division, Rayne Institute, St Thomas' Hospital, London, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Marber
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Chiara
authors.initials: C
authors.lastname: Melloni
authors.affiliation: Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: Lea
authors.initials: L
authors.lastname: Sarov-Blat
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Aberle
authors.affiliation: South Australian Health and Medical Research Institute, Flinders University and Medical Centre, Adelaide, SA, Australia.
authors.forename: Philip E
authors.initials: PE
authors.lastname: Aylward
authors.affiliation: Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: Gengqian
authors.initials: G
authors.lastname: Cai
authors.affiliation: Department of Cardiology, Academic Medical Center-University of Amsterdam, Amsterdam, Netherlands.
authors.forename: Robbert J
authors.initials: RJ
authors.lastname: de Winter
authors.affiliation: Kerckhoff Heart and Thoraxcenter, Bad Nauheim, Germany.
authors.forename: Christian W
authors.initials: CW
authors.lastname: Hamm
authors.affiliation: Division of Cardiology, New York Methodist Hospital, Brooklyn, NY, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Heitner
authors.affiliation: Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Kim
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
authors.forename: Amir
authors.initials: A
authors.lastname: Lerman
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Manesh R
authors.initials: MR
authors.lastname: Patel
authors.affiliation: Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada.
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Tanguay
authors.affiliation: Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Lepore
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Hussein R
authors.initials: HR
authors.lastname: Al-Khalidi
authors.affiliation: Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA.
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Sprecher
authors.affiliation: Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.
authors.forename: Christopher B
authors.initials: CB
authors.lastname: Granger
mesh_terms: D000368:Aged; D019540:Area Under Curve; D003521:Cyclopropanes / Q000008:administration & dosage*; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D018810:Magnetic Resonance Angiography; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000401:mortality; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D016896:Treatment Outcome; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: C543534:6-(5-((cyclopropylamino)carbonyl)-3-fluoro-2-methylphenyl)-N-(2,2-dimethylprpyl)-3-pyridinecarboxamide; D003521:Cyclopropanes; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D048051:p38 Mitogen-Activated Protein Kinases