Journal Article

Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial

de Winter, Robbert J, Heitner, John F, Cai, Gengqian, Lerman, Amir, Granger, Christopher B, Newby, L Kristin, Marber, Michael S, Melloni, Chiara, Al-Khalidi, Hussein R, Aberle, Laura H, Kim, Raymond, Sarov-Blat, Lea, Hamm, Christian W, Patel, Manesh R, Lepore, John J, Sprecher, Dennis L, Aylward, Philip E, Tanguay, Jean-Francois

2014

Overview

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. 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. 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. p38 MAPK inhibition with oral losmapimod was well tolerated in NSTEMI patients and might improve outcomes after acute coronary syndromes. GlaxoSmithKline.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: Acute coronary syndromes / Aged / Area Under Curve / Biological and medical sciences / Biomarkers / Cardiology. Vascular system / Cardiovascular system / Coronary heart disease / Cyclopropanes - administration & dosage / Double-Blind Method / Drug Administration Schedule / Female / Heart / Heart attacks / Heart failure / Humans / Internal Medicine / Kaplan-Meier Estimate / Kinases / Magnetic Resonance Angiography / Male / Medical sciences / Middle Aged / Miscellaneous / Myocardial infarction / Myocardial Infarction - drug therapy / Myocardial Infarction - mortality / p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors / Patient safety / Pharmacology. Drug treatments / Protein Kinase Inhibitors - administration & dosage / Proteins / Pyridines - administration & dosage / Stroke / Treatment Outcome