Journal Articles

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

June 12, 2014

Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. The Lancet. June 12, 2014. Prof L Kristin Newby, MDa; Prof Michael S Marber, MBBSc; Chiara Melloni, MDa; Lea Sarov-Blat,PhDd; Laura H Aberle, BSPHa; Prof Philip E Aylward, BM BChe; Gengqian Cai, PhDd; Prof Robbert J de Winter, MDf; Prof Christian W Hamm, MDg; John F Heitner, MDh; Prof Raymond Kim, MDb; Amir Lerman,MDi; Manesh R Patel, MDa; Prof Jean-Francois Tanguay, MDj; John J Lepore, MDd; Hussein R Al-Khalidi,PhDa; Dennis L Sprecher, MDd;Prof Christopher B Granger, MDa, on behalf of the SOLSTICE Investigators

Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; King’s College London BHF Centre, Cardiovascular Division, Rayne Institute, St Thomas’ Hospital, London, UK; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; South Australian Health and Medical Research Institute, Flinders University and Medical Centre, Adelaide, SA, Australia; Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA; Department of Cardiology, Academic Medical Center—University of Amsterdam, Amsterdam, Netherlands; Kerckhoff Heart and Thoraxcenter, Bad Nauheim, Germany; Division of Cardiology, New York Methodist Hospital, Brooklyn, NY, USA; Division of Cardiology, Department of Medicine, Duke University School of Medicine, Durham, NC, USA; Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; Montreal Heart Institute, Université de Montréal, Montreal, QC, Canada; Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA; Heart Failure Discovery Performance Unit, GlaxoSmithKline, Philadelphia, PA, USA; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC, USA.

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.

Findings

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 32·3–42·9vs 49·4 ng/L, 38·7–63·0; p=0·04). Mean troponin I AUC values did not differ.

Interpretation

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

Funding GlaxoSmithKline.

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