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

L Newby, Michael Marber, Chiara Melloni, Lea Sarov-Blat, Laura Aberle, Philip Aylward, Gengqian Cai, Robbert De Winter, Christian Hamm, John Heitner, Raymond Kim, Amir Lerman, Manesh Patel, Jean-François Tanguay, John Lepore, Hussein Al-Khalidi, Dennis Sprecher, Christopher Granger

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    Abstract

    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.

    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.

    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 32·3-42·9 vs 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.

    Original languageEnglish
    Pages (from-to)1187-1195
    Number of pages9
    JournalLancet
    Volume384
    Issue number9949
    DOIs
    Publication statusPublished - 2014

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  • Cite this

    Newby, L., Marber, M., Melloni, C., Sarov-Blat, L., Aberle, L., Aylward, P., Cai, G., De Winter, R., Hamm, C., Heitner, J., Kim, R., Lerman, A., Patel, M., Tanguay, J-F., Lepore, J., Al-Khalidi, H., Sprecher, D., & Granger, C. (2014). Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: A randomised phase 2 trial. Lancet, 384(9949), 1187-1195. https://doi.org/10.1016/S0140-6736(14)60417-7