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

Publication ,  Journal Article
Newby, LK; Marber, MS; Melloni, C; Sarov-Blat, L; Aberle, LH; Aylward, PE; Cai, G; de Winter, RJ; Hamm, CW; Heitner, JF; Kim, R; Lerman, A ...
Published in: Lancet
September 27, 2014

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 32·3-42·9 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.

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Published In

Lancet

DOI

EISSN

1474-547X

Publication Date

September 27, 2014

Volume

384

Issue

9949

Start / End Page

1187 / 1195

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Treatment Outcome
  • Pyridines
  • Protein Kinase Inhibitors
  • Myocardial Infarction
  • Middle Aged
  • Male
  • Magnetic Resonance Angiography
  • Kaplan-Meier Estimate
  • Humans
 

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Newby, L. K., Marber, M. S., Melloni, C., Sarov-Blat, L., Aberle, L. H., Aylward, P. E., … SOLSTICE Investigators, . (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
Newby, L Kristin, Michael S. Marber, Chiara Melloni, Lea Sarov-Blat, Laura H. Aberle, Philip E. Aylward, Gengqian Cai, et al. “Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.Lancet 384, no. 9949 (September 27, 2014): 1187–95. https://doi.org/10.1016/S0140-6736(14)60417-7.
Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, et al. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet. 2014 Sep 27;384(9949):1187–95.
Newby, L. Kristin, et al. “Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial.Lancet, vol. 384, no. 9949, Sept. 2014, pp. 1187–95. Pubmed, doi:10.1016/S0140-6736(14)60417-7.
Newby LK, Marber MS, Melloni C, Sarov-Blat L, Aberle LH, Aylward PE, Cai G, de Winter RJ, Hamm CW, Heitner JF, Kim R, Lerman A, Patel MR, Tanguay J-F, Lepore JJ, Al-Khalidi HR, Sprecher DL, Granger CB, SOLSTICE Investigators. Losmapimod, a novel p38 mitogen-activated protein kinase inhibitor, in non-ST-segment elevation myocardial infarction: a randomised phase 2 trial. Lancet. 2014 Sep 27;384(9949):1187–1195.
Journal cover image

Published In

Lancet

DOI

EISSN

1474-547X

Publication Date

September 27, 2014

Volume

384

Issue

9949

Start / End Page

1187 / 1195

Location

England

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Treatment Outcome
  • Pyridines
  • Protein Kinase Inhibitors
  • Myocardial Infarction
  • Middle Aged
  • Male
  • Magnetic Resonance Angiography
  • Kaplan-Meier Estimate
  • Humans