Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction

Background An enhanced inflammatory response predicts worse outcomes in heart failure (HF). We hypothesized that administration of Interleukin-1 (IL-1) receptor antagonist (anakinra) could inhibit the inflammatory response and improve peak aerobic exercise capacity in patients with recently decompensated systolic HF. Methods and Results We randomly assigned 60 patients with reduced left ventricular ejection fraction (<50%) and elevated C-reactive protein (CRP) levels (>2 mg/L), within 14 days of hospital discharge, to daily subcutaneous injections with anakinra 100 mg for 2 weeks, 12 weeks, or placebo. Patients underwent measurement of peak oxygen consumption (VO2 [mL•kg−1•min−1]) and ventilatory efficiency (the VE/VCO2 slope). Treatment with anakinra did not affect peak VO2 or VE/VCO2 slope at 2 weeks. At 12 weeks, patients continued on anakinra showed an improvement in peak VO2 from 14.5 [10.5–16.6] to 16.1 [13.2–18.6] mL•kg−1•min−1 (P=0.009 for within-group changes), whereas no significant changes occurred within the anakinra 2-week or placebo groups. The between groups differences, however, were not statistically significant. The incidence of death or re-hospitalization for HF at 24 weeks was 6%, 31%, and 30%, in the anakinra 12-week, anakinra 2-week and placebo groups, respectively (Log-rank test P=0.10). Conclusions No change in peak VO2 occurred at 2 weeks in patients with recently decompensated systolic HF treated with anakinra, whereas an improvement was seen in those patients in whom anakinra was continued for 12 weeks. Additional larger studies are needed to validate the effects of prolonged anakinra on peak VO2 and re-hospitalization for HF.

show abstract

“…There is, however, no evidence of ‘rebound’ (to above baseline levels) which is seen with other anti-inflammatory drugs (i.e. losmapimod 32 ).…”

Section: Discussionmentioning

confidence: 92%

Interleukin-1 Blockade in Recently Decompensated Systolic Heart Failure

Tassell

Canada

Carbone

et al. 2017

Circ: Heart Failure

181

View full text Add to dashboard Cite

show abstract

“…36 Clinical trials with the p38α/β inhibitor losmapimod have shown improvement of vascular endothelial function and reduction of inflammation both systemically and locally in the atherosclerotic plaques, 36 yet a recent trial failed to show a reduction in major adverse cardiovascular events in patients presenting with acute coronary syndrome. 37 Together with the data from the p38α/β inhibitor trials, the new data presented here on the proinflammatory role of the p38δ isoform may shift the focus of p38 MAPK research in cardiovascular disease toward this less studied isoform.…”

Section: Limitations Of the Studymentioning

confidence: 75%

p38δ MAPK

Rajamäki

Mäyränpää

Risco

et al. 2016

ATVB

View full text Add to dashboard Cite

Objective— Activation of the inflammasome pathway in macrophages results in the secretion of 2 potent proinflammatory and proatherogenic cytokines, interleukin (IL)-1β, and IL-18. Atherosclerotic lesions are characterized by the presence of various endogenous activators of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, including cholesterol crystals and extracellular ATP. The aim of this study was to comprehensively characterize the expression of inflammasome pathway components and regulators in human atherosclerotic lesions. Approach and Results— Twenty human coronary artery RNA samples from 10 explanted hearts were analyzed using an inflammasome pathway–focused quantitative polymerase chain reaction array. Advanced atherosclerotic plaques, when compared with early-to-intermediate lesions from the same coronary trees, displayed significant upregulation of 12 target genes, including the key inflammasome components apoptosis-associated speck-like protein containing a CARD domain, caspase-1, and IL-18. Immunohistochemical stainings of the advanced plaques revealed macrophage foam cells positive for NLRP3 inflammasome components around the necrotic lipid cores. The polymerase chain reaction array target p38δ mitogen-activated protein kinase was upregulated in advanced plaques and strongly expressed by lesional macrophage foam cells. In cultured human monocyte–derived macrophages, the p38δ mitogen-activated protein kinase was activated by intracellular stress signals triggered during ATP- and cholesterol crystal–induced NLRP3 inflammasome activation and was required for NLRP3-mediated IL-1β secretion. Conclusions— Increased expression of the key inflammasome components in advanced coronary lesions implies enhanced activity of the inflammasome pathway in progression of coronary atherosclerosis. The p38δ mitogen-activated protein kinase was identified as a novel regulator of NLRP3 inflammasome activation in primary human macrophages, and thus, represents a potential target for modulation of atherosclerotic inflammation.

show abstract

“…A recently completed large phase III trial to study the ability of Losmapimod (a selective p38 inhibitor) to reduce the incidence of cardiovascular events in subjects with acute coronary syndrome (LATITUDE-TIMI 60, NCT02145468) showed a good safety profile. 48 Similarly, MEK1/2 (the upstream activator of Erk1/2) inhibitors are being currently tested in phase III trials for the treatment of multiple oncologic pathologies, 49,50 and Trametinib, a MEK1/2 inhibitor, has been approved for the treatment of melanoma containing BRAFV600E or V600K mutations. 40,50 While other fields have adopted kinase inhibitors, the use of cellular therapies in the treatment of rosacea is a novel, highly exciting opportunity to enhance the lives of patients that suffer from this currently incurable disease.…”

Section: Discussionmentioning

confidence: 99%