Safety and Efficacy of Losmapimod in Non-ST-Segment Elevation Acute Myocardial Infarction - SOLSTICE

Description:

Losmapimod is a novel p38 mitogen-activated protein kinase (MAPK) inhibitor that has been shown in preclinical studies to improve vascular function, reduce plaque inflammation, and reduce infarct size. The current trial is a phase II trial that sought to study the safety and efficacy of losmapimod in patients with non–ST-segment elevation myocardial infarction (NSTEMI).

Hypothesis:

Losapimod would be safe and efficacious compared with placebo in reducing inflammatory biomarkers and infarct size in patients with NSTEMI.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Age ≥45 years
  • Symptoms within 24 hours of presentation
  • No persistent ST elevations
  • Local lab troponin (T or I) >ULN
  • Randomization within 18 hours of presentation
  • Early invasive strategy planned, with PCI >2 hours post first study drug

    Number of enrollees: 526
    Duration of follow-up: 3 months
    Mean patient age: 63 years
    Percentage female: 29%

Primary Endpoints:

Safety:
- Adverse events
- Serious adverse events
- Clinical outcomes (death, MI, stroke, recurrent ischemia, heart failure)

Efficacy (co-primary):
- hs-CRP at 12 weeks
- Troponin I AUC (through 72 hours)

Secondary Endpoints:

  • hs-CRP time course
  • IL-6 time course
  • Peak troponin I (at 72 hours or hospital discharge)
  • BNP (at discharge or at 12 weeks)
  • Infarct size as % of LV and LVEF (CMR)

Drug/Procedures Used:

Patients with NSTEMI were randomized in a 1:1:1 fashion to either losmapimod 7.5 mg initially followed by 7.5 mg BID, losmapimod 15 mg loading followed by 7.5 mg BID, or placebo.

Concomitant Medications:

Statins (93%)

Principal Findings:

A total of 526 patients were randomized: 199 to 7.5 mg BID losmapimod, 192 to 15 mg loading + 7.5 mg BID losmapimod (391 total in both losmapimod arms), and 135 to placebo. Approximately 30% had diabetes mellitus, and 21% had undergone prior percutaneous coronary intervention (PCI). The median duration of symptoms was 3.2 hours. PCI was performed in 59%, coronary artery bypass grafting (CABG) in 13%, and the remainder were medically managed. Premature withdrawal from the study was high (approximately 36%), although only about 7% were due to adverse events. Adverse effects were common (70%), although serious adverse events were noted in approximately 24% in both arms. The incidence of hepatic transaminitis (3 x upper limit of normal [ULN]) was about 2% with losmapimod.

Median high-sensitivity C-reactive protein (hs-CRP) levels were lower in the losmapimod arm as compared with placebo at 72 hours (7.4 vs. 15.3, p < 0.001), but not at 12 weeks (1.4 vs. 1.5, p = 0.30). Similarly, median interleukin (IL)-6 levels were lower in the losmapimod arm as compared with placebo at 24 hours (6.6 vs. 10.6, p < 0.001), but not at 12 weeks (2.4 vs. 2.6, p = 0.25). There was no difference in troponin I area under the curve (AUC) (p = 0.62) or peak troponin I AUC (p = 0.76). B-type natriuretic peptide (BNP) levels were similar at 72 hours (66.6 vs. 72.3 pg/ml, p = 0.50), but lower with losmapimod at 12 weeks (37.2 vs. 49.4 pg/ml, p = 0.04).

The composite clinical outcome (death, MI, stroke, recurrent ischemia, congestive heart failure) was similar between the two arms (16.4% vs. 18.2%, p = 0.56). Similarly, death/MI/stroke was similar (12.9% vs. 15%, p = 0.59). In the cardiac magnetic resonance (CMR) subset at week 12 (n = 93), losmapimod was associated with higher left ventricular ejection fraction (LVEF) as compared with placebo (5.14%, 95% confidence interval [CI] 0.28-10.0%, p = 0.039), with a favorable trend towards infarct size reduction (-2.19, 95% CI -4.78 to 0.40).

Interpretation:

The results of the phase II SOLSTICE trial indicate that losmapimod, a novel p38 MAPK inhibitor, is reasonably safe in patients with NSTEMI, although study drug discontinuation was high in this study. Losmapimod was noted to have salutary effects on acute inflammatory biomarkers, with lower BNP and improved LVEF noted at 3 months. Further studies are needed to assess the clinical utility of this class of drugs in patients with NSTEMI.

p38 MAPKs are a class of protein kinases that are responsive to various stress stimuli (cytokines, UV, heat shock, etc.) and are involved in cell differentiation, apoptosis, and autophagy. p38 MAPK inhibitors are also being tested in autoimmune diseases and inflammatory diseases such as chronic obstructive pulmonary disease.

References:

Presented by Dr. L. Kristin Newby at American Heart Association Scientific Sessions, Los Angeles, CA, November 5, 2012.

Clinical Topics: Cardiac Surgery, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Aortic Surgery, Cardiac Surgery and Heart Failure, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Follow-Up Studies, Cytokines, Autoimmune Diseases, Biological Markers, Troponin I, Stroke Volume, Confidence Intervals, Cyclopropanes, Magnetic Resonance Spectroscopy, Natriuretic Peptide, Brain, Inflammation, Myocardial Infarction, Apoptosis, Area Under Curve, Interleukin-6, Troponin T, Pyridines, Autophagy, Percutaneous Coronary Intervention, Pulmonary Disease, Chronic Obstructive, C-Reactive Protein, Heart Failure, p38 Mitogen-Activated Protein Kinases, Coronary Artery Bypass, Diabetes Mellitus, Cell Differentiation


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