Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial

Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial

Canakinumab targets IL-1beta, a highly specific mediator of inflammation

• the IL-1 pathway has considerable preclinical data to support its involvement in atherogenesis
  • atherogenesis can be described as an inflammatory processs that leads to lipid accumulation in monocyte-derived macrophages that become foam cells
    
    
• CANTOS investigators tested the hypothesis that inhibiting the action of the cytokine interleukin-1 (IL-1) beta would have beneficial effects on a composite endpoint in patients with a prior myocardial infarction and a high-sensitivity C-reactive protein (hsCRP) level that constituted a vascular risk (=2 mg/L) (2)
  • three different doses of the IL-1 beta neutralising antibody Canakinumab were tested against placebo over 48 months
    • trial compared three doses of canakinumab (50 mg, 150 mg, and 300 mg, administered subcutaneously every 3 months) with placebo. The primary efficacy end point was nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death.
      
      
  • a dose-dependent reduction in hsCRP was demonstrated without significant alteration in lipid levels
    • Canakinumab did not reduce lipid levels from baseline
      
      
    • there was a dose graded reduction in the primary endpoint of first occurrence of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death with the pre-specified, complex statistical threshold for primary and secondary endpoints being met with the 150-mg dose. There was no difference in all-cause mortality, however, there was a significant increase in infection-related deaths when all treated patients were compared with placebo
      
      
    • the study authors concluded "Antiinflammatory therapy targeting the interleukin-1ß innate immunity pathway with canakinumab at a dose of 150 mg every 3 months led to a significantly lower rate of recurrent cardiovascular events than placebo, independent of lipid-level lowering"

Reference:

• Tabas I, Lichtman AH. Monocyte-macrophages and T cells in atherosclerosis. Immunity 2017;47:621-34
• Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31