Meeting NewsPerspective

New from CANTOS: Outcomes improve when canakinumab affects IL-6 pathway

Paul Ridker
Paul M. Ridker

MUNICH — Modulation of the interleukin-6 signaling pathway with canakinumab treatment was associated with reduced CV events, regardless of lipid levels, according to new data from the CANTOS trial reported at the European Society of Cardiology Congress.

Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, and colleagues analyzed 4,833 patients with stable atherosclerosis, history of MI and elevated C-reactive protein levels who had IL-6 levels measured before randomization and after treatment with placebo or subcutaneous canakinumab (Novartis) 50 mg, 150 mg or 300 mg every 3 months.

Ridker and colleagues analyzed whether on-treatment IL-6 levels impacted the rate of major adverse CV events. The findings were simultaneously published in the European Heart Journal.

“IL-6 is a central signaling cytokine in the innate immunity cascade,” Ridker said during a presentation. “Plasma IL-6 levels predict future vascular risk independent of traditional risk factors. Mendelian randomization studies suggest that polymorphism in the IL-6 receptor signaling pathway associates with both downstream high-sensitivity CRP levels and lifelong risks of coronary heart disease. Interleukin 1-beta, the target of canakinumab, induces IL-6 production by several cell types including vascular endothelium and smooth muscle cells. Addressing both baseline and on-treatment levels of IL-6 levels in CANTOS could provide pathophysiologic insights with relevance for inflammation biology and for the development of novel agents for cardiovascular protection.”

Compared with placebo, patients assigned canakinumab who had on-treatment IL-6 levels below the cohort median value of 1.65 ng/mL had a 32% reduction in major adverse CV events (adjusted HR = 0.68; 95% CI, 0.56-0.82), Ridker said.

Additionally, patients assigned canakinumab who achieved IL-6 levels below the median also had reduced risk for major adverse CV events plus unstable angina requiring urgent revascularization (adjusted HR = 0.7; 95% CI, 0.59-0.84), CV mortality (adjusted HR = 0.48; 95% CI, 0.34-0.68) and all-cause mortality (adjusted HR = 0.52; 95% CI, 0.4-0.68).

However, those assigned canakinumab who had IL-6 levels above the median after the first dose of the drug had no benefit above placebo in any outcomes, Ridker said.

“CANTOS demonstrates that targeting the IL-1-beta-to-IL-6 pathway of innate immunity with canakinumab reduces cardiovascular event rates. CANTOS thus provides critical proof-of-concept that inflammation inhibition, in the absence of lipid lowering or blood pressure reduction, can improve atherothrombotic outcomes,” Ridker said. “The current analysis suggests that the magnitude of IL-6 reduction following a single dose of canakinumab tracks closely with the anticipated clinical benefits of long-term canakinumab treatment.” – by Erik Swain

References:

Ridker PM, et al. Clinical Trial Updates. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.

Ridker PM, et al. Eur Heart J. 2018;doi:10.1093/eurheartj/ehy310.

Disclosures: The study was funded by Novartis. Ridker reports he has consulted for and received grant support from Novartis and is listed as co-inventor on patents related to inflammatory biomarkers in diabetes and CVD held by Brigham and Women’s Hospital and licensed to AstraZeneca and Siemens. Please see the study for a list of the other authors’ relevant financial disclosures.

Paul Ridker
Paul M. Ridker

MUNICH — Modulation of the interleukin-6 signaling pathway with canakinumab treatment was associated with reduced CV events, regardless of lipid levels, according to new data from the CANTOS trial reported at the European Society of Cardiology Congress.

Paul M. Ridker, MD, MPH, director of the Center for Cardiovascular Disease Prevention and the Eugene Braunwald Professor of Medicine at Brigham and Women’s Hospital, and colleagues analyzed 4,833 patients with stable atherosclerosis, history of MI and elevated C-reactive protein levels who had IL-6 levels measured before randomization and after treatment with placebo or subcutaneous canakinumab (Novartis) 50 mg, 150 mg or 300 mg every 3 months.

Ridker and colleagues analyzed whether on-treatment IL-6 levels impacted the rate of major adverse CV events. The findings were simultaneously published in the European Heart Journal.

“IL-6 is a central signaling cytokine in the innate immunity cascade,” Ridker said during a presentation. “Plasma IL-6 levels predict future vascular risk independent of traditional risk factors. Mendelian randomization studies suggest that polymorphism in the IL-6 receptor signaling pathway associates with both downstream high-sensitivity CRP levels and lifelong risks of coronary heart disease. Interleukin 1-beta, the target of canakinumab, induces IL-6 production by several cell types including vascular endothelium and smooth muscle cells. Addressing both baseline and on-treatment levels of IL-6 levels in CANTOS could provide pathophysiologic insights with relevance for inflammation biology and for the development of novel agents for cardiovascular protection.”

Compared with placebo, patients assigned canakinumab who had on-treatment IL-6 levels below the cohort median value of 1.65 ng/mL had a 32% reduction in major adverse CV events (adjusted HR = 0.68; 95% CI, 0.56-0.82), Ridker said.

Additionally, patients assigned canakinumab who achieved IL-6 levels below the median also had reduced risk for major adverse CV events plus unstable angina requiring urgent revascularization (adjusted HR = 0.7; 95% CI, 0.59-0.84), CV mortality (adjusted HR = 0.48; 95% CI, 0.34-0.68) and all-cause mortality (adjusted HR = 0.52; 95% CI, 0.4-0.68).

However, those assigned canakinumab who had IL-6 levels above the median after the first dose of the drug had no benefit above placebo in any outcomes, Ridker said.

“CANTOS demonstrates that targeting the IL-1-beta-to-IL-6 pathway of innate immunity with canakinumab reduces cardiovascular event rates. CANTOS thus provides critical proof-of-concept that inflammation inhibition, in the absence of lipid lowering or blood pressure reduction, can improve atherothrombotic outcomes,” Ridker said. “The current analysis suggests that the magnitude of IL-6 reduction following a single dose of canakinumab tracks closely with the anticipated clinical benefits of long-term canakinumab treatment.” – by Erik Swain

References:

Ridker PM, et al. Clinical Trial Updates. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.

Ridker PM, et al. Eur Heart J. 2018;doi:10.1093/eurheartj/ehy310.

Disclosures: The study was funded by Novartis. Ridker reports he has consulted for and received grant support from Novartis and is listed as co-inventor on patents related to inflammatory biomarkers in diabetes and CVD held by Brigham and Women’s Hospital and licensed to AstraZeneca and Siemens. Please see the study for a list of the other authors’ relevant financial disclosures.

    Perspective

    This analysis further solidifies the relationship between IL-6 and coronary atherothrombosis, which we might now be able to consider a causal relationship, and the impact of reducing IL-6 on clinical endpoints. This analysis is important because the dose response and reduction in IL-6 correlated nicely, and the reduction in the primary endpoint was independent of LDL. It is truly proving the inflammatory hypothesis. That is not to minimize the importance of LDL reduction, but this is proof of principle emphasized, and something that is very, very exciting.

    The data are strong because the trial had 10,000 individuals with coronary disease, prior MI and hsCRP > 2 mg/mL. It appears there was a threshold at the 150-mg dose. Now there is a dose response for lowering IL-6. The question then becomes, is this the drug to help these patients? Do we now move to have it approved? It won’t replace LDL lowering as a goal of treatment, but would be aimed specifically at patients with residual inflammation in the setting of coronary atherosclerosis. This is a drug that seems to be well-tolerated when given every 6 months. One can consider other formulations or a drug that goes farther downstream in the inflammation cascade, inhibiting IL-1. It opens up potential for other drugs; for example, there are other IL-6 inhibitors indicated for arthritis. I believe we will see a lot of development in this space. The platform and the foundation are now so strong that it will open up opportunities to test this even further.

    The cardiology community was excited when the initial CANTOS results were released 1 year ago, and now we are even more excited. We look forward to our patients being the beneficiaries of these observations.

    • Richard Becker, MD

    • Mabel Stonehill Endowed Professor of Medicine
      Chief, Division of Cardiovascular Health and Disease
      University of Cincinnati

    Disclosures: Becker reports no relevant financial disclosures.

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