Antiinflammatory Therapy with Canakinumab for Atherosclerotic Disease

In the CANTOS trial, reduction of CRP levels to less than 2 mg/L lowered the risk of cardiovascular death by one-third independent of other cardiovascular risk factors.

“The CANTOS (Ridker et al., 2017) trial was the first large intervention study confirming that a reduction of CRP levels to less than 2 mg/L lowered the risk of cardiovascular death by one‐third independent of any other cardiovascular risk factors in a sample of 10,000 patients with established CVD.”

Recent data from the CANTOS trial showed that a 1.6-1.7 mg/dL reduction in hs-CRP was associated with a 17% reduction in major vascular events.

“Recent data from the CANTOS trial showed that a 1.6-1.7 mg/dL reduction in hs-CRP was associated with a 17% reduction in major vascular events.50”

An exploratory analysis of a clinical trial evaluating systemic administration of an IL1B neutralizing antibody for ischemic cardiac disease identified a reduction in heart failure hospitalization and heart-failure related mortality.

“an exploratory analysis of a clinical trial evaluating systemic administration of an IL1B neutralizing antibody for the treatment of ischemic cardiac disease36 identified a reduction in heart failure hospitalization and heart-failure related mortality37.”

Anti-inflammatory therapies targeting essential immune modulators are associated with serious adverse events such as a higher incidence of fatal infection and sepsis.

“they are also associated with serious adverse events such as a higher incidence of fatal infection and sepsis36,38.”

A large clinical trial targeting the IL-1β pathway with the neutralizing antibody canakinumab led to a reduction in cardiac events.

“In support of this concept, a large clinical trial targeting the IL-1β pathway with the neutralizing antibody canakinumab led to a reduction in cardiac events31.”

Canakinumab, an anti-IL-1β monoclonal antibody, has clinical efficacy.

“We chose to focus on IL-1β signalling given the availability and clinical efficacy of the anti-IL-1β monoclonal antibody (mAb) canakinumab31.”

Trials have shown that targeted inhibition of the inflammatory pathway, as measured by changes in CRP concentrations, can reduce the rate of cardiovascular events.

“Trials have shown that targeted inhibition of this inflammatory pathway, as measured by changes in CRP concentrations, can reduce the rate of cardiovascular events.5, 6, 7”

The efficacy of GLP-1 medications is consistent with actions of other antiinflammatory agents, such as IL-1 antagonists and colchicine, in reducing cardiovascular events.

“The efficacy of GLP-1 medications is consistent with actions of other antiinflammatory agents, such as IL-1 antagonists and colchicine, in reducing cardiovascular events (63, 64).”

A large clinical trial targeting the IL-1β pathway with canakinumab led to a reduction in ischemic cardiac events.

“a large clinical trial targeting the IL-1 β pathway with the neutralizing antibody, canakinumab, led to a reduction in ischemic cardiac events 36 .”

Reduction in LDL-C has been strongly associated with improved cardiovascular outcomes.

“Reduction in LDL-C has been strongly associated with improved cardiovascular outcomes, and 3 recent trials have demonstrated favorable effects with anti-inflammatory therapies.[21][22][23][24]”

Three recent trials have demonstrated favorable effects with anti-inflammatory therapies.

“Reduction in LDL-C has been strongly associated with improved cardiovascular outcomes, and 3 recent trials have demonstrated favorable effects with anti-inflammatory therapies.[21][22][23][24]”

In the recent CANTOS, a human monoclonal antibody targeting IL-1β led to a reduction in cardiovascular event rates in individuals with a previous myocardial infarction.

“In the recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcome Study), a human monoclonal antibody targeting IL-1β led to a reduction in cardiovascular event rates in individuals with a previous myocardial infarction.58”

In prior large trials (JUPITER, CIRT, CANTOS, SPIRE), placebo groups showed no substantive changes in LDL cholesterol, IL-1β, IL-6, or hsCRP over 3-5 years, and in STRENGTH (corn oil placebo) biomarker levels did not increase over time.

“No substantive biomarker changes were observed in the placebo groups over periods of 3 to 5 years for measures of LDL cholesterol, interleukin-1β, interleukin-6, or hsCRP in the large-scale JUPITER (Justification for the Use of Statin in Prevention: An Intervention Trial Evaluating Rosuvastatin), CIRT (Cardiovascular Inflammation Reduction Trial), CANTOS (Canakinumab Anti-Inflammatory Thrombosis”

Treatment with a targeted interleukin-1β inhibitor has demonstrated clinical benefit.

“where treatment with a targeted interleukin-1β inhibitor has demonstrated clinical benefit.6”

The intimate involvement of inflammation in all stages of atherosclerosis makes intervention to modulate systemic or local inflammatory responses an attractive route to reducing CV risk.

“The intimate involvement of inflammation in all stages of atherosclerosis makes intervention to modulate systemic or local inflammatory responses an attractive route to reducing CV risk (30).”

In the CANTOS study, inhibition of interleukin-1β with canakinumab significantly reduced cardiovascular risk independently of lipid levels.

“In the CANTOS study, inhibition of interleukin-1β with canakinumab significantly reduced cardiovascular risk independently of lipid levels [78].”

Inflammation has a causal role in cardiovascular disease, as established by the CANTOS trial.

“Inflammation’s causal role in cardiovascular disease was established by the CANTOS trial (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), which demonstrated that IL-1β inhibition reduced the risk of cardiovascular events versus the placebo, particularly in participants whose IL-6 levels were initially elevated (7).”

IL-1β inhibition reduced the risk of cardiovascular events versus placebo, particularly in participants whose IL-6 levels were initially elevated.

“which demonstrated that IL-1β inhibition reduced the risk of cardiovascular events versus the placebo, particularly in participants whose IL-6 levels were initially elevated (7).”

The blood and tissue level of IL-6, TNF-α, and CRP increases with age and, to varying degrees, has been associated with adverse age-related outcomes, including physical frailty, cardiovascular disease, dementia, and mortality.

“The blood and tissue level of these proteins increases with age (97) and, to varying degrees, has been associated with adverse age-related outcomes, including physical frailty (98), cardiovascular disease (7, 99), dementia (100), and mortality (101).”

In a double-blind randomized controlled trial of more than 10,000 adults with prior myocardial infarction and elevated CRP, canakinumab given every 3 months lowered rates of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death compared with placebo, without changing LDL cholesterol.

“a recent double-blind RCT of the IL-1β inhibitor canakinumab that assessed more than 10,000 adults with a history of myocardial infarction and elevated circulating CRP levels showed that patients treated with canakinumab subcutaneously every 3 months had lower rates of nonfatal myocardial infarction, nonfatal stroke and CVD death compared with those treated with a placebo, despite having no change”

Canakinumab-treated patients had a lower likelihood of unstable angina leading to urgent revascularization.

“canakinumab-treated patients also exhibited a lower likelihood of unstable angina leading to urgent revascularization44.”

Targeting inflammation can provide significant, clinically relevant cardiovascular benefit.

“The Canakinumab Anti-inflammatory Thrombosis Outcome Study (CANTOS) showed that targeting inflammation can provide significant, clinically relevant cardiovascular benefit.2”

Canakinumab, an anti-IL-1β antibody, significantly reduces recurrent cardiovascular events in stable patients with residual inflammation after myocardial infarction, independent of lipid lowering.

“anti-inflammatory therapy with canakinumab, a human monoclonal anti-IL-1β antibody, significantly reduced recurrent cardiovascular events in >10,000 stable patients who had residual inflammation after myocardial infarction, independent of lowered lipid levels”

Fibroatheromas rarely progress to rupture in animal models, exemplified by the neutralising IL1β antibody being deleterious on the fibrous cap in mice but beneficial in reducing cardiovascular events in the CANTOS trial in humans.

“Another fundamental difference is that fibroatheromas rarely progress to rupture in animal models, exemplified by the recently reported effects of a neutralising IL1 β antibody, which were deleterious on the fibrous cap in mice 141 , but beneficial in reducing cardiovascular events in the CANTOS trial in humans 197 .”

In the CANTOS trial, patients with advanced coronary atherosclerosis on maximal LDL-lowering therapy had an additional reduction in recurrent cardiovascular events when IL-1β was inhibited.

“The results of this study in patients with advanced coronary atherosclerosis who were receiving maximal LDL-lowering therapy showed an additional benefit in the reduction of the rate of recurrent cardiovascular events when IL-1β was inhibited.”

Anti-IL-1β antibody therapy was associated with a small but significant increase in certain fatal infections, explainable by the host defence-compromising potential of pure anti-inflammatory therapy.

“Unfortunately, the anti-IL-1β antibody therapy was associated with a small but significant increase in certain fatal infections212, which can be explained by the host defence-compromising potential of a pure anti-inflammatory therapy33.”

Administration of canakinumab, an antibody against interleukin-1β, reduces cardiovascular event risk independent of lipid level lowering.

“Administration of canakinumab, an antibody against Interleukin(IL)-1β, showed that inhibition of the IL-1β pathway reduces cardiovascular event risk independent of lipid level lowering34.”

When appraised together, the evidence supports apolipoprotein B as being necessary for lipid-mediated atherogenesis by LDL-C to occur.

“However, when appraised together, the evidence supports apolipoprotein B as being necessary for lipid-mediated atherogenesis by LDL-C to occur. 57,58 .”

Blood lipid traits including apolipoprotein B, low-density lipoprotein cholesterol and triglycerides each associate independently with risk of coronary heart disease.

“For example, blood lipid traits (including apolipoprotein B, low-density lipoprotein cholesterol and triglycerides) each associate independently with risk of CHD.”

In the case of drug-target MR, there is little evidence to support presence of such compensatory mechanisms, e.g. genetic variants with large phenotypic effects appear to have the expected dose-response association with disease as compared to genetic variants of smaller phenotypic effect.

“in the case of drug-target MR, there is little evidence to support presence of such compensatory mechanisms -e.g. genetic variants with large phenotypic effects appear to have the expected dose-response association with disease as compared to genetic variants of smaller phenotypic effect 57 40 .”