Canakinumab—effect on reducing inflammation and heart attacks in the Cantos study

In a double-blind, placebo-controlled, randomized study called Cantos, researchers gave placebo and different doses of canakinumab (sold as Ilaris) every three months to 10,061 HIV-negative participants. Prior to entering the study, all participants had experienced a heart attack and had elevated levels of C-reactive protein in their blood (suggestive of inflammation). Many participants were past and current smokers.

The trial lasted for about four years. Participants who received canakinumab had significantly reduced levels of C-reactive protein. Canakinumab did not decrease levels of bad cholesterol (LDL-C) or triglycerides in the blood. Yet people who received this drug at a dose of 150 mg every three months were less likely to have a heart attack than people who received placebo at the same schedule. Canakinumab significantly reduced levels of inflammation. However, it was associated with a greater risk for fatal infections than placebo. Canakinumab also reduced the risk of developing lung cancer.

The Cantos study is very important because it was the first to prove that reductions in inflammation are associated with a modestly reduced risk for heart attack and lung cancer. The results from this study will likely increase research on inflammation, its effect on cardiovascular disease and lung cancer, and ways of reducing inflammation by targeting the IL-1b receptor.

Study details

Researchers assigned participants to receive one of the following, given by subcutaneous injection (under the skin) every three months:

• canakinumab – 50 mg
• canakinumab – 150 mg
• canakinumab – 300 mg
• placebo

The average profile of participants upon entering the study was as follows:

• age – 61 years
• 74% men, 26% women
• current or past smokers – 71%
• 67% of participants had previously undergone procedures/surgery to improve the flow of blood to the heart
• most participants (at least 80%) were taking prescribed medicines to help normalize blood pressure, lower bad cholesterol and reduce the formation of blood clots
• all participants had at least a modest elevation of inflammation with levels of C-reactive protein (CRP) of around 4.20 mg/L (the test used was high-sensitivity CRP – hsCRP)

Most people were in the study for about 3.7 years.

Results—Changes in inflammation

Compared to people who received placebo, those who received canakinumab had their level of hsCRP reduced by the following proportions:

• canakinumab 50 mg – 26%
• canakinumab 150 mg – 37%
• canakinumab 300 mg – 41%

All of these differences between canakinumab and placebo were statistically significant; that is, not likely due to chance alone.

Among canakinumab users, hsCRP levels fell within three months of receiving the drug and stayed low for the duration of the study.

Similar trends were seen with another chemical signal of inflammation, IL-6 (interleukin-6), in people who received canakinumab vs. placebo.

There was no significant decrease in levels of cholesterol among canakinumab users.

Cardiovascular events

Researchers found that rates of heart attack were generally higher among people who received placebo compared to people who received canakinumab. Analysis of the data found that the canakinumab 150-mg dose was associated with a significant reduction in the following:

• non-fatal heart attack
• non-fatal stroke
• death from other complications of cardiovascular disease

Overall, the researchers found that death from serious cardiovascular disease was reduced by between 15% and 17% in people who received the 150-mg and 300-mg doses of canakinumab (compared to placebo).

According to an editorial in The New England Journal of Medicine by cardiologist Robert Harrington, MD, from Stanford University, when these results were further analysed, canakinumab’s “modest overall effect was completely driven by a lower incidence of [heart attacks].”

The 50-mg and 300-mg doses did not result in statistically significant differences in these outcomes compared to placebo.

Adverse events

The term adverse events is used to describe a range of unfortunate incidents that can occur in a clinical trial. Only some of these events are caused by the study medicine. As this was a placebo-controlled study, researchers have a good idea of which side effects canakinumab had. The two main adverse events were as follows:

Neutropenia

• lower-than-normal levels of neutrophils in the blood (neutrophils are important cells that help control infections)

Infections

When the researchers reviewed data from all three groups of participants who received different doses of canakinumab, they found that there were significantly more deaths from complications of infections in those on canakinumab than those on placebo. Why this happened is not clear; the study authors did not link these deaths to lower-than-normal levels of neutrophils. According to the researchers, “the patients who died from infections tended to be older and more likely to have diabetes than those who did not die from infection.”

Inflammatory-related conditions

The receptor for IL-1b is involved in inciting many inflammatory conditions in the body. By interfering with this receptor, canakinumab is able to significantly reduce levels of inflammation.

A benefit

Researchers found that participants in the Cantos trial who received canakinumab experienced a reduced intensity of certain preexisting inflammatory conditions such as arthritis, gout and osteoarthritis.

The following report in this issue of TreatmentUpdate reviews canakinumab’s impact on cancer.

—Sean R. Hosein

REFERENCE:

Ridker PM, Everett BM, Thuren T, et al. Anti-inflammatory therapy with canakinumab for atherosclerotic disease. New England Journal of Medicine. 2017 Sep 21;377(12):1119-1131.