Canakinumab Cuts Secondary CV Events in Phase 3 CANTOS

BASEL, SWITZERLAND — The monoclonal antibody canakinumab (Ilaris, Novartis) given on top of standard care significantly reduced the risk of the composite of cardiovascular death, nonfatal MI, and nonfatal stroke in patients with a prior MI and inflammatory atherosclerosis, according to initial results released from the phase 3 CANTOS trial^[1].

The data are a big win for Novartis, and the market reacted with a more than 2% jump in its shares. But what has clinicians buzzing is that canakinumab, which is already approved for subcutaneous use in rare autoimmune diseases, works by targeting interleukin-1beta (IL-1ß), a key cytokine in the inflammatory pathway.

"This basically represents a new opportunity to treat the leading cause of death in the world and an opportunity that's outside of blood cholesterol and represents the culmination of probably 3 decades of work pursuing the hypothesis that inflammation is an important part of atherosclerosis," Dr Sekar Kathiresan (Massachusetts General Hospital, Boston, MA), who was not involved in the study, told theheart.org|Medscape Cardiology.

Dr Benoit Arsenault (Université Laval, QC) echoed those sentiments on Twitter: "Amazing. This is a giant step forward for the inflammation hypothesis in atherosclerotic cardiovascular diseases."

There's a tremendous amount of animal model, work in cells, and observational epidemiology in humans that suggests inflammation plays a role, but Kathiresan said the last piece of the puzzle was whether a treatment could affect inflammation and reduce the risk of heart attack. "And to date, we haven't had any such treatments."

Statins, the one treatment that potentially has a role in inflammation, reduce the risk of heart attack, but it's been difficult in clinical trials to rule out whether this may just be because of their LDL-cholesterol–lowering effects.

Sweet Serendipity

In an odd turn of events, a paper published yesterday in the New England Journal of Medicine^[2] was able to show that people acquire mutations in their blood cells as they age that predispose them to blood cancer but also surprisingly to MI. And the reason these patients develop an MI seems to be through the IL-1ß inflammation pathway, explained Kathiresan, a co–senior author on the paper.

"It is really a complete coincidence that this paper came out last night and this morning the IL-1ß drug has worked in a clinical trial, and that raises the hypothesis that this subset of patients who might have this blood cell mutation might preferentially benefit from the IL-1ß therapy," he said.

In 2014, a different anti-inflammatory strategy fizzled after darapladib, a selective inhibitor of lipoprotein-associated phospholipase A₂ (Lp-PLA₂), failed to reduce the risk of recurrent CHD events when given on top of optimal medical therapy in patients with ACS in the SOLID-TIMI 52 trial.

Canakinumab was tested in CANTOS at three different doses in combination with standard care in 10,061 patients with a prior MI and a high-sensitivity C-reactive protein level of >2 mg/L. The primary end point was time to first occurrence of MACE, a composite of CV death, nonfatal MI, and nonfatal stroke.

The full results are expected to be presented later this summer at the European Society of Cardiology Congress, and plans are for the company to begin talks with regulatory agencies, a Novartis spokesperson told theheart.org.

"We need to look at the final results, but if they hold up to further scrutiny, it would be a major advance," Kathiresan said.

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Medscape Medical News © 2017 

Cite this: Canakinumab Cuts Secondary CV Events in Phase 3 CANTOS - Medscape - Jun 22, 2017.