CANTOS: Anti-inflammatory Agent Canakinumab Modestly Reduces Major CVD Events

(UPDATED) A fully human monoclonal antibody that specifically targets inflammation reduces the risk of cardiovascular events when added to a background of optimal medical therapy, a new study has shown.

In the CANTOS trial, which included 10,061 patients with a previous MI and high-sensitivity C-reactive protein (CRP) levels ≥ 2 mg/dL, treatment with 150 mg of canakinumab (Novartis) every 3 months reduced the relative risk of nonfatal MI, nonfatal stroke, or cardiovascular death—the study’s primary composite endpoint—by 15% when compared with placebo (P = 0.021).

“This is the first time in 40 years where we have something that’s not about lipid-lowering,” lead investigator Paul Ridker, MD (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “We had no change in LDL cholesterol—there was a 30% to 40% reduction in interleukin-6 and CRP—and yet we had an event rate that’s identical to what you’d get from being treated with a PCSK9 inhibitor.”

The CANTOS findings pave the way for a new approach to treating at-risk patients, Ridker continued.

“This is about personalized medicine,” he said. “It’s saying not all secondary-prevention patients are the same. If your problem is because your inflammatory response has not been inhibited enough, that your CRP is high, that’s residual inflammatory risk. Now we have something to offer those patients. If your LDL cholesterol is high after an MI, then you can think about a PCSK9 inhibitor. You’re not going to give both drugs to patients. We’re trying to figure out how to give the right drug to the right patient.”

Peter Libby, MD (Brigham and Women’s Hospital, Boston, MA), who led the study along with Ridker, said the CANTOS trial is the first “proof-of-principle and validation of the inflammation hypothesis” that he, Ridker, and others have studied for decades. “It opens the door to a whole host of novel targets,” he said.

Clyde Yancy, MD (Feinberg Northwestern University School of Medicine, Chicago, IL), who was not involved in the study, said the excitement of CANTOS is based on gaining new understanding that there may be multiple pathways that lead to atherosclerotic events.

“Even when we do our very best job managing dyslipidemia, there are some patients, perhaps identified with elevated high-sensitivity CRP, perhaps related to inflammation, that are at residual risk and are not protected,” Yancy told TCTMD. “I believe that studies like this, a study that exposes us to a new realm of clinical science and makes us aware of a risk we were not modifying before, are incredibly important.”

The CANTOS study was published August 27, 2017, in the New England Journal of Medicine.

Benefit Driven by Reduction in MI

Canakinumab targets interleukin-β, a cytokine that is involved in the inflammatory response and the interleukin-6 signaling pathway. Interleukin-β is known to play “multiple roles in the development of atherothrombotic plaque,” according to the investigators. These roles include inducing procoagulant activity, promoting monocyte and leukocyte adhesion to vascular endothelial cells, and promoting the growth of vascular smooth-muscle cells.

In CANTOS, investigators tested three doses of canakinumab: 50 mg, 150 mg, and 300 mg, each given with a subcutaneous injection once every 3 months for the 48-month study duration. The reduction in cardiovascular events was only observed with the 150-mg dose, although treatment with the 300-mg dose also appeared to lower the risk of the primary endpoint. In statistical adjustments that accounted for testing multiple doses against placebo, the reduction with the 300-mg dose was not significant.

The benefit with the 150-mg dose was driven by a significant 24% reduction in the relative risk of MI, however, with no significant reduction in the risk of nonfatal stroke or cardiovascular death observed. Treatment with canakinumab did reduce the risk of hospitalization for unstable angina leading to urgent revascularization (OR 0.64; 95% CI 0.44-0.94) and the need for any coronary revascularization (OR 0.68; 0.58-0.81).

This is the first time in 40 years where we have something that’s not about lipid-lowering. Paul Ridker

To TCTMD, Ridker said the relative reduction in clinical events ranged from 5% to 30%, depending on CRP and interleukin-6 levels.

“Maybe we don’t want everybody on this drug,” said Ridker, speculating on how treatment might be managed for the still-investigational canakinumab. “Maybe we give patients the first dose for free to see if they respond? If they’re a responder, with a 25% or 30% risk reduction, that’s pretty good. If they’re not a responder, we don’t want you exposed to the toxicity, and we want you to stay away from the drug. It’s a different way of thinking about care.”

Richard Chazal, MD (Lee Health, Fort Myers, FL), immediate past-president of the American College of Cardiology, also called CANTOS an “important proof-of-concept” study, noting there had been suspicions about the role inflammation might play in cardiovascular disease. In past statin studies, it has been difficult to tease out the effects of lowering LDL cholesterol versus the drug’s pleiotropic effects, which include anti-inflammatory effects. In the JUPITER trial, for example, even though patients with elevated CRP levels were enrolled, it was not known whether the benefit of rosuvastatin was the result of lowering LDL cholesterol or reducing CRP levels.

“Now to have this separate data for a drug that had no effect on LDL cholesterol, and to have a significant effect on cardiovascular events, I think is really, really important,” Chazal told TCTMD. “The fact that there was an increase in infections is a signal that further confirms this seemed to be an anti-inflammatory response.”

For Chazal, who was not involved in the study, CANTOS is less a therapeutic study than one that opens the door to more trials testing different anti-inflammatory agents. “I’m less focused on the magnitude of reduction than on the fact that there was a reduction,” he said.

Yancy agreed. While the treatment effect was significant, by identifying a new treatment target, there may exist multiple different approaches to address that target and to potentially alter the natural history of cardiovascular disease, he said.

‘The Question Will Be Cost’

Udo Sechtem, MD (Robert Bosch Medical Center, Stuttgart, Germany), told TCTMD there are limits to what can be achieved with LDL lowering. “We know that when we fight cholesterol and go as low as we go, 50% of these people still experience cardiovascular events,” he said. “If we can identify those patients who have low LDL level but a high CRP level, it would be a new way of treating people who would otherwise follow a fatal path.”

Regarding the 15% reduction in the primary endpoint, Sechtem called it a modest reduction, but one that is realistic considering how aggressive these patients were treated with background medical therapy. While Ridker likened the CANTOS results to the benefit seen with the PCSK9 inhibitor, Sechtem made another connection.

“The question will be cost,” he said. “The PCSK9 inhibitors are now priced around $10,000 per year, and it’s still prohibitively expensive to give it to the masses who might need it.”

In the FOURIER trial, presented and published in March, treatment with the PCSK9 inhibitor evolocumab (Repatha, Amgen) reduced the risk of cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization by 15% when compared with placebo. The price of that drug, as Sechtem pointed out, has been a major hurdle for payers, patients, and clinicians.

If we can identify those patients who have low LDL level but a high CRP level, it would be a new way of treating people who would otherwise follow a fatal path. Udo Sechtem     

In an editorial accompanying the study, Robert Harrington, MD (Stanford University, CA), makes a similar comment, noting that “any discussion of the use of canakinumab in patients with a previous myocardial infarction must consider cost.” In the United States, when given monthly for approved indications, canakinumab is priced at approximately $200,000 per year.

For Harrington, the CANTOS study moves the inflammatory hypothesis of coronary artery disease forward, but given the “modest absolute clinical benefit,” he says, routine use in previous MI patients is not justified until more data is available and unless a price restructuring and formal cost-effectiveness evaluation supports it. 

To TCTMD, Ridker said the issue of cost is premature. He likens the CANTOS study to the Scandinavian Simvastatin Survival Study (4S), the landmark 1994 trial that first showed the benefit of lowering LDL cholesterol with statin therapy, pointing out anti-inflammatory therapy will improve just as statins evolved and the price will come down.

“The reason [canakinumab] is so expensive is because it’s an orphan drug right now,” said Ridker. “It’s indicated for about 400 people in the US. . . . If they elect to get a label, they’re obviously going to lose orphan status. Talking about numbers [right now] is silly.”

High-Risk Secondary Prevention Patients

Speaking with the media, Ridker stressed that patients included in CANTOS were high-risk secondary prevention patients, who despite being on high-intensity statin therapy, continued to have elevated CRP levels. Ridker noted the median baseline LDL level in CANTOS was lower than the baseline LDL level of patients treated in FOURIER (82 mg/dL in CANTOS vs 92 mg/dL in FOURIER).

Libby added that the inflammation hypothesis in “no way competes with traditional risk factors,” but rather the inflammatory pathways are mechanisms in which cardiovascular risk factors, such as LDL cholesterol, alter the biology of the artery wall in a way that can give rise to heart disease and its complications.       

Regarding adverse events, there was a small but significantly increased risk of death caused by infection or sepsis when all three treatment arms were combined and compared with events in the placebo arm (0.31 vs 0.18 events per 100 patient years; P = 0.02). Neutropenia and thrombocytopenia were more common in patients treated with canakinumab.

In contrast, cancer mortality was significantly lower in patients treated with canakinumab than those treated with placebo, which Ridker said was “remarkable.” Treatment with canakinumab 150 mg and 300 mg reduced the risk of death from any cancer by 22% and 51%, respectively. The reduction was primarily driven by a reduction in the risk of lung cancer. In addition, treatment with canakinumab resulted in a reduction in the risk of arthritis, osteoarthritis, and gout.

To TCTMD, Yancy said he was intrigued by the cancer reduction observed with canakinumab, although he is not yet convinced the effect is real. Typically, modifying pathways with investigational compounds causes anxiety because of adverse effects, but a therapy that might reduce cardiovascular and cancer events “really charges me up,” said Yancy. “You start to ask: what else is out there? You start thinking about further exploration of this pathway, or further opportunity to modify the natural history of diseases. Diseases plural.”  

The National Heart, Lung, and Blood Institute’s Cardiovascular Inflammation Reduction Trial (CIRT), also led by Ridker, will enroll approximately 7,000 patients and randomize them to treatment with low-dose methotrexate, a drug currently used for the treatment of rheumatoid arthritis.

“Right now we know canakinumab works,” said Ridker. “If methotrexate were to work, we’d have a generic and inexpensive way of getting there. I think this is going to open up all kinds of new approaches for a variety of agents that really have been in the rheumatology and immunology world.”