Cover Story | Inflammation for the Cardiologist
One of the biggest trials of 2017 was CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study), which showed that a drug targeting inflammation could reduce the risk of cardiovascular events in well-treated patients with a previous myocardial infarction and signs of excess inflammation.1 Importantly, the benefit of the treatment was independent of any lipid-level lowering.
The results might seem unsurprising, given our burgeoning understanding of the important role of chronic inflammation in cancer, Alzheimer’s, diabetes and a myriad of other conditions. But while many have assumed that inflammation is causal in atherosclerotic cardiovascular disease, until CANTOS the inflammatory hypothesis of atherothrombosis was in fact just a theory, with no clinical evidence to show causality and no effective treatment.
“CANTOS really represents a challenge to our fundamental understanding of what drives atherosclerosis,” says principal investigator Paul M. Ridker, MD, MPH, FACC.
“For the last 40 years, the clinical community has appropriately focused on cholesterol lowering, and they should continue to do so, says Ridker. "But I think CANTOS challenges physicians to think a bit differently about the patient in front of them and think about treating not just risk factors and cholesterol but also inflammation.”
An added bonus: In an exploratory analysis, canakinumab, the drug tested in CANTOS, was associated with a clear dose-dependent risk reduction in lung cancer mortality.2
CANTOS: The Basics
Canakinumab is a fully human monoclonal antibody targeting interkeukin-1ß (IL-1ß), a key cytokine in the inflammatory pathway (see sidebar).
The drug, sold by Novartis under the brand name Ilaris, is currently approved for the treatment of several rare adult and pediatric disorders associated with over-production of interleukin-1 (IL-1), including Muckle-Wells syndrome, Cryopyrin- Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever, and some rare forms of juvenile arthritis. The agent won its first approvals in the U.S. and European Union in 2009.
In CANTOS, 10,061 individuals with a prior myocardial infarction (MI) and a high-sensitivity C-reactive protein (hsCRP) level of ≥2mg/L were randomly assigned to placebo or one of three doses of canakinumab (50, 150 or 300 mg), administered subcutaneously every three months. The trial was conducted at >1000 sites in 39 countries.
"For the last 40 years, the clinical community has appropriately focused on cholesterol lowering, and they should continue to do so, but I think CANTOS challenges physicians to think a bit differently about the patient in front of them and think about treating not just risk factors and cholesterol but also inflammation." — Paul M. Ridker, MD, MPH, FACC
In the 150-mg arm, the primary major adverse cardiovascular endpoint (MACE), a composite of nonfatal MI, nonfatal stroke, and cardiovascular death, was reduced by 15 percent after a median of 3.7 years of follow-up (p = 0.021). A similar effect was seen in the 300-mg arm, but the p value did not meet the prespecified threshold for significance (hazard ratio [HR] vs. placebo, 0.86; p = 0.0314, with a threshold p value of 0.01058). All-cause mortality was not reduced with canakinumab, but a 30 percent reduction in the need for revascularization was seen with the 150 mg dose (p < 0.0001).
“CANTOS is the very first proof that intervening on inflammation can improve outcomes,” says Peter Libby, MD, FACC. “We and others have done many studies that show an association between inflammatory biomarkers and risk, but they didn’t prove causality.”
And while it’s been known for a long time that low-density lipoprotein cholesterol (LDL-C) is causal for atherosclerosis, it’s also been known that even when LDL-C is treated, patients remain at risk for events. “And we don’t really understand how the big risk factors –hypertension, smoking, cholesterol, and diabetes – actually mess with the arteries and result in coronary artery disease,” notes Libby.
“What’s happening under the hood? What is in between these fatty drippings and these risk factors and the blood clot? Now we have some answers to those questions.”
Libby was interested in inflammation long before it became a fashionable topic. In fact, 30 years ago, when he started his research into the vascular biology of atherosclerosis, the cardiologists were so uninterested in inflammation that he had difficulty publishing in the cardiology journals.
It was in a 1986 paper in the American Journal of Pathology that Libby hypothesized the role of Interleukin-1 (IL-1) as an important participant in atherogenesis.4 “When certain inducible functions of endothelium such as IL-1 production are expressed inappropriately, they may contribute to the development of vascular diseases,” he wrote then.
“I hypothesized the role of IL-1 in 1986 and in 2009 when I saw that Novartis had an asset in canakinumab that needed to be studied further, I pitched them on the idea of the CANTOS trial,” Libby shared in an interview. “It’s taken me 30 years to get across the finish line.”
IL-1 has several effects related to atherogenesis. Just to name a few, it induces inflammatory functions in human endothelial cells and stimulates adhesion molecules that recruit leukocytes.5 Also IL-1 has multiple effects on vascular smooth muscle cells, including inducing IL-6 expression.
“A little IL-1 begets bucket loads of IL-6,” says Libby. “IL-6 goes to the liver and flips the switch on the hepatocytes boosting their production of acute phase reactants, which include fibrinogen, a precursor of clots, and plasminogen activator inhibitor, which inhibits fibrinolysis.”
“So, we have a perfect storm where we promote clotting and we block the way in which our body clears clots.”
Fibrinogen and plasminogen activator inhibitor are difficult to measure, “real laboratory nightmares,” according to Libby. But another acute phase reactant is C-reactive protein, “which is probably not causal, but for a variety of fundamental and serendipitous reasons is a terrific, high-fidelity way of looking at this pathway as Dr. Ridker has championed,” Libby adds.
And yet, while all this presented the rationale for a large-scale clinical trial of canakinumab, it all meant little until CANTOS revealed that IL-1ß inhibition reduced cardiovascular risk.
At 48 months, canakinumab treatment had no effect on atherogenic lipid levels, but significantly reduced hsCRP in a dose-dependent fashion. In the two higher dose arms, hsCRP was reduced, compared with placebo, by 37 percent and 41 percent, respectively. Similar effects were seen for IL-6, measured up to 12 months.
“There are those who have tried to set up a false dichotomy between lipids and inflammation,” says co-investigator Peter Libby, MD, FACC, in an interview.
“It’s very important to both Paul and me that we not be seen as in competition with traditional risk factors. Cholesterol is important, hypertension is important, but we have believed for a long time that inflammation is a critical player, fundamental to the progression of the disease and now we’ve proven it.”
Of note, the baseline low-density lipoprotein cholesterol levels in CANTOS were lower than those seen in FOURIER or SPIRE, emphasizing that these patients were well treated with lipid-lowering therapies, but still had what Ridker has termed “residual inflammatory risk” by virtue of their elevated CRP levels.
Less Cancer, More Fatal Infection
The benefits of canakinumab were not for free. Investigators saw a significant increase in neutropenia in treated patients along with a small but significant increase in fatal infections or sepsis (incidence rate, 0.31 vs. 0.18 events per 100 person-years; p = 0.02). Along with this, however, were significant decreases seen in incident rheumatoid arthritis, incident osteoarthritis and incident gout.
“Our rheumatology colleagues are adept at dealing with this issue in patients taking TNF and IL-6 inhibitors. The way they deal with it is instructing their patients about being more vigilant in their response to signs of infection or fever, and making sure they get on a Z-pack quickly,” says Ridker in an interview. He adds that the magnitude of risk seen in CANTOS is actually less than that routinely seen in patients with rheumatoid arthritis.
“I think we’ll be able to manage this issue. But, again, we’re asking cardiologist to think about things that typically internists and rheumatologists deal with, so we need to make sure we understand it all very clearly,” says Ridker.
The other “side effect” of canakinumab seen in CANTOS is more welcome: total cancer mortality was significantly reduced with canakinumab (p = 0.0007).2 At the 300 mg dose, canakinumab was associated with a 67 percent reduction in incident lung cancer and a 77 percent reduction in fatal lung cancer (p = 0.0002).
Because the investigators suspected canakinumab might have an effect on cancer, particularly as their study population was at high risk for lung cancer, notes Libby, the trial design included cancer endpoints and blinded adjudication of events. Those with cancer at baseline (other than basal cell carcinoma) were excluded.
This finding is hypothesis generating and very unlikely to be sufficient to warrant any kind of cancer indication from regulatory authorities, says Ridker. But Libby thinks he understands some of the mechanism behind the findings.
“My interpretation is that in 3.7 years of median exposure, we probably didn’t stop the early oncogenic events, but we probably prevented the spread and the metastasizing of tumors,” Libby says.
IL-1 can induce matrix metalloproteinase (MMP)-2, a key proteinase involved in cancer metastasis which works by breaking down the constituents of the basement membrane that encapsulates the tumors, he explains.
“There is a lot of excitement in oncology with the checkpoint inhibitors, which address adaptive immunity. But, canakinumab addresses innate immunity, which is a whole different set of pathways and is something that the cancer people have been aware of for years,” says Libby. “This is an enormous dividend, to be able to target innate immunity in cancer metastasis and progression.”
Subgroup Analysis Offers Outcomes-Based Payment Metric
In 2016, total Ilaris sales were under $300 million. At current prices and as it is currently used, the drugs costs about $200,000 per patient per year. However, both Ridker and Libby think any discussion of it being too expensive for widespread use in cardiovascular disease is a waste of breath at this point.
“I’m not a businessperson, but clearly if they went for a labeling indication for atherosclerosis, they’re going to lose their orphaned drug price, right?” says Ridker.
Speaking of a cardiovascular indication, Novartis is said to be preparing for an imminent U.S. Food and Drug Administration filing for a cardiovascular indication for canakinumab. It’s a good guess that the company hopes to avoid the pricing issues that have dogged the rollout of the PCSK9 inhibitors. They may have found a path to payment.
At the annual meeting of the American Heart Association in November 2017, Ridker presented a secondary analysis from CANTOS that showed that patients treated with canakinumab who had an on-treatment hs-CRP <2 mg/L at three months had a 25 percent relative risk reduction in MACE (p < 0.0001) and 31 percent risk reductions for both cardiovascular death and all-cause mortality (p < 0.0001) after adjustment.3
"There is a lot of excitement in oncology with the checkpoint inhibitors, which address adaptive immunity. But, canakinumab addresses innate immunity, which is a whole different set of pathways and is something that the cancer people have been aware of for years. This is an enormous dividend, to be able to target innate immunity in cancer metastasis and progression." — Peter Libby, MD, FACC
Patients with on-treatment hsCRP above the 2 mg clinical threshold had only a nonsignificant 10 percent reduction in MACE (p = 0.11), and no apparent reduction in cardiovascular death (adjusted HR, 0.99; p = 0.95) or all-cause mortality (adjusted HR, 1.05; p = 0.56).
“So, I can tell the patient, that if your CRP comes down after the first injection you’re going see a 25 percent reduction in heart attacks and strokes and a 30 percent reduction in cardiovascular death and all-cause mortality,” says Ridker. “On the other hand, if the CRP is still over 2 mg/L at three months, I would probably recommend against taking the drug again. There will be some benefit, but it’s pretty small.”
The proportions of those treated who achieved hsCRP levels <2 mg/L were 44 percent, 55 percent and 65 percent in the 50 mg, 150 mg and 300 mg canakinumab groups, respectively.
“This is precision medicine and it’s where we need to go,” says Libby. “No matter how they price canakinumab if it gets approval for cardiovascular indications, it’s not going to be cheap, but it’s also not going to be $200,000 a year. That’s the orphan drug price and I strongly suspect it will change.”
CANTOS is just the beginning. Ridker is also running CIRT (Cardiovascular Inflammation Reduction Trial), which is looking at whether low-dose methotrexate, an anti-inflammatory used in rheumatoid arthritis, might improve cardiovascular outcomes in at-risk individuals. Primary findings from CIRT are not expected for a couple more years.
The mechanisms of action of methotrexate are not fully understood, says Libby, but the agent appears to also target the IL-6 pathway.
Two other trials are testing colchicine, an inexpensive drug long used to treat certain inflammatory conditions. COLCOT (Colchicine Cardiovascular Outcomes Trial) and LoDoCo2 (Low-Dose Colchicine 2) are both looking at colchicine for secondary prevention of cardiovascular events, but these trials may not present findings before 2019.
“We would love to do CANTOS 2, which would be a coronary syndrome trial, and we have a few other tricks up our sleeves too,” says Libby. “And obviously the cancer part needs to be studied more.”
While there are still naysayers of the inflammatory hypothesis, there are many fewer today than there were a year ago, notes Libby. And, overall, both investigators have been quite pleased with the reactions they’ve gotten to CANTOS.
“The single nicest compliment I got at the ESC Congress in August 2017 was from someone who said, ‘you know, this is just like when 4S was presented in 1994!’ Suddenly, after 4S, clinicians had to pay attention to lipid lowering and the drugs we had then weren’t even very good. Now they’re realizing they also have to lower inflammation if the CRP is high.”
Don’t miss the ACC.18 Late-Breaking Clinical Trial presentation from CANTOS on March 12 and the Featured Interventional Clinical Research presentation on March 11.
- Ridker PM, Everett BM, Thuren T, et al. N Engl J Med 2017;377:1119-31.
- Ridker PM, MacFadyen JG, Thuren T, et al. Lancet 2017;390:1833-42.
- Ridker PM, MacFadyen JG, Everett BM, et al. Lancet 2017; Nov 13:[Epub ahead of print].
- Libby P, Ordovas JM, Auger KR, et al. Am J Pathol 1986;124 179-85.
- Libby P. J Am Coll Cardiol 2017;70:2278-89.
Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Sports and Exercise Cardiology, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Novel Agents, Exercise, Hypertension, Smoking
Keywords: ACC Publications, Cardiology Interventions, United States Food and Drug Administration, Acute-Phase Proteins, Adaptive Immunity, American Heart Association, Antibodies, Monoclonal, Anti-Inflammatory Agents, Arteries, Arthritis, Juvenile, Arthritis, Rheumatoid, Atherosclerosis, Biological Markers, Basement Membrane, Carcinoma, Basal Cell, Cardiovascular Diseases, Cholesterol, Cholesterol, LDL, Colchicine, Coronary Artery Disease, C-Reactive Protein, Cryopyrin-Associated Periodic Syndromes, Diabetes Mellitus, Drug Delivery Systems, Endothelial Cells, Endothelium, Familial Mediterranean Fever, Fibrinogen, Fibrinolysis, Glucans, Glucose, Gout, Hepatocytes, Hypertension, Immunity, Innate, Inflammation, Interleukin-1, Interleukin-6, Leukocytes, Lipids, Liver, Lung Neoplasms, Matrix Metalloproteinase 2, Methotrexate, Muscle, Smooth, Vascular, Myocardial Infarction, Neoplasms, Neutropenia, omega-Chloroacetophenone, Oncogenes, Orphan Drug Production, Osteoarthritis, Pharmaceutical Preparations, Plasminogen Inactivators, Research Personnel, Rheumatology, Risk, Risk Factors, Risk Reduction Behavior, Running, Secondary Prevention, Sepsis, Smoking, Stroke, Thrombosis
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