Research

Alternate Target

While the medical community has long focused on lowering cholesterol to prevent heart attacks and stroke, a novel drug now zeroes in on inflammation.

By Charlotte Huff featured image

On the day he suffered a heart attack at age 47, Ray Lahaye stubbed out his nearly three-pack-a-day smoking habit, shifted his diet into a healthier gear, and started walking, sometimes twice daily.

But Lahaye’s cardiologist, along with prescribing a statin medication and another to lower blood pressure, was still on the lookout for additional ways to reduce the retired mail carrier’s cardiovascular risk. Some five years ago, he suggested that Lahaye consider enrolling in a research study designed to assess whether a drug that reduced inflammation — rather than cholesterol — could decrease the chance of a heart attack or stroke.

Lahaye, now 66, was intrigued by the opportunity to contribute to research and signed on. Every three months he rolled up his sleeve for two injections. “It was either saline or the real stuff,” he says.

The findings from that randomized study, published in August 2017 in two leading medical journals, open up another potential avenue to combat heart disease, although it’s unclear how immediately useful they will be for patients.

The roughly six-year-long study, which compared three doses of canakinumab to a placebo, found that one of the higher doses reduced cardiovascular events by 15 percent, according to findings published in the New England Journal of Medicine. A separate analysis in The Lancet looked at cancer cases among the study’s participants and suggested that the drug’s inflammation-suppressing effects might also slow the progression of malignancies, and of lung cancer in particular. To date, existing cardiovascular drugs have primarily been used to help reduce cholesterol levels, specifically low-density lipoprotein, or LDL (“bad cholesterol”).

For the first time we have evidence that treating some aspect of inflammation is likely to benefit patients [by] reducing heart disease risk.

“The scientific result is very exciting. For the first time we have evidence that treating some aspect of inflammation is likely to benefit patients [by] reducing heart disease risk,” says cardiologist Sekar Kathiresan, who directs the Center for Genomic Medicine at Boston’s Massachusetts General Hospital and was not involved with the study.

However, he cautions that the study “also exposes some of the challenges of targeting inflammation.” Kathiresan cites the small but elevated risk of fatal infections that the researchers identified. That result shouldn’t be surprising given that inflammatory cells are key to fighting infection, he says. “That’s what we are seeing — a little bit of the yin and the yang of inflammation.”

Canakinumab, made by Novartis, has already been approved to treat rare inflammatory conditions, such as systemic juvenile idiopathic arthritis (SJIA), and is known for that indication as Ilaris. The injectable medication is a human monoclonal antibody that inhibits interleukin-1 beta, a protein that, when overexpressed, can boost inflammation in the body.

The heart disease study enrolled 10,061 patients who, like Lahaye, had already experienced a heart attack and whose bloodwork showed elevated inflammation levels.

In addition to the slightly elevated infection risk, the study, which was sponsored by Novartis, comes with other caveats, both clinical and practical.

Researchers didn’t find that canakinumab reduced the rate of deaths; an accompanying editorial described the primary finding — a 15 percent decrease in cardiovascular events — as “modest” and driven by fewer heart attacks and not strokes. Plus, the future price tag is a big question mark, as the drug’s patient population could expand considerably if it’s approved for heart disease. Right now, it costs about $200,000 annually for the treatment of SJIA. Two years after the approval of PCSK9 inhibitors, which are powerful lipid-lowering drugs, debate persists about their relative benefit, given their high cost. (See “The PCSK9 Cost-Benefit Debate,” page 28.)

But the findings published in August from CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) nevertheless provide some vindication for cardiologist Paul Ridker and his research colleagues at Boston’s Brigham and Women’s Hospital, who have long argued that inflammation can foster heart disease, along with cholesterol levels.

“Right now the cardiovascular world treats [all of] these individuals exactly the same,” he says. “What I’m arguing is, ‘Wait a minute. Not everybody who’s at risk for a second heart attack is at risk for the same reason.’ ”

A New Front

The battle to reduce heart disease has been stymied for decades now by a life-threatening conundrum. Statins have made significant headway in reducing cholesterol, but some men and women with normal levels remain vulnerable to heart attacks and strokes.

“There are some people who, no matter how high a statin dose you [give them], they are still having progression of their heart disease,” says Eric Topol, a cardiologist and geneticist at Scripps Research Institute in La Jolla, California, and a member of Genome’s advisory board. “We need more [in our] armamentarium.”

Finding new weapons has been slow going. Ridker and his research colleagues started pursuing a potential inflammatory link to heart disease more than two decades ago. By measuring a marker of inflammation, called C-reactive protein (CRP), among men participating in the Physicians’ Health Study, in 1997 they were able to show a correlation between higher levels of the inflammatory blood marker and a heightened risk of heart attack or stroke. (Ridker is listed as a co-inventor on patents, held by Brigham and Women’s, related to testing for pro-inflammatory markers.)

Inflammation is now believed to contribute to heart disease through various mechanisms, Topol says. Smoking is one perpetrator, along with high blood pressure and underlying genetics. Low-density lipids create problems when they seep into the wall of an artery, he says, and the body reacts to them as a foreign substance.

“There can be a very strong, even vicious inflammation response that leads to a loss of integrity of the wall of the artery,” Topol says. “So now there is a crack and the body naturally wants to seal the crack, so it forms a blood clot there.” Over time, he says, that clot can either break off, creating risk of a stroke, or become sufficiently large to impede blood flow.

Still, Topol says, measuring CRP levels provides only a “crude marker,” because the CRP can be elevated for other reasons: for example, the patient may be battling an infection. What was missing from the larger picture, Kathiresan says, “was definitive evidence in people that treatment of that inflammatory process would actually reduce risk of heart attack.”

Statins target lipids; aspirin affects platelets. But, Ridker says, they also appear to reduce inflammation. The advantage of testing canakinumab, he says, is that prior research had shown that it lowers CRP levels without changing cholesterol. In other words, changes in cholesterol levels would not confound the results of the study. “That gave us the opportunity to have a very perfect scalpel to actually test this core [inflammation] hypothesis,” he says.

Two drugs in one?

The CANTOS study, which began enrolling patients in 2011, randomized participants to get either a placebo injection or one of three doses of canakinumab, ranging from 50 milligrams to 300 milligrams. The patients were already taking other heart medications; nearly all were on at least one statin.

The 150-milligram dose was the one that achieved a statistically significant effect (although the 300-milligram dose was close). The 15 percent reduction was based on the primary endpoint the researchers studied: a composite analysis of heart attacks, strokes, and any cardiovascular deaths. The rate of fatal infections was also statistically significant, occurring in roughly one out of every 1,000 individuals treated.

“I think that’s basically where the [prescribing] hang up is going to be,” says Kathiresan, noting that doctors will have to educate patients about the infection risk for a drug that so far hasn’t been shown to extend lifespan.

But the researchers also flagged another potential life-saving benefit: reduction of cancer risk. It’s a finding that Ridker is quick to say must be replicated by other research to see if it holds up.

Among the 10,061 patients enrolled in CANTOS — none of whom had been previously diagnosed with cancer — the number of cancer deaths decreased as the canakinumab dose increased. (Roughly three-fourths of participants were current or former smokers.) In The Lancet study, Ridker’s team found that the chance of dying from cancer was roughly half in the group taking 300 milligrams of canakinumab versus the placebo group, primarily due to fewer lung cancer deaths.

Cardinale Smith, a physician specializing in lung and esophageal cancer at New York City’s Icahn School of Medicine at Mount Sinai, calls the initial cancer findings “hypothesis-generating” and very much worth further study. It’s already known that smoking helps to boost inflammation in the body, she says. “This [study] shows that correlation in a way that perhaps we didn’t have before.”

Inflammatory Tradeoff

Canakinumab, considered an orphan drug (meaning that it is targeted at a patient population of fewer than 200,000), costs about $16,000 per dose. The injections are administered more frequently to current patients (for example, monthly for systemic juvenile idiopathic arthritis), compared to four times a year in the CANTOS participants.

Despite his reservations about the infection risk, Kathiresan points out that for some patients — such as heart attack survivors who continue to smoke — the potential dual payoffs in terms of lung cancer and heart disease might outweigh that risk. Another possibility, Ridker says, is that the drug could be started and only continued in those patients whose CRP levels drop the most, as the study showed the greatest heart benefits in that group.

As Ridker continues to pursue inflammatory drug mechanisms, he stresses that the role of statins remains crucial in combatting heart disease. “We want every patient to get their cholesterol level down,” he says. “This is by no means undermining the cholesterol hypothesis.”

Lahaye says that canakinumab’s infection risk doesn’t worry him. He’d take any steps to avoid a repeat of his first heart attack, which began with a weird tingling in his fingers that he likely would have ignored if his wife hadn’t insisted on taking him to the hospital.

While being examined there, he suffered a heart attack. Lahaye, who has decided to continue being followed through CANTOS, has been told that if he’s been getting a placebo injection, he’ll soon be switched to canakinumab.

Meanwhile, Ridker is leading another study, this one funded by the National Heart, Lung, and Blood Institute, to examine methotrexate and heart disease. Methotrexate is a very old, generic drug, which has broad anti-inflammatory effects and is commonly prescribed for rheumatoid arthritis.

While Ridker does not expect results for several years, the promising canakinumab findings, Kathiresan says, make the new research particularly worth watching. “It is generally safe and very cheap,” he says of methotrexate. “So if that’s effective, then you might have a real possibility [for] widespread adoption.”

Kathiresan says it’s important to remember that inflammatory processes are complicated. “While inflammation can guard against infection,” he says, “it also appears to potentially encourage cancer or chronic diseases like atherosclerosis. I think we have to find medicines that strike the right balance.”