Cardiologists have been on edge for months, waiting for the details surrounding recent reports of the stunning failures of two new heart drugs.
The drugs — pelacarsen and ziltivekimab — were widely expected to usher in a new era in preventing heart disease. Companies, betting on the drugs’ promise, made huge investments in developing them.
So when doctors saw preliminary announcements that the drugs were not helping patients in large clinical trials, many felt blindsided, although still hopeful that there was more to the story than they knew.
“The whole cardiovascular community was gobsmacked,” said Dr. Karol Watson, a director of UCLA’s preventive cardiology program.
Were the drugs close to succeeding, just barely missing a statistically significant benefit? Or were there at least subgroups of patients who were helped?
Now the answers are in. There was not a shred of evidence that the drugs helped anyone. By every measure, they were no better than placebos.
The results, Dr. Watson noted, “are about as neutral as they can be.” The full data were presented on Saturday morning at the annual meeting of the American Heart Association and in simultaneous publications in The New England Journal of Medicine.
One drug, pelacarsen, by Novartis, is known to make levels of the Lp(a) blood protein plunge. The protein is widely believed to cause heart attacks and strokes. The other, ziltivekimab, by Novo Nordisk, stops inflammation, thought to be a major component of plaques in arteries. Neither drug made a dent in heart disease outcomes during these clinical trials.
Dr. Paul Ridker of Mass General Brigham, who was the principal investigator for the inflammation trial — known as the Zeus study — had been a true believer.
He was convinced by suggestive evidence that squelching inflammation could protect people from heart disease. There was, he said, an earlier encouraging study involving an experimental anti-inflammatory drug made by Novartis, as well as studies indicating that colchicine, an anti-inflammatory drug used to treat gout, could also be protective.
Until the day he saw the results, Dr. Ridker said in a recent interview, he had thought the Zeus study was “a brilliant idea,” bound to show that the Novo drug, ziltivekimab, which blocks an inflammatory protein called il-6, was effective. The participants all had severe heart disease, advanced kidney disease and a blood protein that is a marker of inflammation.
Instead of protecting patients in Zeus, though, Dr. Ridker announced on Saturday that no one had been helped by the drug. Every subgroup of patients in the 6,376-patient study fared the same. Those taking the drug did no better than those taking a placebo, even though the drug did reduce inflammation.
“Did we pick the wrong target, the wrong patient population?” Dr. Ridker said.
Or did the patients have heart disease that was so advanced it could not be helped? “Maybe the horse was out of the barn,” he said.
Others in the field are wondering if the hypothesis itself was wrong. Maybe inflammation is a sign of disease, not a cause, as white hair is a sign of aging.
Novo announced in September that it was stopping two other studies of ziltivekimab that involved patients with heart failure. An independent committee determined that the drug was not helping them. The company is continuing to test its drug in patients who have had a heart attack. That study will conclude next year.
Dr. Ridker, who proposed the link between inflammation and heart disease more than a quarter-century ago, has not given up hope. He noted that there was genetic and epidemiological evidence as well as evidence from animal studies that a different protein in the same inflammation pathway should protect against heart attacks and strokes.
“We already know this is going to work,” Dr. Ridker said. Now, he added, the question is: “How do we find the right drug for the right patient?”
The principal investigator for Horizon, the Lp(a) study, is Dr. Steven Nissen of the Cleveland Clinic. He said his concern was that the study’s disappointing results would lead patients to drop out of two other studies testing drugs that reduce Lp(a) levels.
“A single trial doesn’t necessarily give us all the answers,” Dr. Nissen said. And, he added, high levels of Lp(a) are “a powerful risk factor.” It remains possible, he said, that patients in the Horizon trial had heart disease so advanced that it was too late for the Novartis drug to help.
Another hypothesis was that the patients’ other risk factors — blood pressure and L.D.L. cholesterol — were so well controlled that their risk was about as low as it could go, said Dr. Roger Blumenthal, director of the Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease. Reducing Lp(a) levels could not lower it further.
Dr. Ridker had another idea. All the Horizon patients were taking anti-clotting medications. Lp(a) is thought to cause heart disease by promoting blood clots. Perhaps the anti-clotting medications diluted the drug’s effects.
But the bottom line was that, for whatever reasons, the Novartis drug had utterly failed.
“Was there anything that we could point a finger to that said, ‘Yeah, there’s a benefit’?” Dr. Nissen asked.
No, he added, “there was nothing.”
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