During scientific discovery, there are triumphant moments when researchers present their findings to a delighted audience who jump to their feet for a standing ovation. It happened in a conference room full of doctors in May after learning that a new drug, daraxonrasib, nearly doubled the survival time of pancreatic cancer patients.
Then there’s the reaction that Dr. Steven Nissen expects Saturday at the American Heart Association’s annual conference, when he unveils the results of a large study testing an experimental drug intended to reduce the risk of heart attacks and strokes.
“I’m going to have to resist the audience gasping,” said Nissen, a preventative cardiologist at the Cleveland Clinic in Ohio.
Many at Nissen’s presentation will already know that the drug he studied, pelacarsen, failed to achieve its key goal: reducing the risk of major cardiovascular events by reducing a sticky protein-encased fat in the blood called lipoprotein(a), or Lp(a).
But Nissen knows the crowd remains hopeful that the drug has shown glimmers of success in secondary measures; maybe it worked for people with health conditions like diabetes, or prevented some or all bad outcomes. Perhaps too many people abandoned the trial before it could achieve its goal.
“It wasn’t a near miss. It just didn’t have any effect on the results, and I don’t think virtually anyone is ready to hear that,” Nissen told CNN.
“This is the first time that anyone has been able to study a drug to treat this disorder, which over a billion people suffer from, and you know, it was widely expected to be positive, favorable. I mean, it was uniformly expected to be favorable. So everyone is going to be pretty surprised when they see the results.”
In other words, instead of being a blockbuster, the drug is just a fiasco. Novartis, which has already invested tens of millions of dollars in the development of this drug, has decided to abandon it.
In science, big failures can be as important as big successes, and the new study raises questions that could force cardiologists to rethink the role of lipoprotein(a) in the development of cardiovascular disease.
Nissen and his colleagues have spent the past seven years testing pelacarsen, which interferes with the body’s ability to produce Lp(a). Too much Lp(a) is thought to promote clotting in the arteries around the heart and increase inflammation, making it a double whammy for heart attack risk.
Some people inherit the tendency to produce more Lp(a) than others, and studies have shown that people with the highest blood levels are two to four times more likely to have a heart attack than others. with to those with the lowest levels, according to the American Heart Association.
“I see these patients,” Nissen said. “I will see young women who have a stroke in their 30s and whose only risk factor is high lipoprotein(a) levels.
“It’s a purely genetic risk.”
The study randomly divided 8,350 people with a previous cardiovascular event like a heart attack or stroke and high Lp(a) levels into two groups: Half received pelacarsen, while the other half received a placebo. Neither patients nor study investigators knew who received the drug and who did not. Most patients were followed for almost five years.
At the end of the study, the researchers’ main comparison between the two groups was an outcome called MACE – major adverse cardiovascular event. This included any type of cardiac death, as well as non-fatal heart attacks, strokes and whether patients needed an urgent procedure to treat a blocked blood vessel, such as heart bypass surgery.
However, when the results of the study were revealed, a surprise occurred. While high-risk patients taking pelacarsen had much lower lipoprotein(a) levels than at the start of the study, they were at virtually the same risk of dying from heart disease or having a serious cardiovascular event as people in the placebo group. Approximately 12% of patients in each study group experienced a serious cardiac event during the study, whether they received pelacarsen or not.
The full results of the study published Saturday in the New England Journal of Medicine. Although the researchers looked at the data in different ways, breaking down the results based on underlying medical conditions like diabetes and looking at the drug’s impact on different types of cardiovascular events, there were virtually no differences.
The drug did exactly what everyone expected, reducing Lp(a) levels by about 77% on average in patients who took it. But there was no evidence that it had an impact on the risk of death from cardiovascular disease, heart attack, stroke or the risk of a person needing a stent or bypass to treat a clot near their heart.
“I’m flabbergasted,” said Dr. Fatima Rodriguez, chief of preventive cardiology at Stanford University who was not involved in the research. “There is no signal.”
The big question is what to do now.
This year, for the first time, the American Heart Association and the American College of Cardiology recommended that every adult be tested for Lp(a) at least once in their lifetime. A single test seems sufficient because studies have shown that a person’s level is relatively stable over the course of their life. drug manufacturers, including Novartis actively raises awareness of the risk of Lp(a) and promotes new testing guidelines.
There are currently no treatments that specifically address the risk of elevated Lp(a). For this reason, some experts, like Dr. Karol Watson, a cardiologist and professor at the David Geffen School of Medicine at UCLA, have said it may be premature to encourage universal screening.
Proponents of the tests argue that knowing a patient’s Lp(a) level can be used to narrow down their risk for heart disease, Watson said.
“I kind of call bullshit on that because there are a lot of things that we know are associated with risk, like homocysteine level. No one tells us to measure that because there’s nothing we can do,” Watson added, referring to an amino acid that can damage vessels and contribute to heart disease if it builds up in the blood.
Yet when the new testing guidelines were launched, several promising Lp(a)-lowering therapies were on the horizon. Many expected a medical breakthrough when pelacarsen entered the final stages of clinical testing in 2019. Early studies, including Nissen’s, showed that it could effectively reduce Lp(a) levels by 70 to 80 percent.
The drug was expected to be the first in a new wave of treatments.
“What we’ve done now is put together a whole group of people who are really anxious about this, and we’re still telling them we have nothing to offer them,” Watson said.
In science, the study conducted by Nissen would be described as a negative trial or a failure. But it’s a somewhat misnomer, Stanford’s Rodriguez thinks.
“This is a very important trial, and negative trials are sometimes even more important than positive trials,” Rodriguez said.
This trial was so well conducted, Rodriguez said, and its results are so clear, that it will send scientists back to the drawing board to reconsider what is known and what is not.
“That can help us say, okay, are we just looking at the wrong marker, which is a possibility, or is this the wrong drug or the wrong population?” she added. Or maybe the whole theory that Lp(a) is a cardiac risk factor is wrong.
Nissen also has some theories about his results. He says the patients in the trial were older, so perhaps beyond a point in their heart disease where lowering Lp(a) offered any benefit. They all had well-controlled LDL, or “bad” cholesterol. Studies have shown that aggressively lowering LDL cholesterol with statins can help mitigate the risk of having high Lp(a). Finally, although pelacarsen reduced Lp(a) by almost 80%, levels may need to be even lower, on the order of 90-95%, to demonstrate a reduction in cardiac risk.
There are other, more potent Lp(a)-lowering drugs that are already in clinical trials, he notes. He also thinks these types of medications might be more effective if taken earlier in the disease process, before a person experiences their first heart attack or stroke — what’s called primary prevention.
For now, people who get tested for lipoprotein(a) and have elevated levels can manage their risk by addressing anything known to contribute to heart risk. Nissen said exercise, weight loss and, most importantly, a statin to lower LDL cholesterol as much as possible should all be part of a person’s preventative care.
Dr. Anurag Mehta, a cardiologist at Emory Healthcare and an Lp(a) expert, hopes the study results won’t discourage people from getting tested.
“I think it’s one of the strongest markers of heart disease risk,” Mehta said. There are benefits to getting tested, understanding your risks, and knowing what steps you can take to control what you can. “It is…
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