A promising drug for an inherited heart risk flops, stunning doctors

In the course of scientific discovery, there are triumphant moments when researchers present their findings to a rapt audience that jumps to its feet for a standing ovation. It happened in a conference room full of doctors in May after they learned a new drug, daraxonrasib, nearly doubled survival time for pancreatic cancer patients.

Then there's the reaction that Dr. Steven Nissen expects at the American Heart Association's annual conference on Saturday, when he reveals the results of a large study testing an experimental drug meant to lower risk of heart attack and stroke risk.

"I'm going to have to weather the gasp in the audience," said Nissen, a preventive cardiologist at the Cleveland Clinic in Ohio.

Many at Nissen's presentation will already know that the drug he studied, pelacarsen, didn't succeed at its key measure: lowering risk of major cardiovascular events by reducing a sticky, protein-wrapped fat in the blood called lipoprotein (a), or Lp(a).

But Nissen knows the crowd is holding out hope that the drug showed glimmers of success in secondary measures; maybe it worked for people with medical conditions like diabetes, or prevented some bad outcomes, if not all. Maybe too many people dropped out of the trial before it could meet its mark.

"It wasn't a near miss. It just didn't have an effect on outcomes, and I don't think virtually anybody's prepared to hear that," Nissen told CNN.

"This is the first time anybody's been able to study a drug to treat this disorder, which more than a billion people have, and you know was widely expected to be positive, to be favorable. I mean, uniformly expected to be favorable. So everybody's going to be pretty surprised when they see the results."

In other words, instead of a blockbuster, the drug is just a bust. Novartis, which has already sunk tens of millions of dollars into the drug's development, has decided to abandon it.

No breakthrough for patients yet

In science, big failures can be as important as big successes, and the new study raises questions that may 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 as well as raising inflammation, making it a double whammy for heart attack risk.

Some people inherit the tendency to make more Lp(a) than others, and studies have shown that people with highest levels in their blood are two to four times more likely to have a heart attack compared 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 their only risk factor is high lipoprotein (a).

"It's a pure genetic risk."

The study randomly divided 8,350 people who'd previously experienced a cardiovascular event like a heart attack or stroke and high levels of Lp(a) into two groups: Half received pelacarsen, while the other half got a placebo. Neither the patients nor the study investigators knew who was getting the drug and who wasn't. Most patients were followed for nearly five years.

At the end of the study, researchers' main comparison between the two groups was an outcome called MACE — major adverse cardiovascular event. It included any kind of heart-related death, as well as non-fatal heart attacks, strokes, and whether patients had needed an urgent procedure to treat a blocked blood vessel, like heart bypass surgery.

When the study results were unblinded, however, there was a surprise. While high-risk patients taking pelacarsen had much lower levels of lipoprotein (a) than at the start of the study, they had virtually the same risk of dying of heart disease or having a serious cardiovascular event as someone in the placebo group. Roughly 12% of patients in each arm of the study had a serious heart-related event over the course of the study, whether they got pelacarsen or not.

The full results of the study published in the the New England Journal of Medicine on Saturday. Although researchers looked at the data several different ways, breaking out outcomes by underlying medical conditions like diabetes and looking at the drug's impact on separate types of cardiovascular events, there was essentially no difference.

The medication did exactly what everyone expected it would, lowering Lp(a) levels by an average of about 77% in patients who took it. But there was no sign that it had any impact on the risk of death from cardiovascular disease, heart attacks, strokes, or the risk that a person might need a stent or bypass surgery to treat a clot near their heart.

"I am flabbergasted," said Dr. Fatima Rodriguez, chief of preventive cardiology at Stanford University and was not involved in the research. "There is no signal."

The big question is what to do now.

What 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 lifetimes. One test is thought to be enough because studies have shown that a person's level is relatively stable over the course of their life. Drug manufacturers, including Novartis, have been actively raising awareness of the risk of Lp(a) and promoting the new testing guideline.

There's currently no treatment that specifically addresses the risk of high Lp(a). For that reason, some experts, like Dr. Karol Watson, a cardiologist and professor at the David Geffen School of Medicine at UCLA, thought it might be premature to encourage universal screening.

Testing proponents argue that knowing a patient's Lp(a) level can be used to refine their heart disease risk, Watson said.

"I kind of say hogwash to that because there's a lot of things we know that 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.

Still, when the new testing guidelines were launched, several promising Lp(a)-lowering therapies were on the horizon. Many anticipated a medical breakthrough when pelacarsen moved into the final stage of clinical testing in 2019. Early studies, including Nissen's, showed it could effectively reduce Lp(a) levels by 70% to 80%.

The drug was expected to be the first in a new wave of treatments.

"What we've done now is set up a whole bunch of people who are really anxious about this now, and we still tell them we have nothing to offer them," Watson said.

Lessons from a failed trial

In science, the study Nissen led would be called a negative or failed trial. But that's something of a misnomer, Stanford's Rodriguez thinks.

"This is such an 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's known and not known.

"It can help us kind of say, all right, is it that we're just looking at the wrong marker, which is one possibility, or is it that it's the wrong drug or the wrong population?" she added. Or maybe the whole theory that Lp(a) is a driver of heart risk is misguided.

Nissen has some theories about his results, too. He says patients in the trial were older, so perhaps past a point in their heart disease where lowering Lp(a) offered any benefit. They all had their LDL, or "bad" cholesterol, well controlled. Studies have shown that aggressively lowering LDL cholesterol with statin medications may help mitigate the risk from having high Lp(a) numbers. Finally, while pelacarsen lowered Lp(a) by nearly 80%, it may be that levels have to be even lower, on the order of 90% to 95%, to show a reduction in heart risk.

There are other, stronger Lp(a)-lowering medications already in clinical trials, he notes. He also thinks these kinds of drugs may do the most good if they're taken earlier in the disease process, before a person has their first heart attack or stroke – what's known as primary prevention.

What patients can do

For now, people who are tested for lipoprotein (a) and have a high level can manage their risk by addressing everything else that's known to contribute to heart risk. Nissen said exercise, weight loss, and importantly, a statin to lower LDL cholesterol as much as possible, should all be part of a person's preventive care.

Dr. Anurag Mehta, a cardiologist with Emory Healthcare and an expert on Lp(a) says he hopes the study results won't discourage people from getting tested.

"I do think that it is one of the strongest markers of heart disease risk," Mehta said. There's benefit in being tested, understanding your risk and knowing the steps you can take to control what you can. "That's where the utility is."

The road to scientific progress is often rocky.

The first statin medication, called Compactin, which was discovered by a Japanese biochemist in the 1970s, lowered cholesterol, but it had so many safety problems it was never brought to market.

Modern statins are "amongst the most incredible drugs we've ever had at reducing morbidity and mortality," Nissen said. Maybe it will be the same story for Lp(a)-lowering medications.

"I got thrown off the horse. I'm going to get back on the horse," Nissen said. He's going to finish two other ongoing trials for newer Lp(a)-lowering medications and hope for better results next time. "We hope we can help these patients."