In the course of scientific discoveries, research sometimes witnesses moments of triumph, when researchers present their results to an audience that rises from their seats in applause.
This is precisely what happened in May, when doctors learned that a new drug called Daraxonrasib had nearly doubled the survival time of pancreatic cancer patients.
But Dr. Steven Nissen expects a different reaction when he presents Saturday, during the American Heart Association's annual conference, the results of a large study that tested an experimental drug to reduce the risk of heart attacks and strokes.
“I'm going to have to face gasps of amazement going up in the room,” said Nissen, a preventive cardiologist at the Cleveland Clinic in Ohio.
The drug, Pelacarsen, did not achieve its primary goal of reducing the risk of major cardiovascular events, despite its ability to reduce levels of lipoprotein (a) (Lp(a)), a type of fat in the blood associated with an increased risk of heart disease.
Nissen expected that the secondary results would show some positive indicators, such as achieving benefit in diabetes patients or reducing certain complications, but the drug did not show any significant effect.
"It wasn't just a narrow miss, it wasn't that the drug made any impact on the results, and I don't think almost anyone is ready to hear that," he told CNN.
Expectations were high, because this was the first large trial to test a drug targeting this protein, high levels of which are believed to affect more than a billion people. Novartis, which invested tens of millions of dollars in developing the drug, decided to abandon it.
Major scientific failures may be as important as successes, and the new trial raises questions about the role of lipoprotein(a) in the development of cardiovascular disease.
Nissen and his colleagues spent seven years testing belacarsen, which blocks the body's production of this protein. It is believed that high levels promote the formation of clots and inflammation in the arteries, which increases the risk of heart attacks.
Its high levels are linked to genetic factors, as some people are more predisposed to producing it in large quantities. Studies indicate that those with the highest levels are two to four times more likely to suffer a heart attack than those with the lowest levels, according to the American Heart Association.
“I see these patients,” Nissen said. “I see young women who are having strokes in their 30s, and their only risk factor is high lipoprotein A.”
The trial included 8,350 people who had previously suffered a heart attack or stroke and had high levels of the protein. Half of them received belacarsen, while the other half received a placebo, and the researchers followed them for approximately five years.
However, the results showed that about 12% of the participants in each group experienced serious heart complications, with no significant difference between those who took the drug and those who received the placebo.
Although belacarsen reduced protein levels by about 77%, it did not reduce the risk of death from heart disease, heart attacks and strokes, or the need for stents or bypass surgery. Additional analyses, including those looking at patients with diabetes and different types of complications, did not reveal any clear benefit.
“I'm amazed,” said Dr. Fatima Rodriguez, chief of preventive cardiology at Stanford University, who was not involved in the study. “There are no signs of effectiveness.”
For the first time this year, the American Heart Association and the American College of Cardiology recommended that all adults be tested for lipoprotein(a) levels at least once in their lifetime, because levels remain relatively stable over time.
But the recommendation sparked controversy in the absence of a treatment targeting the risks associated with high levels of this protein. Dr. Carol Watson, a cardiologist and professor at the David Geffen School of Medicine at the University of California, Los Angeles, believes that expanding screening may be premature, since doctors do not have a treatment that specifically targets this factor.
She said: “I see that this statement is not based on a convincing basis, as there are many things that we know are related to risk, such as the level of homocysteine. However, no one asks us to measure it, because there is nothing we can do about it.”
Promising treatments for lowering lipoprotein(a) were in advanced stages of development when the screening recommendations were issued. Preliminary studies also showed that belacarsen is able to reduce its levels by between 70% and 80%, which raised hopes that it would be the first drug in a new generation of treatments.
“What we've done now is we've made a significant number of people feel very concerned about this, while still telling them we have nothing to offer them,” Watson said.
Although the Nissen trial has been described as negative, Rodriguez believes it is still very important, because its results may prompt scientists to reconsider their understanding of the relationship between lipoprotein(a) and heart disease. She said that the experiment was conducted according to a precise methodology, and that its results raise several possibilities.
Nissen has possible explanations, too. He suggests that the participants were older and may have reached an advanced stage of heart disease where protein reduction no longer provided any benefit. Their LDL cholesterol levels were largely under control, and intensive lowering with statin medications may help reduce the risks associated with lipoprotein(A).
It is also possible that reducing protein levels by about 80% was not enough, and that a 90% to 95% reduction would be needed to show a significant benefit.
Nissen pointed out that other more effective drugs in lowering protein are already undergoing clinical trials, and may achieve better results if used at an early stage, before patients experience their first heart attack or stroke, which is known as primary prevention.
In the absence of treatment targeting lipoprotein(a), people with high levels of lipoprotein(a) can reduce their heart disease risk by treating other controllable risk factors.
Nissen said that exercising, losing weight, and most importantly taking statin medications to lower LDL cholesterol as low as possible, should be part of preventive care.
Dr. Anurag Mehta, a cardiologist at Emory Healthcare and an expert in lipoprotein (A), hopes that the results of the study will not lead people to refrain from getting tested. He expressed his actual belief that “this is one of the strongest indicators of the risk of heart disease,” adding that screening helps understand the level of risk and determine the steps needed to control factors that can be changed.
Bellacarsen's failure does not mean the end of the road for research. Statin drugs, in turn, faced obstacles in their early development. The first drug in this class, called Compactin, was discovered in the 1970s, but it was not put on the market due to safety concerns.
Modern statin drugs have become “among the most impressive drugs we have historically known for reducing morbidity and mortality,” Nissen said, expressing his hope that the same success will be repeated with treatments designed to lower lipoprotein (A).
He concluded: “I fell off the horse, but I will get back on it.” He confirmed that he will continue two clinical trials to test newer drugs targeting the protein, in the hope of achieving better results and helping patients.
