In early September, Novartis reported that pelacarsen, a drug once expected to become a blockbuster, had failed to reduce the risk of heart disease or stroke in people with existing cardiovascular disease. The result has surprised cardiologists because pelacarsen lowers lipoprotein(a), or Lp(a), by more than 80%—an approach based on decades of evidence linking high Lp(a) levels to cardiovascular risk. Researchers are now awaiting more details from the trial and results from other Lp(a)-lowering treatments.
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Michelle O’Donoghue, a cardiologist at Brigham and Women’s Hospital in Boston, Massachusetts, said her initial reaction was “a state of disbelief.”
Pelacarsen lowers levels of lipoprotein(a), a cholesterol-carrying molecule often called Lp(a) or “Lp little a”. Like low-density lipoprotein (LDL), high levels of Lp(a) increase the risk of heart attacks and other cardiovascular problems. Unlike LDL, also known as “bad cholesterol”, Lp(a) levels are determined primarily by genetics rather than lifestyle. As a result, approximately one in five people with high Lp(a) levels cannot lower them through dietary changes or exercise. Statins and other drugs can reduce LDL levels, but no approved medicines significantly lower Lp(a).
That is why cardiologists have been excited about pelacarsen and several other Lp(a)-lowering drugs in late-stage clinical trials. “Lp(a) has really been a hot topic in the cardiovascular field over the last few years, in part because there’s been a lot of enthusiasm for these treatments,” says O’Donoghue, who is an investigator on one of the trials.
These treatments lower Lp(a) by more than 80%. Researchers needed to determine whether that reduction would lead to better clinical outcomes, including fewer cardiovascular deaths, heart attacks, strokes and emergency bypass surgeries.
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It is not yet clear why the trial, known as Lp(a)HORIZON, failed. Novartis’s announcement did not provide those answers, and representatives for the company did not respond to requests for comment.
The high-profile setback has left cardiologists questioning what they know about the relationship between Lp(a) and major cardiovascular problems. They are also wondering whether other Lp(a)-lowering therapies could meet a similar fate. US pharmaceutical companies Amgen and Eli Lilly are conducting large-scale clinical trials of treatments that target Lp(a) through a different approach.
“We were hoping this would be the first step into a big new field of treatment,” says Harpreet Bhatia, a cardiologist at the University of California, San Diego. He and other researchers are now waiting for more detailed results from the Novartis trial and findings from other studies to determine whether Lp(a)-lowering treatments still have a future.
Hidden cholesterol
Both Lp(a) and LDL carry cholesterol, a fatty substance produced primarily in the liver. The body needs cholesterol, but excessive levels can cause it to accumulate on artery walls, forming hard plaques known as atherosclerosis. These plaques can grow large enough to restrict blood flow or rupture, causing blood clots that may trigger a heart attack.
Study after study has shown that people with high Lp(a) levels have a greater risk of coronary artery disease—including heart attacks, heart-valve problems and heart failure—than people with low levels.1 Over the past 30 years, genetic evidence has strengthened the view that Lp(a) is not merely a marker of risk but also a causative factor.2
“Genetically, I don’t think there is any further evidence that this is a drug target,” says Borge Nordestgaard, a cardiologist at the University of Copenhagen and president of the European Atherosclerosis Society in Gothenburg, Sweden.
Structurally, Lp(a) is similar to LDL. Both are essentially particles of fat surrounded by a protein called apolipoprotein B.
Both particles are produced in the liver, but Lp(a) has an additional tail made of apolipoprotein(a). This tail loops through a segment called a “kringle”, a name taken from a twist in a type of Scandinavian pastry.
Lp(a) levels depend partly on the number of copies of a particular type of kringle encoded by the apolipoprotein(a) gene. People carry between one and more than 40 copies. The lower the copy number, the smaller the particle and the higher the Lp(a) level, apparently because liver cells can produce and secrete smaller particles more easily.
Researchers are still working to understand how these structural differences affect the particle’s function and its role in cardiovascular disease. Particle for particle, Lp(a) carries six times the risk of LDL. This could be because it deposits cholesterol on artery walls efficiently or because it promotes inflammation that contributes to plaque formation. Nordestgaard thinks the main effect could instead involve blood clotting: the particle’s tail may make it harder for the body to break down a clot, resulting in a larger blockage.
Many countries recommend that adults have their Lp(a) levels tested at least once. The European Atherosclerosis Society and the Society of Cardiology first recommended testing in 2019, and American societies followed suit earlier this year. Because no approved treatments lower Lp(a), the standard approach for people with high levels is to reduce other cardiovascular risk factors aggressively.
High Lp(a) levels do not always lead to cardiovascular problems. Bhatia says that some older people have high levels but never experience cardiovascular events. “In some cases, plaque may not be visible on imaging tests,” he says. “It’s a big picture of risk, and Lp(a) may be just one piece of that big puzzle.”
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Source: www.nature.com