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This cholesterol drug promised to be a game-changer. Why did it flop in the clinic — and is there still hope?
Cassandra Willyard is a science journalist in Madison, Wisconsin.
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Lipoprotein(a) is a cholesterol-carrying molecule that raises the risk of cardiovascular disease. Credit: Juan Gaertner/Science Photo Library
In early September, pharmaceutical giant Novartis issued a press release that sent shock waves through the cardiology community. A drug called pelacarsen, once expected to be a potential blockbuster, had failed to reduce the risk of heart problems and stroke in people with underlying cardiovascular disease.
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Michelle O’Donoghue, a cardiologist at Brigham and Women’s Hospital in Boston, Massachusetts, says her initial reaction to the news was “a state of disbelief”.
Pelacarsen lowers the levels of a type of cholesterol-carrying molecule called lipoprotein(a), often referred to as Lp(a) or Lp little a. Similar to low-density lipoprotein, or LDL, high levels of Lp(a) increase the risk of heart attacks and other heart-related problems. But unlike LDL (sometimes called bad cholesterol), Lp(a) levels are determined mostly by genetics, rather than lifestyle. So, the roughly one in five people who have high Lp(a) levels cannot reduce them through changes in diet and exercise. And although people can lower their LDL levels with statins and other medications, there are no approved drugs that substantially lower Lp(a).
That is why cardiologists were so excited about pelacarsen and a handful of other Lp(a)-lowering drugs that are currently in late-stage clinical trials. “Lp(a) has really been the talk of the town over the past several years in the cardiovascular community, in part because of a lot of enthusiasm over these therapies,” says O’Donoghue, who is an investigator on one of the trials. The therapies lower Lp(a) by 80% or more. All researchers had to prove was that this reduction leads to better clinical outcomes — fewer heart-related deaths, heart attacks, strokes and emergency bypass surgeries.
Why the trial, known as Lp(a)HORIZON, failed isn’t yet clear (see go.nature.com/4sv4ekx). Novartis representatives did not reply to a request for comments. But the high-profile miss has cardiologists questioning what they know about the relationship between Lp(a) and major heart-related problems, and wondering whether other Lp(a)-lowering therapies will meet a similar fate. The US drug firms Amgen and Eli Lilly have large trials under way to test therapies that target Lp(a) using a different approach.
“We had hoped that this would be the first step into a big new area of therapy,” says Harpreet Bhatia, a cardiologist at the University of California, San Diego. Now, he and other researchers are awaiting further details on the Novartis trial and the results from other trials to see whether there is still a future for such approaches to reducing Lp(a).