Highly anticipated cholesterol drug fails to prevent heart attacks, strokes

An experimental drug that held great promise in driving down a dangerous form of cholesterol didn’t show any measurable impact on heart attack or stroke in a clinical trial. The failure of the Novartis drug pelacarsen to help people who have high levels of lipoprotein(a) stunned researchers, who called it a massive blow to preventive cardiology. Results of the clinical trial of pelacarsen, an injection, presented Saturday at a meeting of the American Heart Association, found there were zero decreases in stroke, heart attack, cardiovascular deaths or the number of procedures to open blocked arteries or restore blood flow to the heart. “I really thought that this was going to be a slam dunk,” said Dr. Amanda Doran, an assistant professor of medicine in the division of cardiovascular medicine at Vanderbilt University Medical Center. Vanderbilt was one of nearly 800 sites involved in the clinical trial, called Horizon. “We were pretty invested, so it obviously hurts.” Pelacarsen targets a stealthy and particularly lethal form of cholesterol called lipoprotein(a), or Lp(a). Much like low-density lipoprotein — LDL, or the “bad” cholesterol — Lp(a) causes plaque to build up in arteries. But it also helps form blood clots, and unlike LDL, it is entirely genetic. About 1 in 5 Americans have high Lp(a), according to the American Heart Association. Most don’t realize they’re at risk. Because people are born with those high levels, diet and exercise have no effect. That’s why heart experts have been so keen to find a drug that would handle the problem. The Horizon trial included 8,322 people with high Lp(a) levels and who’d already had a heart attack, stroke or other heart problem within 10 years of starting the trial. The drug did reduce Lp(a) significantly, by 78%, compared to a placebo drug that cut levels by 13%. But that huge reduction ultimately meant nothing in terms of cardiovascular health. Dr. Steven Nissen, the chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, led the trial. He said the dismal results took him by “extreme surprise.” “Everybody, me included, believed that lowering levels of lipoprotein(a) substantially would reduce the risk of major cardiovascular events,” he said. “There is simply no evidence here that people that got more reduction did better.” The findings, also published Saturday in the New England Journal of Medicine, confounded Nissen and other cardiologists who’ve long known that controlling other markers of heart health — LDL and blood pressure, for example — provides clear benefits. “I have not seen a more shockingly neutral trial in a while,” said Dr. Karol Watson, co-director of the UCLA Program in Preventive Cardiology and a professor at UCLA’s David Geffen School of Medicine. Watson was not involved with the research. There are several theories as to why the drug didn’t work as anticipated. It’s possible, Watson said, that the therapy was given too late in life to make a difference. The average age of Horizon’s study participants was 60, and they were followed for an average of five years. “Remember that Lp(a) is a genetic disorder, so from the time a baby’s conceived, their Lp(a) is high. If we just swooped in in the last five years, maybe that’s too late,” Watson said. Study participants were also treated aggressively in other ways to drive down their LDL cholesterol and get blood pressure readings into a healthy range. Participants may have also been taking aspirin because of a history of heart attack or stroke, which could have lessened Lp(a)’s clotting risk. “How much of the Lp(a)-associated risk was remaining? We just don’t know,” Watson said. Does Lp(a) still matter as a marker of heart health? Doctors have only recently begun screening for it. Earlier this year, the American College of Cardiology and the American Heart Association released guidelines that every adult should have their Lp(a) levels measured. It’s a blood test that’s done once because levels are fixed and don’t change over time. Experts stress that Lp(a) remains an important and valuable indicator of heart disease risk, even though the Horizon study failed to show any health benefit to driving down Lp(a) levels. “None of that invalidates Lp(a) as a robust marker of cardiovascular disease risk,” said Dr. John Wilkins, a cardiologist at Northwestern Medicine and a professor in the division of cardiology at Northwestern University’s Feinberg School of Medicine. Wilkins was also one of the authors of the Lp(a) guidelines. “It’s still worth testing for Lp(a) because it can help identify individuals with a higher probability of an event, and we do have other interventions that can help reduce their risk,” Wilkins said. “It’s just that at present, at least with this particular drug in this particular group of patients, we did not see benefit. That doesn’t mean that we might not find something or some way to lower Lp(a) that reduces risk. We just need more science to figure that out.” UCLA’s Watson and Vanderbilt’s Doran agreed. “We have really good data to show that Lp(a) levels are predictive of disease,” Doran said. “People who have high Lp(a) need to be aware of that in order to pursue aggressive prevention strategies.” What’s next in treating Lp(a)? No further study of pelacarsen is planned, Nissen said, but similar drugs are in the pipeline: Eli Lilly’s lepodisiran, Amgen’s olpasiran and Silence Therapeutics’ zerlasiran. All are injections that work by blocking the liver’s ability to produce Lp(a), but use different approaches. Pelacarsen is what’s known as an antisense oligonucleotide. The others use a technology called small interfering RNA, or siRNA, and may have fewer side effects, such as injection site reactions, Nissen said, than pelacarsen. Like pelacarsen, all reduce Lp(a). Clinical trials to show whether they have any real-world heart health effects are ongoing. Eli Lilly is also studying an oral drug called muvalaplin, and CRISPR gene-editing technology designed to permanently switch off the gene that produces Lp(a) is in early development. “I’m still so hopeful,” Doran said. “We’re going to get it in the end.”