An experimental Novartis drug that sharply lowered a genetic form of cholesterol called lipoprotein(a) failed to protect patients from heart attacks or strokes in a large five-year trial, researchers reported Saturday. The result is a blow to doctors who hoped it would become the next major weapon against heart disease.
The drug, pelacarsen, cut Lp(a) levels by about 78%, compared with 13% in the placebo group. Yet the trial, known as Horizon, found no reduction in strokes, heart attacks, cardiovascular deaths or procedures to reopen blocked arteries or restore blood flow to the heart.
Steven Nissen, the Cleveland Clinic cardiologist who led the study, presented the findings at an American Heart Association meeting in Chicago, with details published in the New England Journal of Medicine and NEJM Evidence. Nissen said the results caught him by extreme surprise and that patients with larger Lp(a) reductions fared no better.
I think it's a big deal because the expectation was so high that this would end up being positive,
Harlan Krumholz, Yale University cardiologist
The trial enrolled more than 8,300 adults with high Lp(a) who had already suffered a heart attack, stroke or other heart problem, at nearly 800 sites. Participants averaged 60 years old and were followed for an average of five years.
Novartis, which sponsored the study, said last month that it had missed its goals but released no specifics. The company said in a statement that the work provides meaningful evidence about the link between Lp(a) and heart disease. Nissen said no further study of pelacarsen is planned.
A genetic risk factor
Like LDL, the so-called bad cholesterol, Lp(a) builds plaque in the arteries, but it also helps form blood clots and is entirely inherited. Because people are born with high levels, diet and exercise do nothing to lower them.
About 1 in 5 Americans have elevated Lp(a), according to the American Heart Association, and Nissen put the global figure at roughly a billion people. Earlier this year, the American College of Cardiology and the heart association issued guidelines saying every adult should have Lp(a) measured in a one-time blood test.
Theories for the failure
Researchers are weighing several explanations. High Lp(a) may turn out to be a marker of some other risk rather than a cause of heart attacks. Karol Watson, a UCLA cardiologist, said the drug may have come too late in life, while Roger Blumenthal of Johns Hopkins University said treatment may need to start earlier or last longer.
Stanford cardiologist David Maron, president of the American Society for Preventive Cardiology, suggested the trial should have required higher Lp(a) levels for entry. Participants were also aggressively treated for cholesterol and blood pressure, and some may have taken aspirin, which could have blunted Lp(a)'s clotting risk.
Experts said the failure does not undercut Lp(a) testing. John Wilkins, a Northwestern Medicine cardiologist who helped write the screening guidelines, said the level remains a robust marker of cardiovascular risk that helps identify patients who need other preventive care.
Rival drugs remain in testing, including Eli Lilly's lepodisiran, Amgen's olpasiran and Silence Therapeutics' zerlasiran. Those use a different technology, small interfering RNA, and may cause fewer side effects such as injection site reactions, Nissen said. Results are expected over the next few years.
