A promising drug falls short
An experimental cholesterol drug that researchers had high hopes for did not reduce heart attacks or strokes in a clinical trial, according to NBC News. The drug, pelacarsen, is made by Novartis and is given by injection. It is meant for people with high levels of lipoprotein(a), also called Lp(a).
Results of the trial, called Horizon, were presented Saturday at an American Heart Association meeting and published in the New England Journal of Medicine. They showed no decreases in stroke, heart attack, cardiovascular death or procedures to open blocked arteries or restore blood flow to the heart.
Dr. Amanda Doran of Vanderbilt University Medical Center, one of nearly 800 trial sites, said she had expected a win. “I really thought that this was going to be a slam dunk,” she said. “We were pretty invested, so it obviously hurts.”
What the trial found
Horizon enrolled 8,322 people who had high Lp(a) and had already experienced a heart attack, stroke or other heart problem within 10 years of the trial's start. Participants averaged 60 years old and were followed for an average of five years.
Pelacarsen lowered Lp(a) by 78%, compared with 13% for a placebo. That large reduction did not translate into better cardiovascular outcomes.
Dr. Steven Nissen of the Cleveland Clinic, who led the trial, said the results took him by “extreme surprise.” He said, “There is simply no evidence here that people that got more reduction did better.” Dr. Karol Watson of UCLA, who was not involved, said, “I have not seen a more shockingly neutral trial in a while.”
Why Lp(a) matters and why the drug may have missed
Like LDL, the so-called bad cholesterol, Lp(a) contributes to plaque buildup in arteries. It also helps form blood clots. Unlike LDL, it is entirely genetic, so diet and exercise do not change it. The American Heart Association says about 1 in 5 Americans have high Lp(a), and most do not know it.
Researchers offered several possible explanations for the result. Watson said treatment may have come too late, since Lp(a) is high from birth and the trial intervened later in life. Participants were also treated aggressively for LDL cholesterol and blood pressure, and some may have taken aspirin, which could have blunted Lp(a)'s clotting risk. “How much of the Lp(a)-associated risk was remaining? We just don’t know,” Watson said.
Testing still matters, and other drugs are coming
Earlier this year, the American College of Cardiology and the American Heart Association released guidelines recommending that every adult have Lp(a) measured. It is a one-time blood test because levels stay fixed. Dr. John Wilkins of Northwestern Medicine, an author of those guidelines, said the findings do not undermine Lp(a) as a marker of risk. “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,” he said.
Nissen said no further study of pelacarsen is planned. Similar drugs are in development, including Eli Lilly’s lepodisiran, Amgen’s olpasiran and Silence Therapeutics’ zerlasiran. They block the liver's production of Lp(a) using siRNA technology rather than the antisense approach used by pelacarsen, and Nissen said they may cause fewer side effects such as injection site reactions. Trials of their effects on heart health are ongoing.
Eli Lilly is also studying an oral drug, muvalaplin, and a CRISPR gene-editing approach to permanently switch off the Lp(a) gene is in early development. Doran remained optimistic: “We’re going to get it in the end.”
