An experimental drug with great promise for reducing a dangerous form of cholesterol showed no measurable impact on heart attacks or strokes in a clinical trial. The failure of Novartis’ drug Pelacarsen to help people with high levels of lipoprotein(a) stunned researchers, who called it a major blow to preventive cardiology.
Results from the clinical trial of pelacarsen, an injection, presented Saturday at a meeting of the American Heart Association, found there was no decrease in strokes, heart attacks, cardiovascular deaths or the number of procedures to open blocked arteries or restore blood flow to the heart.
“I really thought this was going to be a breeze,” said Dr. Amanda Doran, 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 deadly form of cholesterol called lipoprotein(a) or Lp(a). Like low-density lipoproteins – LDL, or “bad” cholesterol – Lp(a) causes plaque buildup in the arteries. But it also contributes to blood clots and, unlike LDL, is entirely genetic.
About 1 in 5 Americans have elevated Lp(a), according to the American Heart Association. Most don’t realize they are at risk.
Because people are born with such high levels, diet and exercise have no effect. This is why cardiology experts were so keen to find a drug that would solve the problem.
The Horizon trial included 8,322 people with high levels of Lp(a) who had already had a heart attack, stroke or other heart problem within 10 years of starting the trial.
The drug actually reduced Lp(a) significantly, by 78%, compared to a placebo drug which reduced levels by 13%.
But this huge reduction ultimately had no meaning in terms of cardiovascular health.
Dr. Steven Nissen, academic director of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic, led the trial. He said the dismal results took him by “extreme surprise”.
“Everyone, including me, believed that a substantial decrease in lipoprotein(a) levels would significantly reduce the risk of major cardiovascular events,” he said. “There is simply no evidence here that people who got a greater reduction had better outcomes.”
The findings, also published Saturday in the New England Journal of Medicine, disconcerted Nissen and other cardiologists who had long known that monitoring other markers of heart health — LDL and blood pressure, for example — had clear benefits.
“I haven’t seen a more neutral trial in a long time,” said Dr. Karol Watson, co-director of the UCLA Preventive Cardiology Program and professor at the David Geffen School of Medicine at UCLA. Watson was not involved in the research.
There are several theories as to why the medication did not work as expected. It’s possible, Watson said, that the therapy was administered too late in life to make a difference. The average age of participants in the Horizon study was 60, and they were followed for an average of five years.
“Remember, Lp(a) is a genetic disease, so from the time a baby is conceived, their Lp(a) is high. If we rushed in the last five years, it may be too late,” Watson said.
Study participants were also treated aggressively in other ways to lower their LDL cholesterol levels and bring their blood pressure into a healthy range. Participants may also have taken aspirin due to a history of heart attack or stroke, which could have reduced the risk of Lp(a) clotting.
“How much of the risk associated with Lp(a) remained? We just don’t know,” Watson said.
Is Lp(a) still important as a marker of heart health?
Doctors have only recently begun to screen 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. This is a one-time blood test because the levels are fixed and do not change over time.
Experts emphasize that Lp(a) remains an important and valuable indicator of heart disease risk, even though the Horizon study demonstrated no health benefits by reducing Lp(a) levels.
“None of this invalidates Lp(a) as a robust marker of cardiovascular disease risk,” said Dr. John Wilkins, a cardiologist at Northwestern Medicine and professor in the division of cardiology at Northwestern University Feinberg School of Medicine. Wilkins was also one of the authors of the Lp(a) guidelines.
“It’s always worth testing for Lp(a) because it can help identify individuals with a higher probability of an event, and we have other interventions that can help reduce their risk,” Wilkins said. “It’s just that right now, at least with this particular drug in this particular group of patients, we haven’t seen any benefit. That’s not to say that we couldn’t find something or a way to lower Lp(a) that reduces risk. We just need more science to understand that.”
UCLA’s Watson and Vanderbilt’s Doran agreed. “We have very good data showing that Lp(a) levels are predictive of disease,” Doran said. “People with elevated Lp(a) levels need to be aware of this in order to pursue aggressive prevention strategies. »
What’s the next step in treating Lp(a)?
No further studies of pelacarsen are planned, Nissen said, but similar drugs are in the works: Eli Lilly’s lepodisiran, Amgen’s olpasiran and Silence Therapeutics’ zerlasiran.
These are all injections that block the liver’s ability to produce Lp(a), but use different approaches. Pelacarsen is what is called 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 real effects on heart health are underway.
Eli Lilly is also studying an oral drug called muvalaplin, and CRISPR gene-editing technology designed to permanently turn off the gene that produces Lp(a) is in its early stages.
“I’m still so hopeful,” Doran said. “We’re going to get it in the end.”
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