Pelacarsen Trial Fails to Cut Heart Attack and Stroke Risk Despite Dropping Cholesterol Levels
An experimental injection developed to target a stubborn form of cholesterol failed to prevent heart attacks and strokes in a major clinical trial, researchers reported. Novartis sponsored the study of pelacarsen, which successfully slashed blood levels of lipoprotein(a), or Lp(a), by roughly 78 percent over five years. Despite that sharp biochemical drop, the medication showed zero measurable impact on cardiovascular events compared to a placebo, npr.org reported.
The phase III international study, named HORIZON, enrolled 8,323 adults across 42 countries who already had established cardiovascular disease. Participants received either a monthly subcutaneous dose of 80 milligrams of pelacarsen or a placebo starting in 2019, according to data presented at the American Heart Association meeting in Chicago and published in the New England Journal of Medicine. At a median follow-up of 4.7 years, 12.3 percent of patients on pelacarsen experienced a major adverse cardiovascular event, compared to the 12.1 percent rate in the placebo group, Fierce Biotech reported.
Dr. Steven Nissen and Dr. C. Michael Gibson discuss the Lp(a) HORIZON trial and its implications for Mendelian randomization: Pelacarsen 80 mg SC monthly lowered Lp(a) but did not significantly alter 4-component MACE rates in established cardiovascular disease populations,… pic.twitter.com/MhDjh6zkW0
Researchers Express Shock Over Null Findings in HORIZON Study
The outcome surprised cardiologists who viewed the therapy as a promising frontier in preventive medicine. Steven Nissen, a cardiologist at the Cleveland Clinic who led the trial, said the results left him shocked. Dr. Amanda Doran, an assistant professor of medicine at Vanderbilt University Medical Center, noted that investigators initially considered the trial a guaranteed success before the data emerged.
Elevated Lp(a) affects roughly 20 percent of the global population, translating to about a billion people. Because levels are fixed and do not change over time, doctors rely on a single blood test to identify patients at risk. While the trial failed to demonstrate health benefits from lowering Lp(a), experts emphasized that the marker remains a valuable indicator of heart disease risk.
And one more big CV study miss for #AHA26 Failure of Novartis $NVS Lp(a) drug raises questions about cardiovascular strategy https://t.co/t0YkJRg6xN via @cooney_liz @matthewherper
Theories Emerge on Why Pelacarsen Did Not Alter Patient Outcomes
Cardiologists are currently examining several hypotheses to explain the trial’s neutral outcome. Roger Blumenthal of Johns Hopkins University suggested that therapy might need to be administered earlier in life before patients develop advanced arterial hardening.
Another explanation focuses on the drug itself, leaving room for other experimental treatments still moving through clinical pipelines. Drugmakers including Amgen and Eli Lilly are currently testing rival siRNA and oral therapies designed to lower Lp(a) levels using different mechanisms. BMO Capital Markets analysts observed in a November 3 note that while pelacarsen missed its mark, upcoming readouts from those competing programs were due to test whether deeper reductions yield different clinical results.
Frequently Asked Questions About the Pelacarsen Trial
What is lipoprotein(a) and why is it difficult to treat?
Lipoprotein(a), or Lp(a), is a stealthy form of cholesterol determined largely by gene variants that remain constant throughout a person’s life. Until recently, physicians lacked any pharmacological tools capable of lowering elevated levels.
How much did pelacarsen reduce Lp(a) in patients?
The injectable medication suppressed Lp(a) levels by an average of 78 percent compared to a baseline drop from 236 nmol/L down to 64.4 nmol/L after 12 months in the study arm.
Today #AHA26 and @NEJM the 2 big trials of secondary prevention of heart disease with an IL-6 antibody and Lp(a) antisense oligonucleotide. No beneficial effect, overall and across all subgroupshttps://t.co/lbsVSUEArahttps://t.co/D021HH9iij pic.twitter.com/lQWqSVWpeb
Are other pharmaceutical companies still testing similar drugs?
Amgen and Eli Lilly are continuing clinical trials on alternative experimental treatments, such as olpasiran and lepodisiran, which target Lp(a) through different mechanisms and higher enrollment thresholds.
How many clinical sites participated in the HORIZON trial?
The international study ran across 797 sites in 42 countries, screening 14,249 adults before enrolling 8,323 participants with a history of cardiovascular events.
Lp(a) HORIZON trial: Pelacarsen 80 mg SC monthly yielded similar 4-component MACE rates vs. placebo over a median follow-up of 57 months in patients with established cardiovascular disease and elevated Lp(a), showing neutral effects on cardiovascular outcomes. Download slides… pic.twitter.com/xdouJHgjDU
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