Pelacarsen Fails to Reduce Cardiovascular Events in HORIZON Trial

An experimental drug developed by Novartis and Ionis Pharmaceuticals to lower lipoprotein(a) failed to show any measurable impact on heart attacks, strokes, or cardiovascular deaths in a landmark clinical trial. Researchers presented the results of the Phase 3 HORIZON trial on November 7, 2026, at the American Heart Association’s scientific sessions in Chicago.

HORIZON Trial Details and Lp(a) Drop

The international study enrolled 8,322 patients between the ages of 18 and 80 across 797 sites in 42 countries, beginning participant recruitment in December 2019 and concluding in July 2022. Every participant in the double-blind, randomized, placebo-controlled trial had established cardiovascular disease—defined as a prior heart attack, stroke, or symptomatic peripheral arterial disease occurring between three months and 10 years before screening—and was already taking standard treatments, including lipid-lowering drugs.

Patients administered either a monthly self-injected 80-mg dose of pelacarsen or a matching placebo. After one year, the therapy lowered Lp(a) levels by a mean of 78%, compared with about 3% in the placebo group, and reduced LDL cholesterol by 13.3 percentage points. Despite the substantial biochemical drop, major adverse cardiovascular events occurred in 12.3% of the pelacarsen group and 12.1% of the placebo group over a median follow-up of 4.7 years.

At 12 months, the median Lp(a) was recorded at 64.4 nmol/L among patients receiving pelacarsen, contrasted with 233.4 nmol/L for those on the placebo. None of the primary major adverse cardiovascular events endpoints favored the experimental medication. A three-component composite occurred in 10.2% of the pelacarsen cohort compared to 10.1% of the placebo group, yielding a hazard ratio of 1.01 with a 95% confidence interval ranging from 0.88 to 1.16. A broader composite endpoint that included death from coronary heart disease was observed in 9.4% versus 9.7% of patients, producing a hazard ratio of 0.97 and a 95% confidence interval spanning from 0.85 to 1.12.

Everybody, me included, believed that lowering levels of lipoprotein(a) substantially would reduce the risk of major cardiovascular events.

Dr. Steven Nissen, the chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic

Cardiologists React to Unexpected Findings

The neutral clinical outcome stunned researchers who viewed the genetic cholesterol carrier as a prime target for intervention. High levels of this marker, defined as 125 nmol/L or greater or 55 mg/dL or higher, associate with roughly a 1.4-fold increased long-term risk of stroke or heart attack, while levels reaching 250 nmol/L or 115 mg/dL associate with at least a twofold long-term risk.

Because standard lipid therapies do not adequately address it, the pharmaceutical industry invested heavily in RNA-targeting therapies designed to suppress the particle by acting as a small segment of synthetic genetic material that enters liver cells to block production.

Other specialists voiced similar astonishment regarding the unexpected results. Meanwhile, Karol Watson, a cardiologist at the University of California, Los Angeles, emphasized that the scientific narrative is far from finished, remarking that the story is merely starting. Following the announcement of the trial outcome, Novartis announced it will discontinue development of pelacarsen for atherosclerotic cardiovascular disease, though the Swiss pharmaceutical company intends to continue investigating the therapy for calcific aortic valve stenosis.

Safety Data and Theories Behind the Neutral Outcome

However, trial investigators noted that premature discontinuation of the assigned regimen occurred more frequently among participants receiving the drug, happening in 35.1% of the pelacarsen cohort compared to 18.3% of the placebo group, with trial limitations also pointing toward a predominantly White and male population alongside potential COVID-19 confounding factors.

In addition to pelacarsen or the placebo, patients enrolled in the study were treated with LDL-lowering statins—with 77.6% receiving high-intensity statin therapy—and more potent PCSK9 cholesterol-lowering drugs like Amgen’s Repatha. Robert Rosenson, director of metabolism and lipids at Mount Sinai Fuster Heart Hospital in New York City, noted that patients whose conditions worsened during the multiyear trial were likely placed on PCSK9 inhibitors, which creates uncertainty about whether that strategy offset cardiovascular risk.

Despite the trial results, medical experts emphasize that screening remains important. Dr. Nissen and other investigators maintain that clinical trials examining other investigational compounds targeting high Lp(a) through different mechanisms—such as Amgen’s olpasiran and Eli Lilly’s lepodisiran, which have demonstrated the capacity to lower Lp(a) levels by approximately 95%—remain ongoing. Readers seeking guidance on cardiovascular health or participation in clinical trials should consult qualified medical professionals for personalized advice.

The take-home message is the story’s not over, Karol Watson noted, urging individuals to stay enrolled in ongoing studies and continue standard health assessments.

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