Novartis Cholesterol Shot Shows No Benefit in Large Heart Trial

Novartis reported Saturday that its experimental drug pelacarsen produced zero decreases in heart attacks, strokes, or cardiovascular deaths in a major clinical trial. The study, known as Horizon, involved 8,322 participants with high levels of lipoprotein(a), a genetic form of cholesterol that drives plaque buildup and blood clot formation. Despite the drug reducing these dangerous lipid levels by 78%, the intervention showed no measurable impact on major cardiovascular events compared to a placebo.

The results were presented at a meeting of the American Heart Association and published in the New England Journal of Medicine. Dr. Steven Nissen, who led the trial as chief academic officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic, described the outcome as a source of "extreme surprise." He noted that the scientific community had widely assumed that substantially lowering Lp(a) would reduce the risk of major cardiovascular incidents, yet the data provided no evidence of such benefit.

Lp(a) is distinct from low-density lipoprotein, commonly known as bad cholesterol, because it is entirely determined by genetics. Approximately one in five Americans have high levels, a risk factor that diet and exercise cannot alter. Because the condition is present from conception, heart specialists have long sought pharmaceutical interventions to manage the associated risks. The Horizon trial specifically targeted patients who had already experienced a heart attack, stroke, or other cardiac event within the previous 10 years.

Researchers and clinicians expressed disappointment over the neutral findings. Dr. Amanda Doran, an assistant professor of medicine at Vanderbilt University Medical Center, stated that she believed the trial would be a "slam dunk." Vanderbilt served as one of nearly 800 sites in the study. Doran acknowledged that the medical community was heavily invested in the outcome, making the lack of efficacy a personal and professional setback.

Several theories have emerged to explain why the drug did not translate its chemical effects into health benefits. Dr. Karol Watson, co-director of the UCLA Program in Preventive Cardiology, suggested that the therapy may have been administered too late in the disease process. The average age of participants was 60, and the follow-up period averaged five years. Watson argued that intervening only in the final years of a lifelong genetic condition might be insufficient to reverse established damage.

Watson also pointed out that trial participants received aggressive treatment for other cardiovascular risk factors, including LDL cholesterol and blood pressure. Many may have also been taking aspirin, which could have mitigated the clotting risks associated with high Lp(a). This concurrent management makes it difficult to determine how much residual risk from Lp(a) remained unaddressed during the study period.

The findings do not diminish the importance of Lp(a) as a diagnostic marker. Dr. John Wilkins, a cardiologist at Northwestern Medicine and an author of recent guidelines recommending Lp(a) testing for all adults, maintained that the drug's failure does not invalidate the biometer. He emphasized that identifying high Lp(a) levels still helps clinicians identify patients at higher probability for cardiac events, allowing for earlier and more aggressive prevention strategies using existing interventions.

Novartis has no plans to conduct further studies on pelacarsen, according to Nissen. However, other pharmaceutical companies are advancing similar therapies. Eli Lilly is testing lepodisiran and an oral drug called muvalaplin, while Amgen is developing olpasiran and Silence Therapeutics is working on zerlasiran. These drugs utilize small interfering RNA technology to block liver production of Lp(a), a mechanism Nissen believes may offer fewer side effects than pelacarsen's antisense oligonucleotide approach. Early development is also underway for CRISPR gene-editing techniques designed to permanently disable the gene responsible for Lp(a) production.