Pelacarsen Fails Landmark Phase 3 HORIZON Trial
An experimental drug developed to prevent heart attacks and strokes by reducing lipoprotein(a) failed a crucial phase 3 trial, researchers reported on Saturday. The medicine did not protect volunteers in the closely watched study despite significantly lowering blood levels of the targeted cholesterol-carrying particle.
Novartis and Ionis Pharmaceuticals developed the injectable therapy, known as pelacarsen, to target atherosclerotic cardiovascular disease. The seven-year trial evaluated 8,350 adults who already had heart disease, administering either a placebo or the monthly drug dose. While the therapy slashed circulating levels of lipoprotein(a), commonly called Lp(a), by approximately 78%, that reduction generated zero clinical benefit in curbing cardiovascular events across every subgroup tested.
Bloomberg interviewed Steven Nissen, the senior author of the study and chief academic officer at the Cleveland Clinic’s Heart, Vascular & Thoracic Institute, who shared his perspective on the outcomes. “The trial is completely neutral,” Nissen said. “It is not harmful. It is not helpful. It is just stone cold neutral.” Nissen presented the detailed findings at the American Heart Association scientific sessions in Chicago, alongside simultaneous publication in the New England Journal of Medicine and NEJM Evidence.
Novartis Halts Development After Missing Primary Endpoints
Following the outcome of the HORIZON trial, Swiss drugmaker Novartis announced it is largely abandoning the development of pelacarsen, once projected to be a multi-billion-dollar blockbuster. Novartis will maintain just one ongoing mid-stage clinical trial to test whether the medication can slow down calcific aortic valve stenosis, which is a heart valve calcification disorder.
The trial enrolled 8,322 patients with pre-existing cardiovascular disease and elevated Lp(a). This biological pathway finally saw its first completed Phase 3 cardiovascular outcomes study in the entire industry. Approximately 20% of the global population inherits genes that instruct the liver to produce the extra-sticky cholesterol particle. Incidence is higher for people of African or South Asian ancestry, and unlike standard low-density lipoprotein cholesterol, Lp(a) levels remain unaffected by diet, exercise, or lifestyle changes.
Researchers Question Whether High Lp(a) Causes Heart Attacks
The unexpected trial failure left researchers examining what went wrong. Harlan Krumholz, a Yale University cardiologist, noted that expectations were exceptionally high that the drug would succeed. Researchers are now questioning whether high Lp(a) actually causes heart attacks and strokes or merely acts as a marker for an underlying risk factor.
Additional theories suggest that higher baseline Lp(a) thresholds should be required for trial enrollment. Other pharmaceutical companies are testing alternative experimental Lp(a)-lowering drugs with different mechanisms. Amgen is evaluating olpasiran, while Eli Lilly is testing lepodisiran, with both treatments demonstrating reductions of around 95% in early studies. Amgen’s Phase 3 results are expected in early 2028, and Lilly’s results are anticipated in 2029.
Frequently Asked Questions About the Pelacarsen Trial
What was the primary endpoint of the HORIZON trial?
The trial evaluated a composite primary endpoint of cardiovascular death, myocardial infarction, stroke, and urgent coronary revascularization.
How much did pelacarsen lower Lp(a) levels in patients?
The monthly treatment reduced circulating levels of lipoprotein(a) by an average of 78% to 80% among participants, but that biochemical reduction did not translate into lower rates of cardiovascular events.
Which other pharmaceutical companies are currently studying Lp(a) treatments?
Amgen and Eli Lilly are testing competing experimental therapies targeting the same genetic pathway, with Phase 3 data expected between 2028 and 2029.
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