Pelacarsen Misses Primary Endpoint in Phase 3 Cardiovascular Outcomes Trial

Novartis said on September 4, 2026, that its Phase III Lp(a)HORIZON cardiovascular outcomes trial of pelacarsen did not meet its primary endpoint of reducing the risk of cardiovascular events compared with placebo in patients with elevated lipoprotein(a), or Lp(a), and established cardiovascular disease. The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization, according to the company’s topline announcement, issued from Basel as an ad hoc announcement pursuant to Article 53 of the SIX Swiss Exchange listing rules.

Lower Lp(a) levels were achieved with pelacarsen in the study population, which was receiving guideline-directed treatments including lipid-lowering and antihypertensive therapies, the company said. The topline disclosure did not include numerical event rates, hazard ratios, or statistical values.

“Lp(a)HORIZON was a pioneering cardiovascular outcomes trial designed to answer one of the most important unanswered questions in cardiovascular medicine by evaluating whether lowering Lp(a) can reduce residual cardiovascular risk beyond optimized, guideline-directed care, when other major cardiovascular risk factors are already being managed,” said Shreeram Aradhye, President, Development and Chief Medical Officer, Novartis. “Although lower Lp(a) levels were observed with pelacarsen, the findings did not demonstrate that this translated into reduced cardiovascular risk in the overall study population. These are not the results we hoped for, but they provide important evidence that advances scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes and may help inform future approaches to cardiovascular risk management.”

Novartis said the Lp(a)HORIZON data will be presented at an upcoming medical congress and thanked the more than 8,000 trial participants and investigators. The announcement did not address regulatory filing plans for pelacarsen.

Trial Design and Conduct

Lp(a)HORIZON (NCT04023552) is a randomized, placebo-controlled, double-blind, parallel-group, multi-center global cardiovascular outcomes trial evaluating the effect of pelacarsen on the incidence of four-point major adverse cardiovascular events in 8,323 patients with elevated Lp(a) and established cardiovascular disease. The primary endpoint was evaluated in the overall population with Lp(a) of at least 70 mg/dL and in a subpopulation with Lp(a) of at least 90 mg/dL.

The ClinicalTrials.gov record, maintained by sponsor Novartis Pharmaceuticals, lists the study as completed, with an actual start date of December 12, 2019, and actual primary completion and study completion dates of July 16, 2026. Patients in the experimental arm received pelacarsen 80 mg by monthly subcutaneous injection, matched against placebo injections. The registry describes the trial as a pivotal Phase III study designed to support an indication for the reduction of cardiovascular risk in patients with established cardiovascular disease and elevated Lp(a).

Secondary outcome measures included the time to a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke; a coronary heart disease composite of coronary heart disease death, non-fatal myocardial infarction, and urgent coronary revascularization requiring hospitalization; time to all-cause death; and the change in Lp(a) from baseline at one year. Key inclusion criteria required Lp(a) of at least 70 mg/dL at screening and a history of myocardial infarction or ischemic stroke between three months and ten years before screening, or clinically significant symptomatic peripheral artery disease.

Pelacarsen and the Ionis Agreement

Pelacarsen is an investigational antisense oligonucleotide designed to inhibit Lp(a) production at its source. Novartis obtained global rights to develop, manufacture, and commercialize the drug under a license and collaboration agreement with Ionis Pharmaceuticals (IONS ).

Ionis announced on July 20, 2022, that Novartis had completed enrollment of the study with 8,325 participants and said at the time that topline data were expected in 2025. That release stated that Novartis licensed pelacarsen from Ionis in 2019. The final enrolled population of 8,323 patients is recorded in the trial registry.

Ionis said in 2022 that data from a Phase II study showed pelacarsen reduced Lp(a) levels below the recommended risk threshold for cardiovascular disease events in 98% of participants at the dose used in Lp(a)HORIZON. It described the compound, formerly IONIS-APO(a)-LRx, as an investigational antisense medicine designed to inhibit production of apolipoprotein(a) in the liver.

Elevated Lp(a) as a Treatment Target

Elevated Lp(a) is an inherited, independent, and causal cardiovascular disease risk factor, according to the Novartis announcement. Lp(a) levels are approximately 90% genetically determined and largely unaffected by diet or lifestyle. Lp(a) can contribute to plaque buildup and inflammation in the arteries, which can lead to plaque rupture and cardiovascular events.

Approximately 20% of people worldwide, and nearly one-third of those with premature cardiovascular disease, have elevated Lp(a), the company said, describing it as an inherited cardiovascular risk factor with no approved targeted treatment. U.S. and European guidelines recommend Lp(a) testing once in a lifetime for all adults.

Novartis said the findings provide new evidence on the relationship between Lp(a) lowering and cardiovascular outcomes, and Aradhye said the company remains committed to cardiovascular innovation. The next disclosed step is presentation of the trial data at a medical congress, for which Novartis gave no date.