Novartis announced on September 4 that its Phase III Lp(a)HORIZON trial for pelacarsen did not meet its primary endpoint, failing to demonstrate a reduction in cardiovascular events compared with placebo.
The study evaluated pelacarsen in 8,323 patients with elevated lipoprotein(a), or Lp(a), and established cardiovascular disease. Its primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and urgent coronary revascularization requiring hospitalization.
While pelacarsen achieved lower Lp(a) levels in the study population—patients who were already receiving guideline-directed lipid-lowering and antihypertensive therapies—the reduction did not translate into fewer cardiovascular events in the overall population. The trial also included a prespecified subpopulation analysis for patients with Lp(a) levels of 90 mg/dL or higher.
Elevated Lp(a) is an inherited cardiovascular risk factor affecting roughly one in five people worldwide and nearly one-third of those with premature cardiovascular disease. Lp(a) levels are approximately 90% genetically determined and largely unaffected by diet or lifestyle. US and European guidelines recommend lifetime Lp(a) screening once for all adults. No approved targeted treatment currently exists for elevated Lp(a).
Shreeram Aradhye, president of development and chief medical officer at Novartis, called the trial "a pioneering cardiovascular outcomes trial designed to answer one of the most important unanswered questions in cardiovascular medicine." He acknowledged the disappointment while noting the findings advance scientific understanding of the relationship between Lp(a) lowering and cardiovascular outcomes.
"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," Aradhye said.
Pelacarsen is an investigational antisense oligonucleotide (ASO) designed to inhibit Lp(a) production at its source. Novartis holds global rights to develop, manufacture, and commercialize the drug under a license and collaboration agreement with Ionis Pharmaceuticals.
The trial data will be presented at an upcoming medical congress. Novartis is one of the largest pharmaceutical companies globally, with medicines reaching more than 300 million people worldwide. It is also building out what it describes as an industry-leading cardiovascular pipeline, citing a 40-year legacy in the therapeutic area.
