Lowering Lp(a) Didn't Reduce Cardiovascular Risk in Major Phase 3 Study

Novartis, in partnership with Ionis Pharmaceuticals, announced that the phase 3 Lp(a)HORIZON trial of pelacarsen did not meet its primary end point. The trial measured a composite outcome of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke and urgent coronary revascularization requiring hospitalization, comparing pelacarsen to placebo in patients with elevated lipoprotein(a), or Lp(a), and established cardiovascular disease.

Consistent with earlier studies, pelacarsen substantially lowered Lp(a) levels. However, that reduction did not translate into a measurable decrease in cardiovascular events. Elevated Lp(a) is an inherited cardiovascular risk factor affecting an estimated 1 in 5 people worldwide, and it currently has no approved targeted treatment.

About Elevated Lp(a)

Lp(a) is an inherited, independent and causal cardiovascular disease risk factor, with levels roughly 90% determined by genetics and largely unaffected by diet or lifestyle changes. Elevated Lp(a) can contribute to arterial plaque buildup and inflammation, increasing the risk of plaque rupture and cardiovascular events. An estimated 20% of people worldwide, and nearly one-third of those with premature cardiovascular disease, have elevated Lp(a) levels. Current U.S. and European guidelines recommend a one-time Lp(a) test for all adults.

A First-of-Its-Kind Test of the Lp(a) Hypothesis

"Although pelacarsen substantially lowered Lp(a) levels consistent with previous studies, we are disappointed that this did not translate to cardiovascular risk reduction," said Brett P. Monia, Ph.D., CEO of Ionis, in a statement. He noted that Lp(a)HORIZON was the first pivotal phase 3 trial designed to directly test whether lowering Lp(a) could reduce cardiovascular risk in patients with established cardiovascular disease who were already receiving optimal cardiovascular care.

Monia said that despite missing its primary end point, the trial provides meaningful clarity that will inform how future cardiovascular research and care approach Lp(a) as a treatment target. He added that Ionis will continue advancing its independently commercialized medicines, Tryngolza, Dawnzera and Zanvastro, along with its broader pipeline.

Safety and Next Steps

Pelacarsen demonstrated an acceptable safety profile in the trial, according to the companies. Full data from Lp(a)HORIZON will be presented at an upcoming medical congress.

Pelacarsen is an investigational antisense oligonucleotide designed to inhibit Lp(a) production at its source. Ionis discovered and led the drug's early development before Novartis exercised an option in February 2019 to license its development and commercialization for targeted cardiovascular therapy.

“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,” said Shreeram Aradhye, president of Development and chief medical officer at Novartis.