Novartis halts pelacarsen development for heart disease after 78% Lp(a) reduction fails to deliver clinical benefit
Key Facts
Novartis said on November 7 that it would halt development of pelacarsen for atherosclerotic cardiovascular disease after detailed Phase 3 results showed a substantial reduction in lipoprotein(a) without improved cardiovascular outcomes. The American Heart Association reported that average lipoprotein(a) fell by about 78% with treatment, while cardiovascular outcomes remained unchanged. Principal investigator Steven Nissen said the neutral result was "unexpected and surprising to the medical community." The decision ends the cardiovascular use tested in the study, while leaving one mid-stage study in place to assess the drug in calcific aortic stenosis. The announcement came on the day the detailed results were presented at American Heart Association sessions and published in two medical journals.
The Lp(a)HORIZON study included 8,323 adults with elevated lipoprotein(a) levels and established cardiovascular disease, and was conducted at 797 sites in 42 countries between 2019 and 2026. Participants had a median age of 60 years, women accounted for 27%, and 26% had diabetes. A total of 82% had a prior history of heart attack, 10% had a history of ischemic stroke, and 14% had symptomatic reduced blood flow to the legs. The primary measure was designed to combine cardiovascular death, nonfatal heart attack, nonfatal stroke and urgent coronary revascularization requiring hospitalization, comparing pelacarsen with placebo. The study followed patients for a median of 57 months, or 4.7 years, in both groups.
After a year of treatment, lipoprotein(a) fell by 78.4% in the pelacarsen group, compared with 3.2% in the placebo group, for an estimated treatment difference of 77.7 percentage points. The American Heart Association confirmed that the biomarker decline was not accompanied by a change in cardiovascular outcomes. The study tested whether lowering this protein would reduce major cardiovascular events, rather than merely change its level in the blood; the recorded decline was therefore not enough to establish the targeted clinical benefit. Nissen described the result as neutral despite the clear improvement in protein measurements. Novartis consequently decided to halt development of the drug for this cardiovascular use after the detailed results emerged.
The results came against a backdrop of widespread use of standard treatments among participants: about 75% already met guideline criteria for blood pressure and cholesterol, and 77–78% were taking high-intensity statins. About 21% of patients in the pelacarsen group stopped treatment because of adverse reactions, compared with more than 7% of those who received placebo. These discontinuation rates place the difference in treatment cessation within the safety record presented alongside the efficacy results. Most participants also entered the study with a history of cardiovascular disease, defining the population the trial targeted. Novartis said about one in five people worldwide has elevated lipoprotein(a), and that no approved treatment specifically targets this factor, according to the company’s statement.
Although it is halting the cardiovascular pathway related to atherosclerosis, Novartis will keep one mid-stage study in place to assess pelacarsen in calcific aortic stenosis, a different use from preventing cardiovascular events in Lp(a)HORIZON. Nissen said one trial "does not provide definitive evidence that lowering lipoprotein(a) offers no benefit as a strategy to reduce cardiovascular risk." He pointed to ongoing trials studying different treatment groups, including primary prevention and aortic stenosis. The American Heart Association said three other cardiovascular-outcomes trials targeting the protein with different investigational agents were underway when the results were presented, with their findings expected over the coming years. Novartis closed at $162.55 a share in the November 6 session, the day before the announcement, according to EL7 data; that price alone does not determine the market’s response to the November 7 decision.