Novartis’s pelacarsen cut Lp(a) by 78%, yet heart attacks and strokes did not fall

A monthly injection that lowered lipoprotein(a) by a mean of 78% did nothing measurable for the heart attacks, strokes and cardiovascular deaths it was meant to prevent. Novartis’s pelacarsen was tested in the phase 3 Lp(a) HORIZON trial, whose results were presented Nov. 7 at the American Heart Association’s Scientific Sessions in Chicago. Steven Nissen of the Cleveland Clinic, the senior author, summed up the outcome bluntly: the drug did not work.

Help yourself and the planet: The Cool Down makes it easy to help yourself while helping the planet, with smart, simple changes to save more and waste less in your everyday life.

Get The Cool Down →

We may earn a commission if you sign up.

Elevated Lp(a) is largely inherited, stays stable across a lifetime and does not respond much to statins or lifestyle changes, which is why this trial was watched so closely.

The stakes explain the attention. About 1.4 billion people, roughly 1 in 5, are thought to have elevated Lp(a), according to the AHA release. A level of 125 nmol/L or higher is associated with about a 1.4-fold risk of heart attack or stroke, and 250 nmol/L or higher with at least a twofold risk. No FDA-approved treatment lowers it, which is why a drug that cut the number by more than three quarters carried such high expectations.

Pelacarsen’s antisense mechanism and the 80 mg monthly dose

Pelacarsen is built from synthetic genetic material that enters liver cells and blocks production of Lp(a), according to the American Heart Association’s release. Patients received 80 mg by subcutaneous injection once a month or placebo. The double-blind study ran from 2019 to 2026 at 797 sites in 42 countries and screened 14,249 people to enroll 8,323 adults, with the NEJM-based reports from HCPLive citing 8,350 randomized. Everyone had established cardiovascular disease and Lp(a) of at least 70 mg/dL, with a median of 109 mg/dL at the start.

Mean age was 60, 27% of participants were women, and 26% had diabetes. About 82% had a prior heart attack. Nearly all took antiplatelet drugs and roughly 77% to 78% were on high-intensity statins, so the people tested were already well treated.

Lp(a) down 78%, event rates flat at 12.3% and 12.1%

The biochemical effect was real. As Healio reported, median Lp(a) fell from a baseline averaging 236 nmol/L to 64.4 nmol/L at 12 months on pelacarsen while staying at 233.4 nmol/L on placebo. The clinical effect was absent. Over a median 4.7 years the primary composite of nonfatal heart attack, stroke, urgent revascularization and cardiovascular death occurred in 12.3% of the pelacarsen group and 12.1% of the placebo group, a hazard ratio of 1.02 with a confidence interval of 0.90 to 1.15. In patients whose Lp(a) was 90 mg/dL or higher, the rate was 12.3% in both arms.

The TCTMD account of the full publication notes that no individual component of the composite showed benefit either, and that pelacarsen also lowered LDL cholesterol by about 13%. The full results were published in the New England Journal of Medicine, with extended analyses in NEJM Evidence. Those analyses, covering coronary death, all-cause death and other combinations, found no difference either.

Safety: 19 anaphylaxis cases and 20.6% stopping for side effects

Serious adverse events were slightly less frequent on pelacarsen, 37.3% against 41.1%, but the tolerability profile was worse. Flu-like symptoms, injection-site reactions and acute allergic reactions were more common, and the AHA release counts 19 patients with anaphylaxis on pelacarsen against none on placebo, with no allergy-related deaths. Discontinuation because of adverse events ran about 21% on the drug and just over 7% on placebo. The Cleveland Clinic’s Consult QD summary puts drug-related adverse events at 56.8% against 18.0%.

Other cardiologists reacted with more doubt about the target itself. Leslie Cho, the trial’s first author and principal investigator, maintained that Lp(a) is a causal risk factor and said the result shows how crucial lowering LDL cholesterol remains. Jared Spitz called it about as neutral a trial as a trial can get, and Jeffrey Berger raised the possibility that Lp(a) may not be a target for therapy at all, according to Healio. Donald Lloyd-Jones questioned whether the population, the safety tradeoff and the follow-up length were right, but said Lp(a) should not be abandoned as a causal risk factor.

Three explanations and the Lp(a) trials still running

Nobody has proved why a 78% drop bought nothing. Cleveland Clinic’s summary lists the leading ideas: a median 4.7 years of lowering may be too short if lifelong reduction is what matters; very low LDL cholesterol and controlled blood pressure may have left little residual risk to detect; and event rates ran low, extending the trial to reach its required count. The release also flags that 78% of participants were white and fewer than 4% were of African ancestry, a group with higher average Lp(a), and that some events may have been COVID-related.

Nissen stressed that measuring Lp(a) is still worthwhile, and the 2026 multi-society dyslipidemia guideline recommends testing at least once in adulthood. A single trial does not settle whether lowering Lp(a) helps, he added, and the release says three other outcome trials of Lp(a)-targeting compounds are underway. Per TCTMD, Novartis has ended its pelacarsen cardiovascular program, so the open question passes to rival drugs such as olpasiran and lepodisiran.

This article was produced with the assistance of AI and reviewed by Morning Overview editors prior to publication.

Help yourself and the planet: Get The Cool Down →

We may earn a commission if you sign up.