Lp(a) HORIZON Shows Pelacarsen Lowers Lp(a) 78% But Not Cardiovascular Events

Pelacarsen, an antisense oligonucleotide targeting apolipoprotein(a), lowered lipoprotein(a) [Lp(a)] but did not reduce major adverse cardiovascular events (MACE) compared with placebo in patients with established atherosclerotic cardiovascular disease and elevated Lp(a) in the phase 3 Lp(a)HORIZON trial, presented at the American Heart Association (AHA) Scientific Sessions 2026 and published in the New England Journal of Medicine.¹

At 12 months, Lp(a) fell by 78.4% with pelacarsen and 3.2% with placebo (difference, 77.7 percentage points; 95% CI, 77.0–78.4). Over a median follow-up of 4.7 years, the primary MACE endpoint occurred in 12.3% (511/4157) of the pelacarsen group and 12.1% (503/4165) of the placebo group (hazard ratio [HR], 1.02; 95% CI, 0.90–1.15; P = .76).

Additional data presented at AHA 2026 indicated results were similar among patients with baseline Lp(a) of at least 90 mg/dL (HR, 1.00; 95% CI, 0.87–1.15; P = .99).¹

“I cannot avoid the disappointing conclusion – it didn’t work. Pelacarsen improved Lp(a) measures significantly – 78% lower; however, cardiovascular outcomes were unchanged. The neutral finding was unexpected and surprising to the medical community,” said Steven E. Nissen, MD, senior author and chief academic officer of the Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic in Cleveland, Ohio.²

Lp(a)HORIZON trial design and pelacarsen MACE results

The double-blind, placebo-controlled trial randomized 8350 patients aged 18 to 80 years at 797 sites in 42 countries from December 2019 through July 2022, with 8322 included in the efficacy analysis. Eligible patients had a prior myocardial infarction (MI), ischemic stroke, or symptomatic peripheral artery disease and an Lp(a) level of at least 70 mg/dL.¹

Patients received subcutaneous pelacarsen 80 mg or placebo monthly, and the primary endpoint was a composite of cardiovascular death, nonfatal MI, nonfatal ischemic stroke, or urgent coronary revascularization.¹

Mean age was 59.7 years, 27.0% of patients were women, and 76.6% had a previous MI. Median baseline Lp(a) was 235.8 nmol/L and median LDL cholesterol was 64.6 mg/dL, with 77.6% of patients receiving high-intensity statin therapy. At 12 months, median Lp(a) was 64.4 nmol/L with pelacarsen and 233.4 nmol/L with placebo.¹

None of the MACE endpoints favored pelacarsen.¹ Three-component MACE occurred in 10.2% vs 10.1% of patients (HR, 1.01; 95% CI, 0.88–1.16), and the composite including death from coronary heart disease occurred in 9.4% vs 9.7% (HR, 0.97; 95% CI, 0.85–1.12). Death from any cause occurred in 5.7% vs 5.9% (HR, 0.98; 95% CI, 0.82–1.17), with no between-group differences in any prespecified subgroup.¹

Pelacarsen safety, tolerability, and discontinuation in Lp(a)HORIZON

Serious adverse events occurred in 37.3% (1553/4166) of patients receiving pelacarsen and 41.1% (1709/4154) receiving placebo.¹ Influenza-like reactions (31.9% vs 5.8%) and injection-site reactions (25.6% vs 2.9%) were more common with pelacarsen, as were adverse events leading to permanent discontinuation (20.6% vs 7.5%).¹

Adjudicated anaphylaxis occurred in 19 patients receiving pelacarsen and none receiving placebo, and 8 hypersensitivity reactions led to hospitalization, with no deaths.¹

After a suspected case of anaphylaxis in March 2023, pelacarsen injections were moved to a medically supervised setting for 6 months before at-home dosing resumed. Premature discontinuation of the trial regimen occurred in 35.1% of the pelacarsen group and 18.3% of the placebo group.¹

The investigators noted differential discontinuation as a limitation, along with a predominantly male and White population and possible COVID-19 confounding.¹

“The results were completely neutral across multiple analyses. There was basically no effect on outcomes, not even a trend, even in subpopulations,” said Nissen. “However, this does not mean Lp(a) is irrelevant. It means we need more in-depth research to help us fully understand the underlying mechanisms of Lp(a), its interactions with other CVD risk factors and how it does or does not impact cardiovascular outcomes. So for anyone currently enrolled in an Lp(a) trial, don’t drop out because of these findings. Lp(a) is still an important piece of the overall cardiovascular disease puzzle, an important cause of morbidity and mortality worldwide.”²

The investigators suggested short-term Lp(a) reduction may not confer the benefit linked to lifelong lower levels in mendelian randomization studies, and strict background risk-factor control may have limited any added benefit.¹ Topline results showing the trial missed its primary end point were reported in September 2026.³

Phase 3 outcome trials are ongoing for the small interfering RNA agents olpasiran and lepodisiran and the oral agent muvalaplin, which have lowered Lp(a) by more than 90% and approximately 85%, respectively, in earlier trials.¹ Lepodisiran has also been studied for its effect on oxidized phospholipids carried on Lp(a).⁴

References

1. Cho L, Nicholls SJ, Frndak S, et al. Pelacarsen and cardiovascular outcomes in patients with high lipoprotein(a). N Engl J Med. Published online November 7, 2026. doi:10.1056/NEJMoa2610159

2. American Heart Association. Lp(a) HORIZON trial: Lp(a) fell by 78%, but cardiovascular outcomes unexpectedly neutral. Published November 7, 2026. Accessed November 7, 2026. https://newsroom.heart.org/news/lp-a-horizon-trial-lp-a-fell-by-78-but-cardiovascular-outcomes-unexpectedly-neutral

3. HCPLive. Pelacarsen misses primary endpoint in Lp(a)HORIZON phase 3 trial. https://www.hcplive.com/view/pelacarsen-misses-primary-endpoint-in-lp-a-horizon-phase-3-trial. Published September 5, 2026. Accessed November 7, 2026.

4. HCPLive. Lepodisiran reduces OxPL tied to Lp(a), with Steven Nissen, MD. https://www.hcplive.com/view/lepodisiran-oxidized-phospholipids-lpa. Published September 4, 2026. Accessed November 7, 2026.