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The phase III Lp(a) HORIZON trial found that monthly pelacarsen did not reduce its primary cardiovascular outcome compared with placebo, despite sharply lowering lipoprotein(a). Adverse events leading to treatment discontinuation were also more frequent with pelacarsen. Researchers say the result challenges this treatment approach, but does not settle whether Lp(a) lowering can benefit other populations or therapies.
The phase III Lp(a) HORIZON trial found that pelacarsen did not reduce major cardiovascular events compared with placebo among people with elevated lipoprotein(a) and existing cardiovascular disease, despite substantially lowering the blood marker. Results presented by Steven Nissen at the American Heart Association meeting in Chicago raise questions about this drug’s approach to risk reduction, while leaving the wider Lp(a) treatment hypothesis unresolved.
Among 8,350 participants, the primary outcome—a composite of cardiovascular death, nonfatal stroke, nonfatal heart attack and urgent coronary revascularization—occurred at a rate that showed no advantage for pelacarsen over placebo during a median 57 months of follow-up. The hazard ratio was 1.02, with a 95% confidence interval of 0.90 to 1.15. The confidence interval includes no difference between treatment groups.
Pelacarsen reduced Lp(a) by an estimated 77.7% relative to placebo; LDL cholesterol fell by an estimated 13.3%. But analyses of participants with Lp(a) levels of at least 90 mg/dL also found no benefit, and investigators reported no efficacy across several other composite outcomes or the individual outcomes of heart attack, stroke, urgent revascularization and cardiovascular death. Additional exploratory analyses, including ones accounting for adherence and the degree of early Lp(a) reduction, did not change the overall result, according to Nissen.
Treatment discontinuations linked to adverse events were more common with pelacarsen: 20.6% of participants stopped the drug for that reason, compared with 7.5% in the placebo group. Pelacarsen is an antisense oligonucleotide designed to reduce production of apolipoprotein(a), a component of Lp(a), and was given as an 80-mg monthly injection.
A Large Biomarker Drop, No Event Benefit
The result highlights a gap between changing a biological risk marker and showing that patients experience fewer heart attacks, strokes or cardiovascular deaths. Pelacarsen’s substantial reduction in Lp(a) did not translate into a measurable reduction in the trial’s primary outcome in this population during the reported follow-up. That distinction matters for patients and clinicians: a lower laboratory value alone does not establish that a treatment prevents clinical events.
The trial also raises practical questions about tolerability, given the higher rate of adverse-event-related discontinuation. At the same time, the result does not establish that all ways of lowering Lp(a) will fail. The treatment, patient group, duration and degree of background risk-factor control may all matter, and other drugs are being tested in separate studies.
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How HORIZON Tested Pelacarsen
HORIZON enrolled people with a prior cardiovascular event and Lp(a) levels of at least 70 mg/dL. Participants were assigned to monthly pelacarsen or placebo after a period intended to optimize standard secondary-prevention care. At enrollment, median LDL cholesterol was 64.6 mg/dL and average systolic blood pressure was 125 mmHg; nearly 80% of participants were taking high-intensity statins.
Participants had a mean age just under 60, and about 27% were women. The trial spanned nearly 800 sites in 42 countries. Lp(a) is largely genetically determined and is associated with atherosclerotic cardiovascular disease and aortic stenosis. The source report estimates that elevated Lp(a) affects about one in five people worldwide, though the trial itself studied a selected group with both high Lp(a) and established cardiovascular disease.
Pelacarsen is not the only approach under study. The report identifies lepodisiran and olpasiran as small-interfering RNA (siRNA) therapies advancing to large cardiovascular-outcome trials. These are distinct drugs and their benefits or tolerability cannot be inferred from HORIZON. Donald Lloyd-Jones also noted that PCSK9 antibody drugs lower Lp(a) alongside LDL cholesterol, but said the contribution of Lp(a) reduction to their cardiovascular benefit is not fully understood.
“The Lp(a) HORIZON trial is not the end of the story.”
— Steven Nissen, Cleveland Clinic, presenting the trial at the AHA meeting
Questions Beyond This Trial
The reported result establishes that pelacarsen did not reduce the measured cardiovascular outcomes in the HORIZON population over the study period; it does not show why. The trial does not determine whether a different Lp(a)-lowering drug, a longer treatment period, or treatment before cardiovascular disease develops would produce a different outcome. Those possibilities remain questions for other trials, not conclusions from this one.
It is also unclear how much, if any, of the observed benefit from PCSK9 antibodies is attributable to their effect on Lp(a), rather than their lowering of LDL cholesterol or other effects. The available source report does not provide detailed event counts, a full breakdown of adverse events, or a final explanation for the neutral result. Those details should not be inferred from the hazard ratio alone.
Results From Other Lp(a) Trials
Attention now turns to ongoing outcome trials of lepodisiran, olpasiran and other Lp(a)-lowering therapies. Their results may clarify whether outcomes differ with another drug mechanism or in a different patient population. Nissen urged industry sponsors not to stop research on the basis of one negative trial; that is an appeal, not confirmation that the other drugs will succeed.
Researchers and clinicians will also look for further analyses and peer-reviewed reporting on HORIZON. The key next evidence will be whether other trials show fewer cardiovascular events—not simply lower Lp(a)—and whether any benefit can be balanced against treatment risks and discontinuation rates.
Key Questions
Did pelacarsen lower lipoprotein(a)?
Yes. In HORIZON, pelacarsen lowered Lp(a) by an estimated 77.7% relative to placebo, according to the reported trial results.
Did pelacarsen reduce cardiovascular events in the trial?
No reduction was shown in the primary composite outcome. The reported hazard ratio was 1.02 (95% confidence interval 0.90 to 1.15), indicating no demonstrated advantage over placebo.
Does this result mean Lp(a) is not a cardiovascular risk factor?
No. This trial tested one drug in people with elevated Lp(a) who already had cardiovascular disease. Researchers said the result does not settle the broader question of whether Lp(a) contributes to risk or whether other treatments and populations could benefit.
What other Lp(a)-lowering drugs are being studied?
The report names lepodisiran and olpasiran as siRNA therapies advancing to large cardiovascular-outcome trials. Their clinical outcomes remain unknown.
Source: medpagetoday.com
