TL;DR
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Pelacarsen lowered lipoprotein(a) substantially in the Lp(a) HORIZON trial, but did not reduce the trial’s primary cardiovascular outcome compared with placebo. The result concerns this drug and this secondary-prevention population; researchers said it does not settle whether other approaches or populations could benefit from Lp(a) lowering.
Pelacarsen did not reduce major cardiovascular events compared with placebo in the phase III Lp(a) HORIZON trial, despite lowering participants’ lipoprotein(a) levels by an estimated 77.7%, according to results presented by Steven Nissen of the Cleveland Clinic at the American Heart Association annual meeting in Chicago. The finding challenges expectations for this drug in people with elevated Lp(a) and established cardiovascular disease, while leaving open whether other Lp(a)-lowering treatments or different patient groups may benefit.
The trial’s primary endpoint combined cardiovascular death, nonfatal stroke, nonfatal heart attack and urgent coronary revascularization. Over a median follow-up of 57 months, the rate of that outcome was similar between groups: the hazard ratio for pelacarsen versus placebo was 1.02, with a 95% confidence interval of 0.90 to 1.15. The result did not show a significant reduction in events.
The outcome was also neutral among participants with Lp(a) levels of 90 mg/dL or higher, for whom the hazard ratio was 1.00 (95% CI 0.87-1.15). The report said analyses of other composite endpoints and individual outcomes—including heart attack, stroke, urgent revascularization and cardiovascular death—also found no efficacy signal. Additional exploratory analyses, including analyses by treatment adherence and the size of early Lp(a) reductions, did not change the overall finding.
Pelacarsen was given as an 80 mg monthly injection. Alongside the estimated 77.7% reduction in Lp(a), it reduced LDL cholesterol by an estimated 13.3% relative to placebo. However, adverse events leading to treatment discontinuation occurred in 20.6% of participants taking pelacarsen, compared with 7.5% of those taking placebo, Nissen said at a press conference. The report described tolerability problems as prominent; the supplied results do not specify which adverse events drove the difference.
A Large Lp(a) Drop Without Fewer Events
The results show a clear gap between a biological effect and a demonstrated clinical benefit: pelacarsen lowered Lp(a) markedly, but participants did not experience fewer events covered by the trial’s primary endpoint. That distinction matters to patients, clinicians and drug developers because changes in a risk marker do not, by themselves, establish that a treatment prevents heart attacks, strokes or cardiovascular deaths.
The findings apply to pelacarsen in the population studied, not automatically to all ways of lowering Lp(a). The study enrolled people with established cardiovascular disease who were already receiving preventive treatment. It also reported more treatment discontinuations for adverse events in the pelacarsen group. The balance of clinical benefit and tolerability will need to be assessed separately for any future Lp(a)-targeting therapy that reports outcome data.
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Who Took Part in HORIZON
Lp(a) HORIZON was a phase III cardiovascular outcomes trial conducted at nearly 800 sites in 42 countries. It randomized 8,350 people with Lp(a) levels of at least 70 mg/dL and a cardiovascular event in the previous three months to 10 years. Participants received monthly pelacarsen or placebo, alongside a period of risk-factor optimization and ongoing secondary-prevention care.
The study population had a median Lp(a) level of 236 nmol/L. Median baseline LDL cholesterol was 64.6 mg/dL, average systolic blood pressure was 125 mmHg, and nearly 80% of participants were taking high-intensity statins. The group’s mean age was just under 60; about 27% were women and 78% were white. These characteristics describe the trial population and limit how directly the results can be applied to people without prior cardiovascular disease.
Lp(a) is a largely genetically determined cardiovascular risk factor that is also associated with aortic stenosis. The source report estimates that about one in five people worldwide has high Lp(a). Pelacarsen is an antisense oligonucleotide designed to reduce production of apolipoprotein(a) in the liver, a component involved in forming Lp(a).
“A single trial does not provide definitive evidence of a lack of benefit of lowering lipoprotein(a) as a strategy to reduce cardiovascular risk.”
— Steven Nissen, MD, Cleveland Clinic
Questions Beyond This Trial
HORIZON does not explain why a large Lp(a) reduction failed to produce a detectable reduction in the measured cardiovascular outcomes. The supplied report does not establish whether the result reflects the biology of Lp(a), features of this particular drug, the enrolled population, the follow-up period, or the effects of participants’ existing preventive care. Those possibilities remain questions, not conclusions from the trial.
It is also unclear whether results would differ in primary prevention, among younger people, in patients with aortic stenosis, or with longer treatment. The trial’s neutral result does not prove that Lp(a) is not a causal risk factor, but neither does the substantial biomarker reduction prove that lowering it with another drug will prevent events. Any claims about benefit from other therapies require their own outcome evidence.
Outcome Trials of Newer Therapies
Attention is turning to other Lp(a)-lowering medicines, including the siRNA therapies lepodisiran and olpasiran, which the source report says are advancing into large cardiovascular outcome trials. Researchers have described these approaches as potentially requiring less frequent administration and possibly having different tolerability, but those are prospective expectations, not findings established by HORIZON.
The next key evidence will come from those trials’ reported cardiovascular outcomes, safety results and details of the populations enrolled. Researchers have also called for further study of Lp(a) biology and of whether benefits vary by patient group. Until those data are available, the confirmed conclusion remains specific: in HORIZON, monthly pelacarsen lowered Lp(a) but did not reduce the primary cardiovascular outcome compared with placebo.
Key Questions
What did the Lp(a) HORIZON trial find?
Among people with elevated Lp(a) and existing cardiovascular disease, pelacarsen did not reduce the primary composite outcome compared with placebo over a median of 57 months. The hazard ratio was 1.02 (95% CI 0.90-1.15).
Did pelacarsen lower lipoprotein(a)?
Yes. The report estimated that pelacarsen lowered Lp(a) by 77.7% relative to placebo. That biomarker reduction did not translate into a demonstrated reduction in the trial’s cardiovascular outcomes.
Does this result rule out Lp(a) as a treatment target?
No. The result tests pelacarsen in a particular group of people with established cardiovascular disease. Researchers said one trial cannot settle whether other medicines or different populations could benefit. Those possibilities remain unproven until outcome data are available.
What are lepodisiran and olpasiran?
They are siRNA medicines targeting Lp(a) that the report says are advancing into large cardiovascular outcome trials. Their ability to prevent cardiovascular events has not been established by the HORIZON findings.
Source: medpagetoday.com
