CHICAGO — The investigational antisense oligonucleotide pelacarsen significantly lowered highly elevated lipoprotein(a) [Lp(a)] levels in people with cardiovascular (CV) disease but failed to reduce major CV events, results from a new clinical trial showed.

While the findings did not show lower rates of CV death, heart attack, or stroke in the treatment group than in the placebo group, researchers said it’s too early to throw in the towel on targeting Lp(a).

“These results apply only to this antisense oligonucleotide and secondary prevention patients,” Steven Nissen, MD, chief academic officer at the Cleveland Clinic Heart, Vascular and Thoracic Institute in Cleveland, said in presenting the phase 3 Lp(a) HORIZON trial at the American Heart Association (AHA) Scientific Sessions 2026.

“Background therapy was optimized with baseline LDL [low-density lipoprotein] cholesterol and blood pressure among the lowest achieved of any cardiovascular outcome trial, which may have precluded showing further benefit,” he added. Average LDL cholesterol at 12 months was 13.3% lower in the pelacarsen group, Nissen said.

The trial results were simultaneously published in The New England Journal of Medicine. Extended HORIZON trial results were also published in NEJM Evidence. Pelacarsen is designed to inhibit Lp(a) production at its source.

HORIZON Results

HORIZON randomly assigned 8350 patients to either pelacarsen 80 mg monthly or a matching placebo on a 1:1 basis. At 12 months, the pelacarsen patients showed significant improvement in Lp(a) levels compared with the placebo group: from an average of 236 nmol/L at the start of the trial for both groups to 64.4 nmol/L for the pelacarsen patients vs 233.4 nmol/L for the placebo group. The averages held through 48 months of the study. The patients self-administered the drug.

The American College of Cardiology/AHA joint dyslipidemia guidelines consider that an Lp(a) level of 75 nmol/L or 30 mg/dL or higher confers an increased risk for atherosclerotic CV events, and levels of 125-249 nmol/L (50-99 mg/dL) carry a high risk.

HORIZON failed to meet the primary endpoint of major adverse cardiovascular events (MACE) — defined as a composite of death from CV causes, nonfatal heart attack or stroke, or urgent coronary revascularization. The rate was not significantly different between the two groups: 12.3% vs 12.1% for pelacarsen vs placebo (95% CI, 0.9-1.15; P = .76).

Patients with a baseline Lp(a) level considered high, at least 90 mg/dL, showed a similar finding, Nissen said: 12.3% in both groups had major CV events (95% CI, 0.87-1.15; P = .99). Serious adverse events occurred in 37.3% vs 41.1% of the pelacarsen patients vs the placebo group. The median follow-up was 4.7 years.

The neutral results persisted when the endpoint components were broken out individually, Nissen said.

The extended HORIZON results were pursued because the neutral results of the trial were unexpected, he added. Those findings were “academic and exploratory in nature,” Nissen said, and were meant to complement the primary analyses.

However, those results were much the same as those of the primary study, he said, with no differences in MACE events between the treatment and placebo groups despite robust Lp(a) reduction in the former.

Searching for Answers

The trial had three major limitations, Nissen said.

• It enrolled only patients with a history of CV events. “Effects in primary prevention populations were not studied,” he said.
• The study had a high rate of drug discontinuation of patients on pelacarsen vs placebo (35.1% vs 18.3%), with a disproportionate number of patients in the treatment group having adverse events (20.6% vs 7.5%).
• Nissen emphasized the results apply only to pelacarsen and not to the small interfering RNA (siRNA) drugs in clinical trials to reduce Lp (a), which “may be better tolerated.”

The biological activity of pelacarsen may also explain why it failed to affect CV outcomes in the trial, Nissen added. He said pelacarsen, as an antisense oligonucleotide, is a single-strand DNA molecule that’s complementary to messenger RNA (mRNA) to disrupt the production of apolipoprotein(a), whereas the siRNA agents are synthetic, double-stranded nucleic acids, or oligonucleotides that target a different nucleotide sequence to disrupt the mRNA that produces apolipoprotein(a). “We just don’t know enough yet,” Nissen said.

Despite what he called disappointing results, they do not obviate further study of the link between Lp(a) and CV events, Nissen said. “A single trial does not provide definitive evidence of a lack of benefit of lowering Lp(a) as a strategy to reduce the cardiovascular risk,” he said.

Trial discussant Karol Watson, MD, PhD, professor of medicine and cardiology at the David Geffen School of Medicine at UCLA, said in an interview that she concurred with Nissen’s assessment that reducing Lp(a) remains a potentially valid target for improving CV outcomes.

“We all believe it really is truly causal in the atherosclerotic plaque pathway,” she said. “The question is, can we modify it once you get to someone who’s got full-blown atherosclerosis? We have no data that we can yet, but this is the first trial; there are others to come.”

In her comments as discussant, Watson raised five questions to explore the unexpected HORIZON trial results, as well as some possible answers:

• Did we get the biology wrong? (probably not)
• Was the focus on secondary prevention rather than primary prevention? (maybe)
• Did aggressive lowering of LDL cholesterol mitigate the risks from Lp(a)? (very possible)
• Was the treatment started too late in life for the patient population? (probably, but that’s speculative)
• May other preventive therapies, namely aspirin, have attenuated the risks from Lp(a)? (possibly)

Lowering Lp(a) is “probably much more important in helping to delay the associated risk in the initiation and propagation of atherosclerosis rather than what is already fully established,” she added.

Watson said four ongoing clinical trials — two of the siRNA olpasiran, one of the siRNA lepodisiran, and one of the oral small molecule muvalaplin — should provide answers.

Novartis funded the trial. Nissen reported no relevant conflicts of interest. Watson reported having relationships with Novartis and Eli Lilly and Company.

Richard Mark Kirkner is a medical journalist based in the Philadelphia area.