Lipoprotein(a) Reduction With Pelacarsen Has No Impact on Cardiac Events, Lp(a)HORIZON Finds

Substantially reducing elevated levels of lipoprotein(a), or Lp(a), had no effect on cardiovascular events in people with pre-existing cardiovascular disease in the much-anticipated first report from a clinical outcomes trial of an Lp(a)-lowering therapy.

At median follow-up of 4.7 years, the rate of major adverse cardiovascular events (MACE) was 12.3% with the antisense oligonucleotide pelacarsen versus 12.1% with placebo among patients with established cardiovascular disease and elevated baseline Lp(a) levels in the phase 3 Lp(a)HORIZON trial. This absence of a clinical effect was observed despite a 77.7% greater reduction from baseline Lp(a) concentration at 12 months with pelacarsen versus placebo.

Results from the primary Lp(a)HORIZON analysis and from prespecified secondary analyses of the trial were reported in two late-breaking science presentations at the opening of the American Heart Association Scientific Sessions 2026 and simultaneously published in the New England Journal of Medicine and NEJM Evidence, respectively.

“These results were disappointing and unexpected, particularly given the findings of prior observational and Mendelian randomization studies,” says Steven Nissen, MD, study chair of Lp(a)HORIZON and Chief Academic Officer of Cleveland Clinic’s Heart, Vascular & Thoracic Institute. “And they don’t represent a near miss. The hazard ratio for the primary endpoint in the full study cohort was 1.02, and our extensive secondary analyses showed that no matter how you slice the data, the result was essentially the same — neutral.”

He emphasizes, however, that the Lp(a)HORIZON results apply solely to pelacarsen and use for secondary prevention. “Lp(a)HORIZON is not the end of the story for Lp(a)-lowering therapies,” he says. “This trial enrolled only patients with prior cardiovascular events or established cardiovascular disease. Effects in primary prevention populations are not known. Additionally, pelacarsen is an antisense oligonucleotide that reduces Lp(a) to a lesser degree than the small interfering RNA [siRNA] agents in ongoing trials, including in different patient populations, such as primary prevention and aortic stenosis. A single negative trial does not define the ultimate clinical utility of lowering elevated Lp(a).”

Lp(a)HORIZON backdrop and design

Elevated blood levels of Lp(a) — a genetically determined risk factor for atherosclerotic cardiovascular events and calcific aortic stenosis — are present in about 20% of the global population. Conventional lifestyle measures and dyslipidemia therapies have little effect on Lp(a) concentrations.

Pelacarsen is an antisense oligonucleotide designed to reduce production of apolipoprotein(a), a major component of Lp(a). Earlier clinical studies demonstrated that pelacarsen substantially lowers blood Lp(a) levels, but whether these reductions prevent MACE has been uncertain, prompting the Lp(a)HORIZON trial.

The international study was a double-blind, placebo-controlled investigation among 8,350 adults with a baseline Lp(a) level ≥ 70 mg/dL (~148 nmol/L) who had had a cardiovascular event three months to 10 years prior to enrollment. Participants received guideline-based secondary prevention therapy as indicated. After a 30- to-90-day period for cardiovascular risk-factor optimization, if needed, patients were randomized on a 1:1 basis to receive either pelacarsen 80 mg by subcutaneous injection every month or matching placebo by the same schedule.

While 70 mg/dL was the Lp(a) threshold for enrollment, randomization was stratified by screening Lp(a) level to ensure balanced proportions of patients with concentrations ≥ 90 mg/dL (~192 nmol/L), who represented 78.6% of each treatment group.

The primary end point was time to first occurrence of a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal ischemic stroke or urgent coronary revascularization requiring hospitalization.

Patient characteristics

Participants were enrolled between December 2019 and July 2022; 8,322 of the 8350 enrollees were included in the efficacy analysis. Median follow-up was 57 months (4.7 years). Complete assessment for the primary end point was achieved in 97.2% of participants and vital status ascertained for 99.3%.

The two treatment groups were well matched for all demographic and clinical variables; key baseline characteristics are detailed in the table below.

“These patients were optimally treated with existing therapies,” Dr. Nissen notes. “Their cardiovascular risk factors were managed as well as in any cardiovascular outcome trial to date.”

Primary efficacy results

Pelacarsen produced pronounced and sustained reductions in Lp(a):

• At 12 months, median Lp(a) was 64.4 nmol/L in the pelacarsen group versus 233.4 nmol/L in the placebo group — an estimated 77.7% treatment difference.
• Over the course of the trial, the time-averaged reduction from baseline was 161.2 nmol/L with pelacarsen versus 17.1 nmol/L with placebo.

Despite these starkly different effects on Lp(a) levels, there was no difference between the groups on the primary composite clinical end point, which occurred at the rates detailed in the table below.

In both the full cohort and the subgroup with higher (≥ 90 mg/dL) baseline Lp(a), the absence of clinical benefit with pelacarsen was consistent across a host of prespecified secondary endpoints, including:

• A three-component composite excluding urgent coronary revascularization
• A composite using coronary heart disease death instead of cardiovascular death
• Any of the individual components of the primary end point
• All-cause mortality

Furthermore, the various prespecified secondary analyses found no significant differences in clinical outcomes between the treatment groups. Specific analyses included the following, all of which still yielded neutral results:

• On-treatment analysis, focused on when patients were taking the study drug and 112 days after discontinuation
• Uninterrupted treatment analysis, focused on patients who didn’t stop the study drug for more than 60 days
• Analysis of total events (including subsequent events along with first events)
• Landmark analyses based on the magnitude of Lp(a) reduction and achieved Lp(a) levels at three months
• Multiplicity-controlled subgroup analyses based on various baseline clinical characteristics

“No matter how we looked at the data, the result was the same — no effect,” Dr. Nissen observes.

Safety and tolerability

Drug-related adverse events were reported in a higher share of pelacarsen recipients (56.8%) than of placebo recipients (18.0%) and included higher rates of constitutional symptoms (31.9% vs. 5.8%, respectively) and investigator-reported hypersensitivity reactions (17.1% vs. 5.4%, respectively).

Notably, adverse events leading to drug discontinuation occurred in 20.6% of pelacarsen recipients versus 7.5% of placebo recipients and contributed to a higher rate of premature discontinuation of the trial regimen for any reason with pelacarsen (35.1%) compared with placebo (18.3%). Mean exposure to study drug was 3.5 years with pelacarsen and 4.0 years with placebo.

“These high rates of discontinuation made the on-treatment secondary analysis particularly important, along with its finding of no heterogeneity of effect,” Dr. Nissen says.

Making sense of the findings

The investigators note that pelacarsen achieved its expected biochemical effect, reducing Lp(a) by about 78% at 12 months and maintaining a substantial time-averaged reduction over 4.7 years. “This is very close to what was seen in phase 2 trials, so the drug did what it was supposed to do in terms of Lp(a) lowering,” Dr. Nissen says.

Yet this did not yield the cardiovascular benefits suggested by lifelong exposure to lower Lp(a) levels in genetic and observational studies. Dr. Nissen says this is one potential explanation for why the expected outcomes benefit was not seen. “If you have a low Lp(a) level from your genetics, it’s present from birth,” he explains. “Here we intervened and lowered patients’ Lp(a) to a more normal level for a median of 4.7 years, but that’s not a lifetime,” he notes. “It may be that a person needs to have lifelong Lp(a) reduction to be protected from Lp(a)-related cardiovascular events.”

He says another potential contributor is that effects of intensive background therapy required in this trial — including very low LDL cholesterol and controlled blood pressure — may have limited the ability to detect an additional benefit. That notion is bolstered by the fact that event rates in Lp(a)HORIZON were “on the low side,” according to Dr. Nissen. “The trial needed to continue a bit longer than we expected in order to obtain the requisite number of events because the event rate was relatively low.”

“Regardless of the findings of Lp(a)HORIZON, it is important to remember that Lp(a) is a causal risk factor,” notes the trial’s first author and principal investigator, Leslie Cho, MD, Co-Section Head of Preventive Cardiology at Cleveland Clinic. “Additionally, Lp(a)HORIZON shows how crucial lowering LDL cholesterol remains.”

What’s next?

Whatever the reason for the study’s unexpected findings, Dr. Nissen underscores the need to continue ongoing outcome trials of additional Lp(a)-lowering therapies and await their results. These therapies include the siRNA agents olpasiran and lepodisiran as well as the oral agent muvalaplin, a small-molecule inhibitor of Lp(a). These agents differ in administration frequency, study populations, eligibility thresholds and magnitude of Lp(a) reduction, so their eventual results could vary substantially from the Lp(a)HORIZON findings.

Dr. Nissen notes that the siRNA agents are more potent reducers of Lp(a) than pelacarsen and that the outcome trials of all three of the above agents include primary prevention patients. “We learned from the CLEAR Outcomes trial that LDL cholesterol reduction with bempedoic acid had a much better hazard ratio for primary prevention than for secondary prevention, possibly because we are treating disease earlier in its course,” he says. “A similar effect may be at play with Lp(a). Plenty of interesting findings are in store for us over the next couple of years.”

The Lp(a)HORIZON study was funded by Novartis. Dr. Nissen reports that the Cleveland Clinic Coordinating Center for Clinical Research (C5Research) has received funding to conduct clinical trials from multiple biopharmaceutical companies, including Novartis. He reports that he is involved in conducting these trials but receives no personal remuneration for his participation. He also consults for these companies but does not accept compensation.