New therapies on the way to lower Lp(a), a cardiovascular risk factor

Lipoprotein(a) was first identified in the 1960s, and research over the ensuing years has confirmed that a high level of this fat — which is similar in structure to low-density lipoprotein (LDL), the “bad cholesterol” — is a factor in cardiovascular disease. High Lp(a) can cause plaque buildup and narrowing of the arteries, inflammation and blood clots. Approximately 20% of the global population has elevated Lp(a), and a person’s Lp(a) levels are genetically determined.

Clinicians understand the need to reduce elevated Lp(a) as a way to lower cardiovascular risk, but Lp(a) is not routinely tested. Guidelines, including the 2024 National Lipid Association guidelines, the 2022 European Atherosclerosis Society, and the 2021 Canadian Cardiology Society, have recommend one-time testing of Lp(a) in all adults.

Currently available therapies such as niacin and PCSK9 inhibitors such as Repatha (evolocumab) and Praluent (alirocumab) can reduce Lp(a) levels, but their impact is modest. Another challenge in treatment is that Lp(a) levels remain unchanged by lifestyle modifications such as increased physical activity or improved diet.

“About 20% of the world population have elevated levels. That represents more than a billion people on our planet that have this disorder, and many of them will have premature events, both men and women, sometimes in their 40s or even in their 30s. And the higher the level, the higher the risk,” Steven Nissen, M.D., said in an interview. Nissen is chief academic officer, Sydell and Arnold Miller Family Heart, Vascular & Thoracic Institute at the Cleveland Clinic.

Currently there are no drugs specifically approved to lower Lp(a) levels, but there are five drugs in development that have shown in phase 2 trials to have a significant impact on Lp(a) levels. (Nissen is involved as an investigator in four of these drugs.) These drugs work to block the production of apolipoprotein(a), a protein component of Lp(a). Two main technological approaches are being used: antisense oligonucleotides and small interfering RNAs, both of which target messenger RNA in liver cells to prevent protein production. Four of the therapies are injections, and one is an oral.

All five drugs are being evaluated based on cardiovascular outcome trials designed to demonstrate whether lowering Lp(a) actually reduces heart attacks, strokes, and cardiovascular deaths. The FDA requires this evidence before approval, as simply lowering the biomarker is insufficient, Nissen said. “Until we show that lowering lipoprotein(a) can protect patients, the FDA is not going to approve the drugs.”

Trial participants in all of the studies are receiving standard background therapies, including statins, with LDL cholesterol levels in some trials averaging in the mid-60s, indicating patients are already well-treated with conventional medications, Nissen said.

The drugs targeting Lp(a)

Pelacarsen: The drug that is furthest along is pelacarsen. Developed by Ionis and licensed to Novartis in 2019, pelacarsen is a second-generation antisense oligonucleotide (ASO). Top-line results of an ongoing phase 3 trial are expected to be released in the first half of this year, and regulatory filings are expected in the second half of this year. Antisense oligonucleotides are single-stranded, synthetic RNA that can bind to target RNA.

The phase 3 trial, Lp(a) HORIZON, is a placebo-controlled study that has enrolled 8,323 patients with cardiovascular disease and elevated Lp(a). The study is comparing monthly subcutaneous (SQ) injections of pelacarsen 80 mg with a matching placebo plus standard of care therapy for cardiovascular disease.

The primary endpoint is a composite of major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent coronary revascularization requiring hospitalization. This endpoint will be evaluated in the overall study population and in a subpopulation of patients with an evaluated Lp(a) of ≥90 mg/dL. A normal level of Lp(a) is considered to be below 30 mg/dl.

A phase 2b study of pelacarsen published in 2020 showed ≥80% reduction in Lp(a) levels with 20 mg administered every week. This trial was a dose-ranging study that assessed five different doses compared with placebo. The trial enrolled 459 patients who were randomly assigned to one of the five treatment doses or placebo. Treatment was continued up to one year or until the last enrolled patient had reached six months of treatment.

Although the phase 2 trial used a dose of 20 mg a week, Nissen said they expect the 80 mg once a month to have the same effect. “These drugs generally are very safe,” Nissen said. “They are working in a very narrowly focused way. Unlike small molecules, which have a lot of off-target effects, off-target effects are very uncommon with these therapies based upon nucleic acids, DNA, or RNA, so safety is not likely to be a big issue. We won't know until we unblind the trial.”

Olpasiran: The next drug that is furthest along is olpasiran, which is an Amgen drug that uses small interfering RNA technology. Given quarterly by injection, it demonstrated in a phase 2 trial reductions exceeding 90% in phase two trials and is currently being studied in approximately 8,000 patients. Olpasiran is an injection given four times a year.

The phase 2 OCEAN(a)-DOSE study found that at a dose of ≥75 mg, olpasiran reduced patients’ Lp(a) by >95% at week 36. The results from the off-treatment extension period show that patients previously dosed with ≥75 mg of olpasiran sustained about a 40% to 50% placebo-adjusted percent reduction in Lp(a) nearly a year after the last dose. No new safety concerns were identified during the off-treatment extension period.

The OCEAN(a)-OUTCOMES study, which has enrolled 7,297 patients, is comparing olpasiran given every 12 weeks with placebo on reducing coronary heart disease death, myocardial infarction, or urgent coronary revascularization in participants with atherosclerotic cardiovascular disease (ASCVD) and elevated Lp(a).

Lepodisiran. In a phase 2 trial, lepodisiran administered subcutaneously showed reduced Lp(a) levels by an average of 93.9% over the 60- to 180-day period after treatment with the highest tested dose (400 mg.) Patients who received the 16 mg and 96 mg lepodisiran doses experienced a 40.8% reduction and a 75.2% reduction in Lp(a) levels over the same time period. Lepodisiran, developed by Lilly, is a small interfering RNA (siRNA). Nissen authored the New England Journal of Medicine paper published in March 2025 that reported the phase 2 ALPACA results. In this study, 320 patients were randomized.

The ACCLAIM-Lp(a) Phase 3 clinical development program, investigating the effect of lepodisiran on the reduction of cardiovascular events in adults with elevated Lp(a), is currently enrolling. This study is currently enrolling patients and is expected to include 16,700 patients, representing the largest of the ongoing studies on Lp(a).

Zerlasiran, developed by Silence Therapeutics, is another small interfering RNA therapy showing significant reductions in Lp(a). Data from the phase 2 ALPACAR-360 study published in the JAMA in November 2024, also authored by Nissen, showed maximum Lp(a) reductions exceeded 90%. At the final visit, 60 weeks following initial drug administration, reductions in Lp(a) persisted and no safety concerns emerged with infrequent dosing. Zerlasiran is an injection.

The company has received regulatory feedback from the FDA for a phase 3 trial, but initiation is dependent on the company finding a development partner.

Muvalaplin: The fifth drug, muvalaplin, also from Lilly, is an oral small molecule that inhibits the formation of Lp(a) by blocking the initial interaction between apolipoprotein(a) and apolipoprotein B. At the 12-week primary endpoint, muvalaplin achieved a reduction of 85.8% intact Lp(a) for the 240 mg dose once daily.

A phase 3 trial, MOVE-Lp(a) will enroll 10,450 patients. The trial began in late 2025 and is expected to be completed in 2031.