Skip to main content
Premium Trial:

Request an Annual Quote

Drugmakers Clamor to Prove 'Lp(a) Hypothesis' in Cardiovascular Disease

Illustration of high- and low-density lipoproteins in a blood vessel

NEW YORK – With multiple promising drugs on the horizon targeting elevated lipoprotein(a), a biomarker associated with cardiovascular diseases, the options for treating health problems due to cholesterol-related arterial blockage may soon be expanding.

There are about a half-dozen drugs in clinical trials — including three in Phase III trials studying cardiovascular outcomes — targeting Lp(a), a type of low-density lipoprotein cholesterol and an established risk factor for atherosclerotic cardiovascular disease (ASCVD). Elevated Lp(a) has been linked to cardiovascular diseases based on observational and genetic studies, but these randomized-controlled therapeutic trials that seek to improve patients' cardiovascular outcomes by lowering Lp(a) may strengthen the evidence of a causal relationship.

"This is the first true test of the Lp(a) hypothesis," said Michael Shapiro, director of the center for prevention of cardiovascular disease and a professor of cardiology and molecular medicine at Wake Forest University School of Medicine in Winston-Salem, North Carolina. 

ASCVD patients have a build-up of cholesterol plaque in their arterial walls that can block blood flow, causing blood clots, heart attacks, strokes, and a host of other problems. Standard care currently involves lifestyle changes, such as to diet and physical activity, or medications that target other risk factors, like statins or PCSK9 inhibitors to lower LDL cholesterol, aspirin to prevent blood clots, and other blood pressure controlling agents, which often must be taken daily.

While there are currently no targeted medicines on the market that specifically lower Lp(a) levels, therapies that promise to home in on this specific ASCVD risk factor may be a promising treatment for the 20 percent to 30 percent of the population — or more than 1 billion people globally — estimated to have elevated Lp(a).

"We've never had anything for lipoprotein(a)," said Shapiro, who's a principal investigator for Phase III trials going on at Wake Forest of Novartis' Lp(a) candidate pelacarsen and Amgen's candidate olpasiran. The only treatment currently on the market in the US to lower Lp(a) is lipoprotein apheresis, which is indicated for patients who have familial hypercholesterolemia, coronary artery disease or peripheral artery disease, and elevated LDL cholesterol, in addition to elevated Lp(a).

Elevated Lp(a) is a risk factor predominantly determined by variation in the LPA gene that encodes for apolipoprotein(a), a component of Lp(a), and levels of this biomarker are largely unaffected by available medications, healthy diet, or physical activity. That means that even if a patient's other risk factors are managed, they will still be at residual risk for ASCVD from elevated Lp(a).

The biomarker was discovered about 60 years ago, in 1963. Since then, it's been established as an independent and highly prevalent risk factor for cardiovascular diseases, said Enkhmaa Byambaa, a professor in the internal medicine department at UC Davis Health, who has researched Lp(a) for nearly two decades.

Findings from early-stage studies of Lp(a)-targeting drugs have seemed promising, with indications that they may significantly lower Lp(a) levels, she noted. "Now, we need to better understand if the reduction of Lp(a) levels can actually be translated into reduction in cardiovascular disease risk," she added.

'Five shots on goal'

There are at least five companies developing Lp(a)-targeting drugs applying multiple different techniques. And cardiologists could get answers to longstanding questions about the role of Lp(a) from one of those programs as early as next year.

The frontrunner, Novartis Pharmaceuticals, is developing an antisense oligonucleotide (ASO) targeting Lp(a), called pelacarsen, a subcutaneously injected agent administered monthly and designed to target messenger RNA and block production of the apo(a) protein. In the pivotal Phase III Lp(a) HORIZON trial of patients with cardiovascular disease and elevated Lp(a), Novartis is assessing whether lowering the biomarker leads to fewer major cardiovascular events. In 2022, investigators completed enrolling more than 8,000 patients into the study, which is slated for completion in 2025. While topline results won't be available until then, data from a Phase II study have shown that pelacarsen can reduce Lp(a) levels to below a recommended risk threshold for 98 percent of participants who received the highest dose regimen.

"It is too early to comment on formal launch plans," David Soergel, global head of Novartis' cardiovascular, renal, and metabolism development unit, wrote in an email, declining to discuss the firm's regulatory strategy for pelacarsen with the US Food and Drug Administration. Later this year, Novartis plans to launch a Phase IIIb study to specifically assess the drug's ability to lower Lp(a) levels in Black and Hispanic patients. "Though Lp(a) can affect anyone, studies such as these are crucial as certain populations have greater prevalence of Lp(a)," Soergel added, noting previous studies have suggested elevated Lp(a) is more common in Black patients than other ethnic groups.

Other biopharmaceutical companies are developing siRNA therapies, another gene-silencing technique that targets mRNA. Amgen's olpasiran, also in a Phase III trial, dubbed OCEAN(a), is administered through a subcutaneous injection every 12 weeks. Olpasiran led to a 95 percent or more reduction in Lp(a) levels 36 weeks after starting treatment in a Phase II trial

Then, there are Eli Lilly's lepodisiran and Silence Therapeutics' zerlasiran, both subcutaneously administered siRNAs and in Phase II trials. 

In a Phase I study, a single dose of Lilly's lepodisiran reduced Lp(a) by 94 percent nearly a year after treatment, suggesting patients could do well with getting the drug just once or twice a year. Last month, Lilly started ACCLAIM-Lp(a), a Phase III study of major adverse cardiovascular events due to lepodisiran. Separately, in Phase II development, Lilly also has muvalaplin, a daily, oral, small molecule inhibitor designed to disrupt Lp(a) formation.

siRNAs are a promising technique because, in addition to their specificity, "by getting into the cellular machinery, you have enough impact on the reduction of the production of the protein for weeks, if not months," said Steven Romano, head of R&D at Silence Therapeutics. According to topline 36-week data from the Phase II ALPACAR-360 trial, those who received zerlasiran every 16 weeks or 24 weeks saw their Lp(a) levels reduce by more than 90 percent.

Results from the Phase II trial, in which researchers will follow patients for 60 weeks, will inform the dose and regimen Silence Therapeutics uses in a registrational Phase III trial slated for launch next year. That large, registrational trial will track patients' cardiovascular outcomes on zerlasiran and its ability to reduce Lp(a) levels, and compare them against a group receiving standard care. He said Silence Therapeutics expects to seek traditional FDA approval for zerlasiran.

Just like there are multiple cholesterol-lowering drugs, the market will benefit from multiple Lp(a)-lowering drugs, Romano reflected, adding, "It's a huge market, and there's certainly room for multiple compounds." 

Shapiro, from Wake Forest, is most interested in the siRNA approach because of their potential potency and since they may require less frequent dosing. "Probably, the siRNAs are going to be the way to go," Shapiro said. "But we'll have to see. We don't actually know that these cardiovascular outcome trials are going to turn out the way we're all hoping."

With these drugs in clinical development, "this gives us five shots on goal," said Steven Nissen, chief academic officer at the Cleveland Clinic's Heart, Vascular & Thoracic Institute, who is a principal investigator on clinical trials of Lp(a)-targeting drugs from Novartis, Lilly, and Silence Therapeutics. "All of them are in various stages of development, [and] all of them are moving forward," with pelacarsen likely to be the "first one to cross the goal line."

Among early-stage candidates, Nissen is also curious about CRISPR Therapeutics' CTX320, an in vivo gene-editing candidate that's expected to enter Phase I trials this year as a one-time intravenous infusion. Lilly and Verve Therapeutics have also said they're working to advance a preclinical candidate for in vivo editing of the LPA gene.

While attempts to use CRISPR to permanently halt production of Lp(a) are early, the potential for a single-dose treatment is exciting, Nissen said. "You can lower levels, potentially by a lot, for life," he said. "It's a ways off, yes, but it's beginning to get to the point where we're going to be able to do studies in our species — in humans — and find out whether we can make this work."

Getting ready for testing

If such drugs are approved, prescribing them will require a change in cardiovascular care management. Currently, without specific treatments that directly lower Lp(a), doctors focus on managing patients' modifiable risk factors through diet and exercise, and prescribe drugs that lower LDL cholesterol.

At present, however, doctors rarely test patients' Lp(a) levels, and guidelines bodies vary in their views on testing. For example, the European Atherosclerosis Society in a 2022 consensus statement recommended testing Lp(a) at least once in all adults and in pediatric patients with a history of ischemic stroke or family history of premature ASCVD or elevated Lp(a). The National Lipid Association in a 2019 scientific statement recommended testing only in patients with certain medical histories, including a personal or family history of premature ASCVD and suspected familial hypercholesterolemia. 

In a joint 2018 clinical practice guideline, the American Heart Association, the American College of Cardiology, and other medical societies recommended testing for patients who have a family history of premature ASCVD. Refining guidelines is an area of focus for the American Heart Association, which last year launched a project to create standard approaches for clinicians to screen and manage patients with high Lp(a).

Lack of clear guidelines on how to manage patients with high Lp(a) levels is likely one reason why testing is infrequent, Nissen said. "It's not being done nearly as often as it should," he said. "Because it's untreatable, physicians have been relatively relaxed about measuring it. That's a mistake."

In an analysis of more than 48,000 patients in multiple countries with a history of ASCVD, only 14 percent of patients had undergone Lp(a) testing, according to a 2022 paper published in Open Heart on which Nissen was the first author. In a separate analysis published in the American Journal of Preventive Cardiology last year, only 0.7 percent of about 2,200 patients prescribed lipid-lowering therapies for secondary prevention of ASCVD had documented Lp(a) test results, and 0.6 percent of about 7,200 patients prescribed such therapies for primary prevention of ASCVD had documented biomarker results.

Moreover, since tests for Lp(a) aren't typically included on a standard lipid panel, physicians must specifically order them, or hospital systems have to adjust test order sets to encourage their use. Researchers at University of California San Diego Health tracked Lp(a) testing rates and found that while none of the patients undergoing transcatheter aortic valve replacement in 2013 were getting tested, nearly 89 percent of patients got tested in 2018, shortly after the hospital added an option for doctors to order Lp(a) testing as part of a lipid panel in 2016.

Lp(a) can be measured with a simple blood test, Nissen said. As such, although Lp(a) can vary due to genetic variation, it doesn't require genetic testing. Ultimately, in his view, the primary barrier to increased Lp(a) testing is ensuring physicians are aware of how results can be used in patient care.

"Virtually every medical center has the availability of testing," Nissen said. "There are concerns that we will have to go on an educational campaign to try to get our colleagues to recognize that they need to find out if patients have a high lipoprotein(a) so that they can offer them counseling and soon, we hope, treatment." 

Even though there aren't treatments for elevated Lp(a) yet, guidelines bodies have determined thresholds for what they consider high Lp(a) levels, and there are steps that physicians can take to help patients who have crossed those thresholds, such as aggressively managing lifestyle risk factors, controlling blood pressure to reduce their general cardiovascular disease risks, and closely monitoring cardiovascular symptoms.

That's what's happening at the Mayo Clinic. Anticipating that Lp(a)-targeting drugs will be forthcoming, the Mayo Clinic decided to begin testing Lp(a) levels for patients participating in a preventive health program about two years ago, in addition to patients who have family history of early coronary artery disease, familial hypercholesterolemia, or recurrent coronary artery disease events in spite of control of other risk factors. After testing, patients with elevated Lp(a) are evaluated for potentially undiagnosed cardiovascular diseases, which can involve reviewing their symptoms and other test results, such as imaging reports that can provide insights about arterial plaque.

Information on Lp(a) levels can help stratify patients' risk, inform proactive lifestyle changes, and encourage screening of first-degree relatives, said Stephen Kopecky, a cardiologist within the preventive cardiology program and director of the statin intolerance clinic at the Mayo Clinic, who's also a coinvestigator on a study of Amgen's olpasiran and principal investigator on a study of Novartis' pelacarsen for compassionate use.

In addition to encouraging patients to take proactive care steps if they have elevated Lp(a), Kopecky said he's started a list of patients who might be interested in Lp(a)-targeting drugs once they reach the market.

It can be difficult to justify testing for something without a treatment, especially given how much information physicians need to discuss with patients during appointments, he added. And there are numerous risk factors for heart disease to consider, leading physicians to historically focus on a handful like diabetes, blood pressure, cholesterol, and smoking — "the things we can do something about," he explained. But, he added that with the promise of new drugs around the corner, Lp(a) has become one of the topics doctors talk to patients about.

On the horizon

Once the first Lp(a)-lowering drugs enter what promises to be a crowded market, physicians will have multiple questions to consider when determining which drug, if any, are right for their patients. For example, patients likely will want to know how frequently the drug is administered and how it's given. An oral drug may be preferrable to an injection, for example, or patients might prioritize wanting a drug that's administered less frequently, regardless of the formulation. 

While these drugs in development are primarily being studied as a secondary prevention option for patients who already have established cardiovascular diseases, they could also prove effective as preventive treatments for at-risk patients. However, even though at least 20 percent of the population has elevated Lp(a), that doesn't mean that they all will be eligible to receive an Lp(a)-lowering drug. 

In clinical trials, most drugs are being studied in patients with highly elevated Lp(a), higher than the lower bound of what guidelines bodies define as "high." The European Atherosclerosis Society, for example, considers patients to have high Lp(a) when it measures over 50 milligrams per deciliter or 125 nanomoles per liter in blood tests, as does the 2018 clinical practice guidelines released by multiple societies. The National Lipid Association similarly notes 50 milligrams per deciliter or 100 nanomoles per liter as high Lp(a). 

However, Novartis is testing pelacarsen in patients with Lp(a) levels of at least 70 milligrams per deciliter; Amgen is evaluating olpasiran in patients with Lp(a) of at least 200 nanomoles per liter; and Lilly is assessing lepodisiran and muvalaplin in those with Lp(a) of at least 175 nanomoles per liter. Silence Therapeutics is testing zerlasiran in those with Lp(a) of at least 125 nanomoles per liter. Subgroup analyses of patients within these clinical trials with high Lp(a) may provide additional insight into which patients are most likely to respond to treatment, Shapiro added. 

Moreover, since Lp(a) is genetically linked and unlikely to be modified by lifestyle factors, guidelines bodies say it only needs to be measured once in a patient's lifetime. In this regard, it's also unclear whether repeated Lp(a) testing will be needed to monitor and confirm that Lp(a) lowering is maintained over time in patients who have received these drugs.

While clinicians are eagerly awaiting the market entrance of Lp(a)-lowering drugs, their availability won't negate the critical role of other, existing treatment approaches for cardiovascular diseases, such as the importance of a healthy lifestyle, Kopecky stressed. Similar to cholesterol-lowering drugs, he doesn't expect that taking an Lp(a)-lowering drug will be a silver bullet that eliminates the risk of cardiovascular diseases entirely for his patients.

For heart disease, "there are so many mechanisms and pathways by which plaque can build up," Kopecky said. "We've never seen any treatment that negates your lifestyle."