Pharma believes it has found the next frontier in preventing heart attacks.
Novartis, Amgen And Elie Lilly are among the drugmakers betting that reducing levels of a particularly bad form of cholesterol could give rise to the next blockbusters in cardiology. The three pharmaceutical giants are in late-stage trials to test whether drugs that reduce Lp(a) can protect people from heart attacks.
If they can, the opportunity could be huge: An estimated one in five people worldwide have high Lp(a), and there’s little they can do to reduce it. Evidence from human genetics suggests the idea might work, but drugmakers aren’t sure. The first results of Novartis’ advanced trials, expected later this year, are therefore important for the entire pipeline.
“History has taught us that you can’t make assumptions,” said Dr. Steve Nissen, academic director of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic, who is the principal investigator of Novartis’ Phase 3 Horizon trial of pelacarsen, the company’s investigational Lp(a)-lowering drug. “We thought raising HDL would be beneficial and it didn’t work, so I think we need to keep an open mind.”
Lp(a), or lipoprotein(a), was first discovered in 1963. It is a more dangerous cousin of the famous LDL cholesterol because it simultaneously clogs arteries and promotes blood clots, posing two risks with a single particle. Nearly 50 years after the discovery of Lp(a), researchers found that people who had high levels of it had a more than twice the risk of heart attack than those who did not have it.
Blood sample for lipoprotein A (LpA) test.
Md Babul Hosen | Istock | Getty Images
The amount of Lp(a) a person has circulating in their body is almost entirely determined by their genes. Lifestyle factors, such as diet and exercise, do not influence Lp(a) levels the way they do LDL levels, leaving people with few good options for reducing them.
Currently, doctors encourage people to focus on factors they can change, such as lowering their LDL cholesterol levels, lowering their blood pressure, treating obesity and diabetes, and exercising. These strategies can help protect people from high Lp(a) for a while, Nissen said. New drugs could treat people for longer.
Novartis, Amgen and Lilly have already proven that their experimental drugs reduce Lp(a) levels by more than 80%. They will now have to show that this translates into tangible benefits. If that happens, the drugs could reach annual sales of $5.6 billion by 2032, according to consensus estimates from Evaluate, a pharmaceutical market intelligence firm.
“We don’t know to what extent the levels will need to be lowered,” Nissen said. “We don’t know what level you need to be at to benefit from lowering your levels. Estimates of how much you need to lower levels to prevent events based on genetic studies are highly variable, so we don’t have an answer, and we won’t have an answer until we unblind the trial.”
That should happen around the middle of the year, Novartis CEO Vas Narasimhan said during the company’s fourth-quarter earnings conference call in February. The trial studies whether the drug pelacarsen from Novartis and partner Ionis prevents outcomes such as heart attacks and strokes in people with high Lp(a) levels who already have cardiovascular disease. Novartis delayed the reading for a year because people weren’t experiencing events as quickly as the company expected during the years-long trial.
Narasimhan said this could be because the researchers were managing other risk factors of the participants. He said Novartis was still excited to see the data and potentially create “a whole new class of drugs that can help a whole group of patients who have no other choice.”
Novartis’ drug uses a different mechanism than its closest competitors, Amgen and Lilly. These drugs, Amgen’s olpasiran and Lilly’s lepodisiran, appeared more potent in mid-term trials, leading to greater reductions in Lp(a).
Results from Amgen’s pivotal trials were expected later this year or early next year, before the company also pushed back the timeline. The company now says it plans to provide an update on the timeline in early 2027.
Jay Bradner, Amgen’s executive vice president of research and development, said it’s impossible to say why it takes more time for enough heart attack sufferers to analyze the results without seeing the data.
“The clarity of the population genetics signal and the encouraging signs of [earlier trials] which makes it a very smart bet,” Bradner said. Novartis’ upcoming results will provide direction on how drugs targeting Lp(a) may affect clinical outcomes, he said, adding that he is “very optimistic about this hypothesis.”
Lilly plans to share data from its Phase 3 trial of lepodisiran in 2029. All trials are designed slightly differently, which could create variations in results, said Dr. Michelle O’Donoghue, a cardiologist at Mass General Brigham Heart & Vascular Institute and principal investigator of Amgen’s OCEAN(a) trial of olpasiran.
“So there is reason to think that the magnitude of benefits might be different across different programs,” she said.
Despite attention from drug manufacturers, few doctors test their patients’ Lp(a) levels. Fewer than 1% of adults were tested in the United States in 2024, and testing was concentrated in a handful of states, according to a study of electronic health records.
Screening involves a routine blood test, like that used to measure other types of cholesterol. Major cardiology organizations have recently begun recommending that every adult be tested for Lp(a) at least once in their lifetime. Currently, some doctors are reluctant to screen for a problem when they don’t have a drug to offer to treat it, Nissen and O’Donoghue said.
The Family Heart Foundation plans to advocate for adding Lp(a) to the standard lipid test that measures other types of cholesterol like LDL, said the organization’s CEO, Katherine Wilemon. Living with elevated Lp(a) and another genetic heart condition herself, Wilemon has pushed for more screening since suffering a heart attack at age 38 and founding the organization in 2011.
She said Lp(a) drugs have already helped raise awareness about testing. If the treatments are successful in clinical trials, further screening could follow. Morningstar analyst Jay Lee believes the market could take time to build, especially since Novartis’ pelacarsen would initially be used in people with elevated Lp(a) levels and a history of cardiovascular events.
Amgen and Lilly are already testing whether the drugs could protect people with high Lp(a) levels from this first event. These results will still be awaited for years, with Lilly’s trial due to be read in 2029.
In the meantime, Lilly isn’t waiting to make other bets. The company is testing a daily pill and has acquired a company that wants to use gene editing to reduce Lp(a) levels with a single treatment.
“We have a number of shots on goal,” said Nissen of Cleveland Clinic. “We hope at least one of them ends up in the back of the net.”
Investors are skeptical, said Asad Haider, an analyst at Goldman Sachs. They are worried about what the delay in the Novartis trial means for the drugs, and they fear that even if the drugs work, it could take years for them to become mega-blockbusters, he said.
“That’s why this Novartis trial is going to be so important in how people think about unlocking,” Haider said.
Wilemon of the Family Heart Foundation believes the market for these drugs exists. She considers testing the most important issue and access the second. She points to PCSK9 inhibitors, powerful drugs that reduce LDL cholesterol levels, which struggled for years to gain traction until drugmakers lowered their prices.
But before adoption comes, comes the data — and she said she and the entire Lp(a) community are keeping their fingers crossed that Novartis’ drugs work.