Pharma believes it has found the next frontier in heart attack prevention.
Novartis, amgen and Eli Lilly are among drugmakers betting that lowering levels of a particularly bad form of cholesterol could lead to the next big hits in cardiology. The three pharmaceutical giants are in late-stage trials to test whether drugs that lower Lp(a) can protect people from heart attacks.
If they can, the opportunity could be huge: an estimated one in five people worldwide have elevated Lp(a), and there's not much they can do to lower it. Evidence from human genetics suggests the idea might work, but drug makers don't know for sure. That makes the results of Novartis' first late-stage tests, expected later this year, important for the entire project.
“History has taught us that you can't make assumptions,” said Dr. Steve Nissen, academic director of the Cleveland Clinic Heart, Vascular and Thoracic Institute, who is the principal investigator of Novartis' Phase 3 Horizon trial of pelacarsen, the company's experimental 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 well-known LDL cholesterol because it simultaneously clogs arteries and promotes blood clots, posing two risks with a single particle. Nearly 50 years after Lp(a) was discovered, researchers found that people who had high levels of it had more than twice the risk of having a heart attack than those who did not have it.
The amount of Lp(a) a person has circulating in their body is determined almost entirely by their genes. Lifestyle factors, such as diet and exercise, do not influence Lp(a) levels as they do LDL levels, leaving people with few good options to reduce it.
Today, doctors encourage people to focus on factors they can change, such as lowering LDL cholesterol, lowering blood pressure, treating obesity and diabetes, and exercising. Those strategies can help protect people from high Lp(a) levels for some time, Nissen said. New drugs could treat people for longer.
Novartis, Amgen and Lilly have already shown that their experimental drugs reduce Lp(a) levels by more than 80%. Now they will have to demonstrate 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 business intelligence firm.
“We don't know how much the levels need to be lowered,” Nissen said. “We don't know how high you have to be to benefit from lowering your level. Estimates of how much levels need to be lowered to prevent events based on genetic studies are very variable, so we don't have an answer, and we won't have one until the date we unveil the trial.”
That should happen by mid-year, Novartis CEO Vas Narasimhan said on the company's fourth-quarter earnings conference call in February. The trial is studying whether the drug pelacarsen from Novartis and its partner Ionis prevents outcomes such as heart attacks and strokes in people with elevated Lp(a) levels who already have cardiovascular disease. Novartis delayed the readout by a year because people weren't experiencing events as quickly as the company expected in the one-year test.
Narasimhan has said that could have to do with the fact that the researchers were controlling for other risk factors in the participants. He said Novartis is 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 option.”
Novartis' drug uses a different mechanism than its closest competitors, Amgen and Lilly. Those drugs, Amgen's olpasiran and Lilly's lepodisiran, appeared more potent in mid-stage trials, leading to greater Lp(a) reductions.
Key test results from Amgen were expected late 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 timelines in early 2027.
Jay Bradner, executive vice president of research and development at Amgen, said it's impossible to say why enough people who suffer heart attacks are taking longer to analyze the results without seeing the data.
“The clarity of the population genetics signal and the encouraging signs of [earlier trials] This makes it a very smart bet,” Bradner said. Novartis' upcoming results will provide guidance on how drugs targeting Lp(a) may affect clinical outcomes, he said, adding that he is “very optimistic about the hypothesis.”
Lilly expects to share data from its Phase 3 trial of lepodisiran in 2029. All of the trials are designed slightly differently, which could create variations in the results, said Dr. Michelle O'Donoghue, a cardiologist at Mass General Brigham Heart & Vascular Institute and principal investigator for Amgen's Ocean(a) trial of olpasiran.
“So there is reason to think that the magnitude of the benefit could be different between different programs,” he said.
Despite the attention of drug manufacturers, few doctors test their patients' Lp(a) levels. According to a study of electronic health records, fewer than 1% of adults were screened in the U.S. in 2024, and testing was concentrated in a handful of states.
Screening involves a routine blood draw, similar to that used to measure other types of cholesterol. Major cardiology organizations recently began recommending that all adults have an Lp(a) test at least once in their lifetime. Currently, some doctors are reluctant to test people for a problem when they have no medication 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 such as LDL, said the organization's executive director, Katherine Wilemon. Living with elevated Lp(a) and another genetic heart condition, Wilemon has pushed for more screening since suffering a heart attack at age 38 and founding the organization in 2011.
He said Lp(a) drugs have already helped raise awareness about testing. If the treatments are successful in clinical trials, more screening tests could be done. Morningstar analyst Jay Lee believes it could take time to build the market, especially since Novartis' pelacarsen would initially be used for people with high Lp(a) levels and a history of cardiovascular events.
Amgen and Lilly are already testing whether the drugs could protect people with elevated Lp(a) from having that first event. Those results are still years away, with Lilly's trial expected to end in 2029.
Meanwhile, Lilly can't wait to place more bets. The company is testing a daily pill and acquired a company that wants to use gene editing to reduce Lp(a) levels with a single treatment.
“We have a lot of shots on goal,” Cleveland Clinic's Nissen said. “We hope at least one of them ends up in the back of the net.”
Investors are skeptical, said Goldman Sachs analyst Asad Haider. They are nervous about what Novartis' trial delay will mean for the drugs, and worry that even if the drugs work, it could be years before they become megahits, he said.
“That's why this Novartis trial will be so important in the way people think about unlocking,” Haider said.
Wilemon of the Family Heart Foundation believes the market for these drugs already exists. She considers detection the most important issue and access the second. She points to PCSK9 inhibitors, powerful drugs that lower LDL cholesterol levels, which struggled for years to gain traction until drug makers lowered their prices.
But before acceptance comes data, and she said she and the entire Lp(a) community are crossing their fingers that Novartis' drug works.
