Pharma believes it has found the next frontier in preventing heart attacks.
novartis, amgen And Eli Lilly Drug makers are betting that reducing levels of bad cholesterol specifically may provide the next breakthrough in cardiology. All 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 do that, the opportunity could be massive: it is estimated that one in five people worldwide has elevated Lp(a), and there is not much they can do to reduce it. Evidence from human genetics suggests this idea might work, but drug makers don’t know for sure. This makes Novartis’ first late-stage trial results, expected later this year, critical to the entire pipeline.
“History has taught us that you can’t make assumptions,” said Dr. Steve Nissen, chief academic officer of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic, who is the principal investigator for Novartis’ Phase 3 Horizon trial of pelacarson, the company’s experimental drug that lowers Lp(a). “We thought raising HDL would be beneficial and it didn’t work, so I guess we have to keep an open mind.”
Lp(a), or lipoprotein(a), was first discovered in 1963. It’s a more dangerous cousin of the famous LDL cholesterol because it simultaneously clogs arteries and promotes blood clots, creating two risks with just one particle. Nearly 50 years after the discovery of Lp(a), researchers found that people who had high levels of it had twice the risk of heart attack than people who did not have them.
How much Lp(a) flows through a person’s body is determined almost entirely by their genes. Lifestyle factors such as diet and exercise do not affect Lp(a) levels the way they do LDL levels, leaving people with few good options for lowering them.
Currently, doctors encourage people to focus on factors they can change, such as lowering their LDL cholesterol, lowering blood pressure, treating obesity and diabetes, and exercising. Those strategies may help protect people from high Lp(a) for some time, Nissen said. New medicines can treat people for longer periods of time.
Novartis, Amgen and Lilly have already proven that their experimental drugs reduce Lp(a) levels by more than 80%. Now, they have to show that it has real benefits. If that happens, the drugs could reach annual sales of $5.6 billion by 2032, according to a consensus estimate from pharmaceutical commercial intelligence firm Evaluate.
“We don’t know how much you would have to reduce the level,” Nissen said. “We don’t know how high you would have to be to get benefit from lowering your levels. Estimates of how much you would have to lower your 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 the date we finish the trial.”
Novartis CEO Vas Narasimhan said on the company’s fourth-quarter earnings call in February that it should be around the middle of the year. The trial is studying whether Novartis and its partner Ionis’ drug pelacarson prevents outcomes such as heart attacks and strokes in people with elevated levels of Lp(a) who already have heart disease. Novartis delayed the readout by a year because people were not experiencing events as quickly as the company had expected over years of testing.
Narasimhan said it may be related to the fact that researchers were managing participants’ other risk factors. 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 options.”
Novartis’ drug uses a different mechanism than its next closest competitors from Amgen and Lilly. Those drugs, Amgen’s olpasiran and Lilly’s lepodisiran, appeared more potent in mid-stage trials, producing larger reductions in Lp(a).
Amgen’s conclusive trial results were expected late this year or early next year, before the company even pushed back the timeline. The company now says it plans to provide a timely update in early 2027.
Jay Bradner, Amgen’s executive vice president of research and development, said that without seeing the data it is impossible to say why enough people have had heart attacks. It is taking longer to analyze the results.
“The clarity of the signal from population genetics and the encouraging signals from (earlier trials) make this a very smart bet,” Bradner said. Novartis’ upcoming results will provide direction on how Lp(a)-targeted drugs might impact 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 the trials are designed slightly differently, which can lead to variations in results, said Dr. Michelle O’Donoghue, a cardiologist at the 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 amount of benefit may vary across different programs,” she said.
Despite attention from drug manufacturers, few doctors test their patients’ Lp(a) levels. According to a study of electronic health records, less than 1% of adults in the US were tested in 2024, and testing was concentrated in a handful of states.
Screening involves regular blood draws as is done to measure other types of cholesterol. Leading cardiology organizations have recently begun recommending that every adult be tested for Lp(a) at least once in their lives. Currently, some doctors are reluctant to test people for a problem when they don’t have a drug to treat it, Nissen and O’Donoghue said.
The Family Heart Foundation plans to advocate for the addition of Lp(a) to the standard lipid test that measures other types of cholesterol such as LDL, said Katherine Wilman, the organization’s CEO. Living with elevated Lp(a) and another genetic heart disease, Wilman 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 the test. If the treatment is successful in clinical trials, more screening may be performed. Morningstar analyst Jay Lee believes it may take time to prepare for the market, especially since Novartis’ pelacarson will 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 can protect people with elevated Lp(a) from a first event. Those results are still years away, with Lilly’s trial expected to come out in 2029.
Meanwhile, Lily can’t wait to raise more stakes. The company is testing a daily pill, and it has acquired a company that wants to use gene editing to reduce Lp(a) levels with a one-time treatment.
“We got a lot of shots on goal,” said Cleveland Clinic’s Nissen. “We hope at least one of them finds the back of the net.”
Goldman Sachs analyst Asad Haider said investors are skeptical. They are nervous about what Novartis’ trial delays mean for the drugs, he said, and they are worried that even if the drugs work, it could take years for them to become mega-blockbusters.
“That’s why this Novartis trial is going to be so important for how people think about unlocking,” Haider said.
The Family Heart Foundation’s Wilman believes there is a market for the drugs. She considers screening as the most important issue and access as the second issue. She points to PCSK9 inhibitors, powerful drugs that lower LDL cholesterol levels, which struggled to gain popularity for years until drug makers lowered their prices.
But before moving forward there comes data — and he said he and the entire LP(A) community are pointing the finger at Novartis’ drug actions.
