Lp(a) drugs from Novartis, Amgen and Eli Lilly aim to prevent heart attacks

Pharma thinks it’s found the next frontier in preventing heart attacks. 

Novartis, Amgen and Eli Lilly are among the drugmakers betting that slashing levels of a particularly bad form of cholesterol could deliver the next blockbusters in cardiology. All three of the pharmaceutical giants are in late-stage trials to test whether drugs that cut Lp(a) can protect people from heart attacks.

If they can, the opportunity could be massive: 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 could work, but drugmakers don’t know for sure. That makes the first late-stage trial results from Novartis, expected later this year, important for the entire pipeline. 

“History has taught us you can’t make assumptions,” said Dr. Steve Nissen, chief academic officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic who is the principal investigator of Novartis’ Phase 3 Horizon trial of pelacarsen, the company’s experimental drug to lower Lp(a). “We thought raising HDL would be beneficial and that didn’t work, so I think we have to keep an open mind.”

Lp(a), or lipoprotein(a), was first discovered in 1963. It’s a more dangerous cousin to the well-known LDL cholesterol because it simultaneously clogs arteries and promotes blood clots, posing two risks with just one particle. Almost 50 years after Lp(a) was discovered, researchers found that people who have high levels of it had a more than twofold higher risk of heart attack than those who don’t. 

How much Lp(a) a person has circulating in their body is almost entirely determined by their genes. Lifestyle factors like diet and exercise don’t influence Lp(a) levels like they do LDL levels, leaving people with few good options to reduce it. 

Currently, doctors encourage people to focus on the factors they can change, such as lowering their LDL cholesterol, decreasing blood pressure, treating obesity and diabetes and exercising. Those strategies can help protect people from high Lp(a) for some time, Nissen said. New medicines could treat people for a longer time. 

Novartis, Amgen and Lilly have already proven their experimental drugs slash levels of Lp(a) by more than 80%. Now, they will need to show that 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 commercial intelligence firm.

“We don’t know how much you have to lower levels,” Nissen said. “We don’t know how high you have to be to benefit from getting your level lowered. Estimates of how much you have to lower levels to prevent events based upon genetic studies are highly variable, so we don’t have an answer, and we won’t have an answer until on the date that we unblind the trial.”

That should happen around the middle of the year, Novartis CEO Vas Narasimhan said on the company’s fourth-quarter earnings call in February. The trial is studying whether Novartis and its partner Ionis’ drug pelacarsen prevents outcomes like heart attacks and strokes in people with elevated levels of Lp(a) 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 yearslong trial. 

Narasimhan has said that might have to do with the fact that researchers were managing participants’ other risk factors. He said Novartis is still excited to see the data and to potentially create “an entire new class of medicines that can help a whole group of patients that have no other option.” 

Novartis’ drug uses a different mechanism than its next closest competitors from Amgen and Lilly. Those drugs, Amgen’s olpasiran and Lilly’s lepodisiran, looked more potent in mid-stage trials, leading to larger Lp(a) reductions.

Amgen’s pivotal trial results were expected later this year or early next before the company also pushed back the timeline. The company now says it plans to provide an update on timing in early 2027.

Jay Bradner, Amgen’s executive vice president of research and development, said it’s impossible to say why it’s taking longer for enough people to have heart attacks to analyze the results without seeing the data.

“The clarity of the signal from population genetics and the encouraging signs from [earlier trials] render this a very smart bet,” said Bradner. The forthcoming results from Novartis will provide direction on how Lp(a)-targeting drugs can affect clinical outcomes, he said, adding that he’s “very bullish 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 variation in the results, said Dr. Michelle O’Donoghue, a cardiologist at the Mass General Brigham Heart & Vascular Institute and the principal investigator of Amgen’s Ocean(a) trial of olpasiran.

“So there’s reason to think that the magnitude of the benefit might be different across the different programs,” she said.

Despite the focus from drugmakers, few doctors test their patients’ Lp(a) levels. Less than 1% of adults were tested for it in the U.S. in 2024, and testing was concentrated in a handful of states, according to one study of electronic health records.

Screening involves a routine blood draw like what’s used to measure other types of cholesterol. Leading cardiology organizations recently started recommending every adult be tested for Lp(a) at least once in their life. Currently, some doctors are reluctant to screen people for a problem when they don’t have any medicines to offer them 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 experiencing a heart attack at 38 and founding the organization in 2011.

She said the Lp(a) drugs have already helped raise awareness about testing. If the treatments succeed in clinical trials, more screening could follow. Morningstar analyst Jay Lee thinks 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 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 read out in 2029. 

In the meantime, Lilly isn’t waiting to make more bets. The company is testing a daily pill, and it acquired a company that wants to use gene editing to slash Lp(a) levels with a one-time treatment. 

“We’ve got a bunch 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’re nervous what the delay in Novartis’ trial means for the drugs, and they’re concerned 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 the unlock,” Haider said.

Wilemon from the Family Heart Foundation thinks the market for the drugs is there. She sees screening as the most important issue and access as the second one. She points to PCSK9 inhibitors, powerful drugs that slash levels of LDL cholesterol, which struggled for years to gain traction until drugmakers lowered their prices.

But before uptake comes the data — and she said she and the whole Lp(a) community are crossing their fingers Novartis’ drug works.