Novartis, Amgen and Eli Lilly are among the pharmaceutical companies developing drugs to lower levels of a particularly poor form of cholesterol called Lp(a) and potentially prevent heart attacks.

Lp(a) levels are almost entirely genetically determined, making them a prime target for drugmakers.

Phase 3 trials will measure whether Lp(a) drugs can reduce the risk of 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 unfavorable 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 humans from heart attacks.

If they can, the opportunity could be massive: an estimated one in five the public 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, crucial for the entire pipeline. 

“History has taught us you can’t generate assumptions,” mentioned 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 individuals 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 citizens with few excellent options to reduce it. 

Currently, doctors encourage individuals 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 humans from high Lp(a) for some time, Nissen stated. Latest medicines could treat individuals 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, a pharmaceutical commercial intelligence firm.

“We don’t know how much you have to lower levels,” Nissen mentioned. “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 remarked on the company’s fourth, according to consensus estimates from Evaluate-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 humans with elevated levels of Lp(a) who already have cardiovascular disease. Novartis delayed the readout by a year because humans weren’t experiencing events as quickly as the firm expected in the yearslong trial. 

Narasimhan has commented that might have to do with the fact that researchers were managing participants’ other risk factors. He remarked Novartis is still excited to see the data and to potentially create “an entire updated 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 business also pushed back the timeline. The business now says it plans to provide an update on timing in early 2027.

Jay Bradner, Amgen’s executive vice president of research and development, remarked it’s impossible to say why it’s taking longer for enough individuals 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,” commented Bradner. The forthcoming results from Novartis will provide direction on how Lp(a)-targeting drugs can affect clinical outcomes, he mentioned, 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, remarked 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 mentioned.

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 citizens for a problem when they don’t have any medicines to offer them to treat it, Nissen and O’Donoghue mentioned.

The Family Heart Foundation plans to advocate for adding Lp(a) to the standard lipid test that measures other types of cholesterol like LDL, stated 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 noted 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 economy, especially since Novartis’ pelacarsen would initially be used for citizens with high Lp(a) levels and a history of cardiovascular events.  This also touches on aspects of bull market.

Amgen and Lilly are already testing whether drugs could protect the public 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 construct more bets. The corporation is testing a daily pill, and it acquired a firm that wants to apply 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 remarked. “We hope at least one of them ends up in the back of the net.”

Investors are skeptical, stated 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 noted.

“That’s why this Novartis trial is going to be so crucial in how individuals think about the unlock,” Haider mentioned.

Wilemon from the Family Heart Foundation thinks the marketplace for the drugs is there. She sees screening as the most key 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 noted she and the whole Lp(a) community are crossing their fingers Novartis’ drug works.