Jan. 21, 2025 – Bernadette McLaughlin is 66 years old, walks 10 miles most days, eats mainly vegetables and tofu, and her standard cholesterol panel looks generally healthy.
But there was one number that made cardiologists raise their eyebrows – her elevated lipoprotein(a), usually written Lp(a), which is more than five times the level that puts someone at significant risk of a heart attack or stroke early in life.
It’s a hereditary condition, little discussed but quite common, affecting 1 in 5 people. McLaughlin’s mother and grandmother both died of heart disease.
There are no approved medications for high Lp(a), but five drugs are in development, and last fall, two of them – muvalaplin and zerlasiran – moved a step closer to consideration by the FDA.
Muvalaplin performed so well in a phase II trial (lowering levels by 86%) that its lead researcher expressed surprise. The drug can be taken in pill form rather than as a shot, which may make it more attractive and cheaper.
But the leader in the testing pipeline, an injectable drug called pelacarsen, may not have final results until later this year. McLaughlin, who lives in Manhattan and works as an aide to people with dementia, said approval of any of the drugs would be “life-changing.”
“It's the psychological aspect of it that I struggle with a lot,” she said. “Because you're always trying to guess with any little thing that happens: Is this the heart attack I'm going to have?”
Most are unaware of their Lp(a) level until they have a heart attack or stroke because testing isn’t widely done, although it’s been gaining adoption. Earlier this year, the National Lipid Association recommended that everyone be tested at least once in their lifetime.
“We're used to having a fix for things, and there is no fix for this yet,” said McLaughlin, who has a cardiovascular disease diagnosis due to plaque buildup that has blocked blood flow in her body. “But I will say that it helps me a lot when I read all of the information about what is coming down in the pipeline. It does give you hope,”
Steven E. Nissen, MD, a leading researcher and chief academic officer of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic, has a message for McLaughlin: “Help is coming.”
Five Drugs in the Pipeline
Muvalaplin and zerlasiran are at the rear of the pack in the years-long timeline of clinical drug trials. All five experimental drugs have been shown to be safe in small early studies and to effectively lower Lp(a) levels. But what the FDA will ultimately look at is whether those results hold among thousands of people in very large phase III trials.
Here’s an update:
- Pelacarsen: This trial will be the first to finish and is scheduled to wrap up in May 2025. During the earlier phase II portion, the drug reduced Lp(a) by up to 80%. It’s given as a shot once per month.
- Olpasiran: This drug is given as a shot every three months, and the trial will conclude in December 2026. The earlier phase II trial showed it could reduce Lp(a) by more than 95%, with a 40% to 50% sustained reduction nearly a year after the last dose.
- Lepodisiran: In a phase I trial, a single injection of this drug produced a sustained Lp(a) reduction of 94% for nearly a year. Of the five drug trials, this is the only one that has included a group of people with high Lp(a) who haven’t yet had a heart attack or stroke, meaning that this may be the only drug the FDA will consider approving for people who haven’t yet had what medical experts call “a first event.” The results are about five years away – the trial doesn’t end until 2029.
- Zerlasiran: The phase II trial just wrapped up and showed infrequent shots can lower Lp(a) levels by nearly 86%. Phase III details haven’t yet been announced.
- Muvalaplin: The daily pill lowered Lp(a) levels by up to 86% during the 12-week phase II study. Phase III details haven’t yet been announced.
With all of the drugs appearing capable of lowering Lp(a) levels, “the differences may not be all that important,” Nissen said.
What the phase III portion of the studies will examine is whether taking the drugs leads to a reduced risk of a heart attack or stroke.
Researchers are mindful of the exciting days when new drugs raised “good” cholesterol, or HDL, but found they didn’t lower the risk of a heart attack or stroke, says Stephen Nicholls, MBBS, PhD, director of the Victorian Heart Institute at Monash University in Melbourne, Australia, and the lead researcher on the Muvalaplin trial.
“The genetics didn't work for HDL, but they work for Lp(a),” he said. “So, I think a lot of us are pretty confident with all the information that we've got about Lp(a) that lowering Lp(a) should be beneficial for patients, but the only way to know is to do these large clinical trials.”
Most of these new drugs work by silencing the instructions from the LPA gene so a protein that is a key part of Lp(a) cholesterol isn’t produced. Muvalaplin works differently. It interferes with one of the steps in how the body assembles what ultimately becomes circulating Lp(a). The other drugs work inside a cell, while muvalaplin works outside of a cell, and that’s why the drug itself can be a very small molecule.
Tiny Molecule, Big Results
Nicholls said muvalaplin appears to be “much more Lp(a)-lowering than I think anybody was expecting. And that puts muvalaplin right in the ballpark of the kind of Lp(a) lowering you'd want to see with a new therapy and comparable to the other agents in development.”
Muvalaplin is being developed by Eli Lilly, but its creation is based on a Canadian research team’s discovery, led by scientist Marlys L. Koschinsky, PhD.
“That’s how, oftentimes, drug discovery works,” said Koschinsky, a professor at Western University’s Schulich School of Medicine and Dentistry in Ontario. “It’s basically having the ability to take what other people have done as a basic scientist and think, ‘Wow, there might be some way to interfere with that process.’ So that's kind of the story of muvalaplin.”
If muvalaplin eventually comes to market, it may be less expensive than injection-based medicines. And the pill form also has other potential benefits, such as being in the system for a shorter period of time. It also could be an important option for people who have liver disease because it’s not entering the liver.
“Some people like to take an injectable every four or six months,” said Dinesh Kalra, MD, chief of cardiovascular medicine and a professor at the University of Louisville School of Medicine in Kentucky. “But if you have a medication that hangs around inside the liver for six months, and you develop a side effect from it, then you have to live with the side effects until the medication washes out of your body six months later.”
An estimated 64 million people in the U.S. are at risk of premature heart disease due to elevated Lp(a), although not all are waiting at the finish line to see the results of these drug trials. Most people do not know they have the condition because perhaps as few as 2% of people have been tested, Kalra said.
McLaughlin joined the lepodisiran trial, but she doesn’t know whether she got the drug or a placebo. She also has another condition that predisposes her to high LDL cholesterol called familial hypercholesterolemia that runs in families. Besides taking four cholesterol medications and aspirin, she follows a strict lifestyle, and she said the trials “mean the world” to her.
“I have five daughters, and these medicines give me hope that I might see their children grow up,” said McLaughlin, who wasn’t offered a test for Lp(a) until she was in her 60s despite regular checkups and even seeing a cardiologist.
Learning of the diagnosis was difficult, but she found support and guidance through the Family Heart Foundation, which offers help to cover the cost of testing.
“I strongly suggest that everyone ask their doctor for this very simple blood test, as it is not part of a standard lipid panel,” McLaughlin said. “It only has to be taken once in a lifetime, and you will know where you stand. If needed, the Family Heart Foundation can help direct you.”
