Drug for Genetic Form of 'Bad' Cholesterol Is Under Way

Muvalaplin, the world's first oral treatment for Lipoprotein(a), the largely genetic form of "bad" cholesterol, has reduced its levels by up to 65% in a phase 1 clinical trial.

Lipoprotein(a), also known as Lp(a), impacts one in five people globally. Elevated levels of Lp(a) are associated with a higher risk of heart attack and stroke, but there is still no approved treatment on the market.

The results of the phase 1 clinical trial presented at the European Society of Cardiology Congress in Amsterdam and published in JAMA suggest that Muvalaplin — the first oral drug ever developed to target Lp(a) — may lower its levels by up to 65%.

The drug works by disrupting the ability for Lp(a) to form in the body and has a favorable safety profile, as the participants mainly experienced mild adverse events due to treatment.

"This drug is a game-changer in more ways than one. Not only do we have an option for lowering an elusive form of cholesterol, but being able to deliver it in an oral tablet means it will be more accessible for patients," says Professor Stephen Nicholls, the lead author of the study and director of Monash University's Victorian Heart Institute and the Victorian Heart Hospital at Monash Health.

Dr. Anurag Mehta, director of preventive cardiology at VCU Health Pauley Heart Center, who was not involved in the study, calls the results an "exciting development" and says that 60 to 65% is a "very good reduction of Lp(a) levels."

He notes that other agents currently studied in phase 3 clinical trials are primarily injectable medications that lead to 80 to 95% reduction of Lp(a) levels. Although Muvalaplin appears to be slightly less effective, it has the advantage of being an oral agent.

According to Dr. Daniel Soffer, Penn Medicine physician and president of the National Lipid Association, we are still far from having Muvalaplin approved as a therapeutic intervention.

However, many people have residual cardiovascular risk due to high Lp(a) levels despite having bad cholesterol and blood pressure well-treated. Although they take therapies like aspirin or undergo cardiovascular procedures like stents, some patients still experience cardiac attacks and strokes.

High-risk patients who develop disease and events despite optimal therapy would benefit from additional treatment like Lp(a) lowering. Currently, several drugs are in late-stage development in stage 3 clinical trials testing that hypothesis. And when those are completed, we will know better whether or not Lp(a) lowering specifically impacts outcomes.


Mehta says that while there were no major safety concerns in the phase 1 clinical trial of Muvalaplin, the population included in the study was small.

"The number of people who have taken Muvalaplin is very low in order to make a direct comparison with other injectable drugs that lower Lp(a) levels,” he told Healthnews.

Soffer says that the phase 2 trials involving thousands of patients will provide more information on the drug's safety profile, but the results look promising thus far.

What is lipoprotein(a)?

According to Soffer, studies show a clear association between high Lp(a) levels and atherosclerotic cardiovascular disease — thickening or hardening of the arteries — and aortic valve stenosis, which occurs when the aortic valve narrows, and blood cannot flow normally. The only gene that impacts aortic valve risk is the gene that regulates and causes high levels of Lp(a).

"It doesn't mean that if you have a gene that causes your Lp(a) levels to increase, you're going to develop heart disease, but it is a very strong risk factor for both atherosclerosis and aortic valve stenosis," he adds.

Mehta says that unlike "bad" LDL cholesterol, which can be controlled with lifestyle changes like exercising or diet, Lp(a) levels are not significantly affected by such interventions.

Soffer says that getting a blood test is the only way to know if you have elevated Lp(a) levels.

The United States (U.S.) guidelines suggest that people who develop cardiovascular disease early or have a family history of premature cardiovascular disease should get tested, Mehta explains. Whereas in Canada and Europe, testing is recommended for everyone at least once in their lifetime.

Muvalaplin is still in the early stages of development, but the early data indicates it could become the first oral drug to target high Lp(a) levels.

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