Lilly’s Cholesterol Pill Shows Early Promise in Phase I Study

Eli Lilly_iStock, jetcityimage

Pictured: Eli Lilly headquarters in Indianapolis/iStock, jetcityimage

A first-in-human Phase I trial showed that Eli Lilly’s investigational oral lipoprotein(a) inhibitor muvalaplin was safe and could elicit sharp reductions in concentrations of the cholesterol formation.

The study, published Monday in the medical journal JAMA, demonstrated that the pill lowered Lp(a) levels within 24 hours of the first administration. Subsequent muvalaplin doses led to further Lp(a) reductions.

The placebo-adjusted decrease in Lp(a) reached a maximum of 63% to 65% in the muvalaplin arm. Of the 114 participants, more than 90% achieved plasma Lp(a) levels lower than 50 mg/dL. These promising signals of efficacy did not come with worrying safety signals, according to the JAMA study. Muvalaplin also did not significantly alter plasminogen levels or activity.

“Muvalaplin is the first oral agent specifically developed to lower levels of Lp(a) by disrupting its formation,” the study’s authors wrote, adding that the drug candidate also represents a novel treatment option for targeting Lp(a).

Lilly has taken muvalaplin into Phase II assessments, according to its website, and is developing the small molecule Lp(a) for cardiovascular diseases.

In atherosclerotic cardiovascular diseases, there sometimes remains a residual likelihood of cardiovascular events despite optimally suppressed levels of low-density lipoprotein (LDL) cholesterol. This points to the need of addressing other risk factors and potentially related biomarkers, among them Lp(a).

A variant of LDL cholesterol, Lp(a) that carries an apolipoprotein(a) molecule covalently bound to apolipoprotein(B). According to the Centers for Disease Control and Prevention, high Lp(a) levels have been tied to worse risks of heart attack or stroke, particularly in people with family histories of these conditions. Lp(a) also plays a role in the narrowing of the aortic valve.

Muvalaplin, an oral small molecule inhibitor of Lp(a), works by disrupting the covalent bond between apolipoprotein(a) and apolipoprotein(B), thereby preventing the formation of the complete Lp(a) molecule.

“This drug is a gamechanger 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,” Stephen Nicholls, director of Monash University’s Victorian Heart Institute who led the trial, said in a statement.

Beyond muvalaplin, Lilly has also started working on other Lp(a)-directed therapies. In October 2018, the company signed a licensing and research collaboration deal with Dicerna Pharmaceuticals to develop RNA interference-based treatments for cardiometabolic indications. This partnership gave rise to lepodisiran, a siRNA candidate whose Investigational New Drug application was approved in May 2021.

Lepodisiran is now currently in Phase II development for diabetes and obesity.

In June 2023, Lilly signed another collaboration contract, this time with Verve for a one-time gene editing program targeting Lp(a).

Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at or

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