New Drug Candidate Targets Lipoprotein(a) to Lower Heart Disease and Stroke Risk

A new drug could become the first treatment for Lipoprotein(a), a form of cholesterol that increases the risk of heart attack and stroke, as announced this week at the European Society of Cardiology Congress in Amsterdam and published in JAMA. The Phase I study included 114 patients, and the lead investigator was Stephen Nicholls, Director of Monash University’s Victorian Heart Institute and Victorian Heart Hospital.

High levels of Lipoprotein(a), known as Lp(a) (or “LP little a”) impact one in five people globally with no approved treatment currently on the market. Lp[a] is caused by a genetic trait and is associated with atherosclerotic disease and aortic stenosis. It forms when bonding occurs between apolipoprotein(a) (apo[a]) and apo B₁₀₀. Lp(a) is similar to LDL cholesterol, sometimes called ‘bad cholesterol’, but is more sticky, increasing risk of blockages and blood clots in arteries. Although Lp(a) apheresis may be used to lower Lp(a) levels in some patients, there are no pharmacological agents currently approved for lowering Lp(a) levels.

Common LDL lowering drugs such as statins don’t have the same lowering effect on Lp(a). Being largely genetic, Lp(a) is also difficult to control through diet, exercise and other lifestyle changes. Professor Nicholls said the global research industry has been working on a targeted solution to treat elevated Lp(a) for the past decade, but advancements so far have been in difficult to administer injection-based therapies that are not yet on the market.

Several therapeutic approaches have been developed to selectively target Lp(a) by reducing hepatic synthesis of apo[a]. Initial studies showed that Lp(a) was lowered by approximately 80% with an antisense oligonucleotide and by up to 98% with RNA interference. These agents are now being investigated in large clinical trials to evaluate their effects on cardiovascular outcomes. Each of these approaches involves injectable therapies.

Muvalaplin is an orally administered small molecule that inhibits Lp(a) formation by blocking the interaction between (apo[a]) and apo B_100. This trial demonstrated that the drug candidate effectively lowers Lp(a) levels by up to 65%.

“When it comes to treating high Lp(a), a known risk factor for cardiovascular disease, our clinicians currently have no effective tools in their kit,” Nicholls said. “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.”

He added that, “Lp(a) is essentially a silent killer with no available treatment, this drug changes that.”

The trial was undertaken in collaboration with Cleveland Clinic and Eli Lilly, the drug will now continue into larger phase clinical trials. It may also have potential to be used in the treatment of other vascular and valve disease.