Heart disease experts are hailing the results of a clinical trial that showed a strongly positive performance by Eli Lilly's drug Lepodisiran, which inhibits the body's production of an especially dangerous type of "bad" cholesterol.
Two eminent cardiologists told UPI the study results are exciting and hold promise to change the medical landscape for tens of millions of Americans who are genetically predisposed to have elevated levels of a pernicious cholesterol variant known as lipoprotein (a).

Their reactions come after Sunday's publication in the New England Journal of Medicine of Phase 2 results for Lilly's "ALPACA" study, in which Lepodisiran was shown to significantly reduce levels lipoprotein (a) by an average of 93.9% after treatment with the highest tested dose.

Those results have boosted the momentum of a decade-long surge of medical interest in lipoprotein (a), which remains a poorly understood variant of the well-known "bad" cholesterol low-density lipoprotein, or LDL.
An estimated 20% of Americans have elevated levels of lipoprotein (a), or Lp(a), which has been strongly associated with heart attack, stroke, atherosclerotic cardiovascular disease and coronary heart disease.

Although many of its properties remain mysterious and there is as yet no conclusive proof that lowering the substance can prevent heart problems, many researchers believe it may be a key piece of the cardiovascular puzzle for those at risk.
Lp(a) wreaks damage by connecting with cholesterol and causing fatty material build-ups in the artery walls. In fact, it has been assessed to be six times more dangerous than LDL in producing such plaque buildups.

A person's risk of having elevated levels of Lp(a) are 70% to 90% genetically determined. Racial differences in Lp(a) concentrations have also been well documented, with Black patients more likely to have elevated Lp(a) than White, Hispanic or Asian patients, according to researchers.

Because no approved therapies exist specifically for this genetic risk factor, extensive efforts are underway to find a drug that can safely lower Lp(a) levels. The main avenue of attack has been to develop drugs that inhibit Lp(a) production at a molecular level through the use of "siRNA therapy," an approach that uses synthetic, short molecules called small interfering RNAs to "silence" the gene responsible for producing a key component of the unwanted lipid.

While Lilly's Phase 2 study results for Lepodisiran generated headlines this week, two other Lp(a) drug candidates are actually already in Phase 3 clinical trials, which means they could be approved sooner than Lepodisiran if results are positive. The HORIZON study is testing the safety and efficacy of pelacarsen from Novartis and Ionis Pharmaceuticals, while Phase 3 of the OCEAN(a)-DOSE study is underway for Amgen Inc.'s drug candidate, olpasiran.

But with the stunningly positive clinical results for Lepodisiran, that candidate has leapt to the forefront, said Dr. Deepak Bhatt, director of the Mount Sinai Fuster Heart Hospital and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai in New York City.

"This study showed a very large reduction in Lp(a)," he told UPI. "And not only that, but the nature of these siRNAs is such that they can be dosed somewhat infrequently, which also makes it very exciting -- you could have something that reduces Lp(a) by a lot, and it would only have to be given every several months, depending on what they they decide to go forward with in future studies.

"That could be a real game-changer."

Assuming that follow-up studies establish a clear link between lower Lp(a) levels and reductions in heart attacks and strokes, Bhatt predicted that testing for Lp(a) -- which is now is done infrequently -- will become the "standard of care" in the United States, as it already is in Europe.

The cardiologist said in his clinical practice he's frequently found elevated Lp(a) levels in people who suffer heart attacks at a young age who don't have any other common risk factors such as smoking, diabetes or high blood pressure.

"I've been amazed at what a high percentage of that type of patient has elevated Lp(a)," he said.

Meanwhile, Dr. Daniel Soffer, an associate professor of clinical medicine at the University of Pennsylvania and past president of the National Lipid Association, said the study results are "exciting" news for patients with elevated Lp(a), whose only current option to lower their levels is through lipoprotein apheresis, a cumbersome, time consuming blood filtering procedure akin to kidney dialysis.

"The apheresis center we have at Penn is the only one within maybe 100 miles, yet we only a treat a handful patients for Lp(a) -- very small numbers," he said. "The procedure needs to be done every two weeks, or even every week. It's a darn nuisance and not widely available."

Thus, there's a keen need for Lp(a)-lowering drugs, said Soffer, who is involved in Amgen's clinical trial for olpasiran. All three of the major drug candidates have been found to lower Lp(a) by at least 80%, he noted, while characterizing the reduction levels achieved by Lepodisiran as "profound with a high degree of safety."

"It's thrilling to see this article confirming what we thought about the Lilly product," he said. "The next big question, of course, is does lowering Lp(a) by that much prevent heart attack, stroke and death? It will be several more years before these Phase 3 trials are completed."

https://www.upi.com/Health_News/2025/04/02/cholesterol-busting-drug-Lepodisiran-trial-lilly/6181743439094/