Cleveland Clinic-Led Trial Finds Novel Drug Can Reduce Lipoprotein(a), an Important Risk Factor of Heart Disease, by More Than 80%

A new Cleveland Clinic-led trial found that over the course of 36 weeks, the drug Zerlasiran reduced lipoprotein(a) levels by more than 80% on average, with minimal side effects.

The findings suggest that the therapy could be a promising treatment to help prevent premature heart disease in people with high levels of Lp(a), which is estimated to affect 64 million people in the United States and 1.4 billion people worldwide. As many as 20%-25% of the world’s population has elevated Lp(a), according to estimates.

Findings from the “ALPACAR - Phase 2 Trial of Zerlasiran: Multiple Doses of a Short-Interfering RNA Targeting Lipoprotein(a) over 60 weeks” trial were presented today during a late-breaking science session at the American Heart Association’s Scientific Sessions 2024 and simultaneously published online in the Journal of the American Medical Association.

Lp(a) has similarities to LDL, also known as bad cholesterol. Lp(a) is made in the liver. Unlike other types of cholesterol particles, Lp(a) levels are 80-90% genetically determined. The structure of the Lp(a) particle causes the accumulation of plaques in arteries, which play a significant role in heart disease.

“We know that Lp(a) substantially increases the risk of cardiovascular disease and aortic stenosis,” said the study’s lead author Steven E. Nissen, M.D., Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic. “Historically, this disorder has been untreatable because levels are primarily determined by the Lp(a) gene. The most promising approach to treatment involves interrupting the production of Lp(a) in the liver through treatment with siRNA drugs like Zerlasiran.”

Although effective therapies to reduce the risk of heart disease by lowering LDL cholesterol and other lipids exist, currently there are no approved treatments to lower Lp(a). Since Lp(a) levels are determined by a person’s genes, lifestyle changes such as diet or exercise have no effect.

Zerlasiran is a small interfering RNA (siRNA) therapeutic, also known as gene ‘silencing’ therapy because it blocks production by a gene of a protein needed to make Lp(a).

The 60-week phase 2 dose-finding trial enrolled 180 participants between January 3, 2023, and April 27, 2023, at 26 global research sites. During the trial, three dosing strategies were studied: 450 mg every 24 weeks for two doses, 300 mg every 16 weeks for three doses, and 300 mg every 24 weeks for two doses.

For the primary end point, the average reduction in Lp(a) during 36 weeks of follow-up, all three regimens lowered Lp(a) more than 80% compared with placebo. Persistent reductions in Lp(a) were observed 60 weeks following initial administration.

The most common treatment-related adverse events were injection site reactions, mostly mild pain reported by 2.4% -7.1% of patients the day following drug administration. There were 20 serious treatment-emergent adverse events, none related to the study drug. Evaluation of results from the current trial will allow selection of doses and dosing intervals for a Phase 3 clinical trial.

“Elevation of lipoprotein(a) has been an elusive disorder for which no effective treatments have been available. Emerging therapies, including RNA interference, represent a highly promising approach for management of increased lipoprotein(a),” said Dr. Nissen. “If current trials demonstrate a reduction in morbidity and/or mortality, identification and treatment of these patients will become a critical public health priority.”

Lp(a) concentration is known to vary among different racial and ethnic groups. One limitation to the ALPACAR trial is that the trial enrolled primarily white, male participants. Because Black patients have higher lipoprotein(a) levels, effects of Zerlasiran in non-White patients needs further study.

The ALPACAR trial was funded by Silence Therapeutics, the company that makes Zerlasiran.

Dr. Nissen has served as a consultant for many pharmaceutical companies and has overseen clinical trials for AbbVie, AstraZeneca, Amgen, Arrowhead, Bristol Myers Squibb, Eli Lilly, Esperion, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis, Pfizer, and Silence Therapeutics. However, he does not accept honoraria, consulting fees or other compensation from commercial entities.