Cleveland Clinic study finds new drug can reduce Lp(a), a risk factor for heart disease, by more than 80%

An estimated 20% to 25% of the world’s population has elevated Lp(a) levels.

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

The findings suggest the therapy could be a promising treatment to help prevent premature heart disease in people with high Lp(a) levels, which are estimated to affect 64 million people in the United States and 1.4 billion people worldwide.  

The trial results were presented during a late-breaking science session at the American Heart Association’s Scientific Sessions 2024 and published simultaneously online in the Journal of the American Medical Association. 

Lp(a) is similar to LDL, also known as bad cholesterol. Lp(a) is produced 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 plaque to build up in the arteries, which plays a major 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 Cleveland Clinic’s Heart, Vascular & Thoracic Institute. 

“Historically, this disorder has been untreatable because levels are determined mainly 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 such as zerlasiran.” 

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

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

The 60-week phase 2 dose-finding trial enrolled 180 participants between 3 January 2023 and 27 April 2023 at 26 research centres worldwide. 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 endpoint, the average reduction in Lp(a) over 36 weeks of follow-up, all three regimens reduced Lp(a) by more than 80% compared with placebo. Persistent reductions in Lp(a) were seen at 60 weeks after the first dose. 

The most common treatment-related adverse events were injection-site reactions, mostly mild pain reported by 2.4%-7.1% of patients the day after the drug was given. There were 20 serious treatment-emergent adverse events, none related to the study drug. Assessment of the current trial results will allow doses and dosing intervals to be selected for a phase 3 clinical trial. 

“Elevated lipoprotein(a) has been an elusive disorder for which no effective treatments have been available. Emerging therapies, including RNA interference, represent a very promising approach to treating elevated lipoprotein(a),” said Dr. Nissen.  

“If current trials demonstrate a reduction in morbidity and/or mortality, identifying and treating these patients will become a critical public health priority.” 

Lp(a) concentrations are known to vary between different racial and ethnic groups. One limitation of the ALPACAR trial is that it mainly enrolled white male participants. Because Black patients have higher lipoprotein(a) levels, the effects of zerlasiran in non-white patients need further study. 

About Cleveland Clinic  

Cleveland Clinic is a nonprofit multispecialty academic medical centre that integrates clinical and hospital care with research and education. Located in Cleveland, Ohio, it was founded in 1921 by four renowned physicians with a vision of providing outstanding patient care based on the principles of cooperation, compassion and innovation. Cleveland Clinic has pioneered many medical breakthroughs, including coronary artery bypass surgery and the first face transplant in the United States. U.S. News & World Report consistently names Cleveland Clinic as one of the nation’s best hospitals in its annual “America’s Best Hospitals” survey. Among Cleveland Clinic’s 81,000 employees worldwide are more than 5,743 salaried physicians and researchers, and 20,160 registered nurses and advanced practice providers, representing 140 medical specialties and subspecialties. Cleveland Clinic is a 6,690-bed health system that includes a 173-acre main campus near downtown Cleveland, 23 hospitals, more than 276 outpatient facilities and locations in southeast Florida; Las Vegas, Nevada; Toronto, Canada; Abu Dhabi, UAE; and London, England. In 2023, there were 13.7 million outpatient visits, 323,000 hospital admissions and observations, and 301,000 surgical cases throughout Cleveland Clinic’s health system. Patients came for treatment from every state and 132 countries.