First-in-human trial of new therapy presented at American Heart Association 2023 Scientific Sessions
Findings from a Phase 1 trial reported by a Cleveland Clinic doctor show that a single dose of an experimental therapy produced greater than 94% reductions in blood levels of lipoprotein (a), a key risk factor for heart disease, and the results lasted almost a year.
Results from “Efficacy and Safety of Lepodisiran: A Long- and Short-course RNA Interference Study Targeting Lipoprotein(a)” were presented during a scientific session at the 2023 American Heart Association Scientific Sessions and published simultaneously in the Journal of the American Medical Association.
Lipoprotein(a), often abbreviated simply as Lp(a), is produced in the liver and has similarities to LDL, also known as low-density lipoprotein or “bad cholesterol.” 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, greatly increasing the risk of heart attacks and strokes.
Although there are effective therapies to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, there are currently no approved drug treatments to lower Lp(a). Since Lp(a) levels are determined by a person’s genes, lifestyle changes (diet or exercise) have no effect .
In the trial, participants who received a lepodisiran injection had lipoprotein(a) levels reduced at the maximum dose by up to 96% in two weeks and maintained levels more than 94% below baseline for 48 weeks. The drug is a small interfering RNA (siRNA) therapeutic that blocks the messenger RNA needed to make a key component of lipoprotein (a) in the liver.
The findings add lepodisiran to the growing list of therapies that could be promising treatments for atherosclerotic cardiovascular diseases in people with elevated levels of Lp(a), which is estimated to affect 64 million people in the United States and 1.4 billion people in the United States. Worldwide.
"These results demonstrated that this therapy was well tolerated and produced very long-lasting reductions in Lp(a), a major risk factor leading to heart attacks, strokes, and aortic stenosis," said lead author Steven Nissen. MD, academic director of the Heart, Vascular and Thoracic Institute at the Cleveland Clinic.
In the trial, researchers enrolled 48 patients in the US and Singapore with an average age of 47 years. The researchers studied six different doses and one placebo, all of which were administered via injections. Participants were monitored for up to 48 weeks after administration.
Peak plasma Lp(a) concentrations were reduced by 49% from baseline levels for the 4 mg dose and by up to 96% for the 608 mg dose versus a 5% decrease for placebo. No safety concerns were observed and the only tolerability concern was mild injection site reactions.
"Despite strong evidence of the importance of elevated Lp(a) as a risk factor for heart disease, effective treatment has been elusive," Dr. Nissen said. "This treatment approach gives hope to the 20% of the world’s population who have elevated Lp(a) levels."
A phase 2 trial studying lepodisiran is currently underway. The trial was sponsored by Eli Lilly and Company (Lilly), the company developing lepodisiran.
