Experimental Gene-Silencing Drug Produces Long-Duration Reduction in Lipoprotein(a), an Important Heart Disease Risk Factor

CLEVELAND: Findings from a Phase 2 clinical trial reported by a Cleveland Clinic physician show a single dose of an experimental therapy (lepodisiran) safely reduced average blood levels of lipoprotein(a) by 94% during the following 180 days. During a full year (360 days) after one dose, lipoprotein(a) levels were reduced by 88.5%. Lipoprotein(a) is a key driver of heart disease and stroke that has traditionally been considered an untreatable risk factor.

Findings were presented today during a late breaking science session at the American College of Cardiology’s annual meeting in Chicago and simultaneously published in the New England Journal of Medicine.

Lipoprotein(a), often shortened to Lp(a), is assembled in the liver and has similarities to low-density lipoprotein (LDL) 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 the accumulation of plaque in arteries and promotes clotting, which greatly increases the risk of heart attack and stroke.

Although effective therapies exist to reduce the risk of heart disease by lowering LDL cholesterol and other lipids, currently there are 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 little effect.

In the trial, researchers enrolled 320 patients in the United States, Argentina, China, Denmark, Germany, Japan, Mexico, Netherlands, Romania, and Spain with a mean age of 62. Results showed lepodisiran reduced Lp(a) by 93.9% from day 60 to 180 following a single dose of 400mg with no major safety concerns.

Lp(a) reduction from days 30 to 360 was 88.5% after a single dose and 94.8% after 2 doses 180 days apart. Lp(a) levels remained 53.4% below baseline 540 days after a single dose and 74.2% 360 days after a second dose.

There were no major safety concerns during the trial, but up to 10% of patients had mild, injection site reactions for a short time, such as pain or redness.

Several therapies such as lepodisiran are currently in development that work by “silencing” the gene that produces a key component of Lp(a), which is estimated to affect 64 million people in the United States and 1.4 billion people worldwide.

“Many people with high Lp(a) don’t experience symptoms, and unfortunately, it is not frequently tested,” said lead author Steven Nissen, M.D., Chief Academic Officer of the Heart, Vascular & Thoracic Institute at Cleveland Clinic.

“It is important for patients with a personal or family history of heart disease to speak with their physician about having an Lp(a) blood test,” Dr. Nissen said. “Effective therapies to reduce Lp(a) are being developed and if they show a reduction in risk of heart attack or stroke, we need to know whom to treat.”

A Phase 3 cardiovascular outcome trial is currently underway by the sponsor of the Phase 2 lepodisiran trial, Eli Lilly and Company, in collaboration with Dr. Nissen and Cleveland Clinic.

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