An experimental pill called enlicitide slashed levels of low-density lipoprotein (LDL) cholesterol, commonly known as “bad” cholesterol, by up to 60%, a new phase three clinical trial published in The New England Journal of Medicine showed. If approved by the Food and Drug Administration, this novel medication could help millions in the U.S. significantly reduce their risk of heart attacks and strokes.
“Fewer than half of patients with established atherosclerotic cardiovascular disease currently reach LDL cholesterol goals. An oral therapy this effective has the potential to dramatically improve our ability to prevent heart attacks and strokes on a population level,” said Ann Marie Navar, M.D., Ph.D., a cardiologist and Associate Professor of Internal Medicine and in the Peter O’Donnell Jr. School of Public Health at UT Southwestern Medical Center. Dr. Navar led the study, which was sponsored by the drugmaker Merck & Co. Inc.
Researchers have known for decades that LDL cholesterol causes cardiovascular disease. Cholesterol-containing particles deposit in blood vessel walls, a process called atherosclerosis, which can then cause heart attacks and strokes. Consequently, lowering LDL cholesterol is a cornerstone of preventing cardiovascular disease in people who do not yet have it and reducing the risk of heart attacks and strokes in people who are already affected.
The development of enlicitide resulted directly from research conducted at UT Southwestern, Dr. Navar explained. Decades ago, Michael Brown, M.D., Professor of Molecular Genetics and Internal Medicine, and Joseph Goldstein, M.D., Chair and Professor of Molecular Genetics and Professor of Internal Medicine, discovered the LDL receptor on liver cells, which removes LDL cholesterol from the blood. This breakthrough not only earned the pair the Nobel Prize in Physiology or Medicine in 1985 but also laid the groundwork for developing statins, the class of medications most commonly prescribed to lower cholesterol levels.
Subsequent research came through the Dallas Heart Study based at UTSW, led by Helen Hobbs, M.D., Professor in the Eugene McDermott Center for Human Growth and Development and of Internal Medicine and Molecular Genetics, and Jonathan Cohen, Ph.D., Professor in the Center for Human Nutrition, the Eugene McDermott Center for Human Growth and Development, and of Internal Medicine. They found a group of people with lower levels of LDL cholesterol due to genetic changes that caused them to make less of the PCSK9 protein. PCSK9 reduces the number of LDL cholesterol receptors on liver cells, slowing the liver’s ability to clear LDL cholesterol from the bloodstream. This finding led to the development of injectable drugs that inhibit PCSK9, first in the form of monoclonal antibodies, and then as a small interfering RNA that inhibits the synthesis of the PCSK9 protein itself. The monoclonal antibodies, evolocumab and alirocumab, reduce circulating LDL cholesterol levels by about 60%.
Despite the efficacy of these drugs, Dr. Navar said, research by her group and others has shown that they are rarely prescribed. Early barriers to therapy included their high cost and insurance issues. Despite reductions in price and improvements in insurance coverage, the vast majority of primary care physicians and a substantial minority of cardiologists still don’t prescribe them, possibly because they are only available as injections, she hypothesized.
Enlicitide works in a similar fashion to the monoclonal antibodies, binding to PCSK9 in the bloodstream, but it is taken once a day orally in pill form.
In the new phase three clinical trial, researchers tested enlicitide’s ability to lower LDL cholesterol in 2,909 patients who either had established atherosclerosis or were considered at risk for developing it due to related conditions. Two-thirds of the patients received the study drug, while the other third received a placebo. Even though the vast majority of these volunteers were already taking a statin, their average LDL cholesterol level was 96 milligrams per deciliter (mg/dl), far above the 70 mg/dl recommended for those with atherosclerosis and 55 mg/dl for those at risk of atherosclerotic cardiovascular disease.
“The study population reflects what we see in clinical practice,” Dr. Navar said. “Even the highest intensity statins are often not enough to get people to their cholesterol goals.”
After 24 weeks, those taking enlicitide reduced their LDL cholesterol levels by about 60% compared with a placebo. Enlicitide also significantly reduced other blood lipid markers associated with cardiovascular disease, including non-HDL lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). The results held steady over a yearlong follow-up period.
“These reductions in LDL cholesterol are the most we have ever achieved with an oral drug by far since the development of statins,” Dr. Navar said.
A separate clinical trial is already underway to study whether this decrease in LDL cholesterol translates into reductions in heart attacks and strokes.
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