A new experimental drug called Encisid dramatically lowered levels of low-density lipoprotein (LDL) cholesterol, often referred to as “bad” cholesterol, by as much as 60 percent, according to a Phase 3 clinical trial published in . New England Medical Journal. If the drug is approved by the Food and Drug Administration, it could offer millions of people in the United States a new way to reduce their risk of heart attack and stroke.
“Currently, less than half of patients with established atherosclerotic cardiovascular disease reach their LDL cholesterol targets. An oral therapy that is this effective has the potential to dramatically improve our ability to prevent heart attacks and strokes at the population level,” said Anne-Marie Navar, M.D., a cardiologist and associate professor of internal medicine in the Peter O’Donnell Jr. School of Public Health at UT Southwestern Medical Center. Dr. Navarre led the study, which was sponsored by the pharmaceutical company Merck & Co.
Why lowering LDL cholesterol is important
For decades, scientists have understood that LDL cholesterol plays a central role in cardiovascular disease. These cholesterol particles can build up inside artery walls in a process known as atherosclerosis. Over time, this buildup can restrict blood flow and cause a heart attack or stroke. Therefore, reducing LDL cholesterol is an important strategy for preventing heart disease and reducing the risk for people who already have heart disease.
From Nobel Prize-winning discoveries to new treatments
According to Dr. Navarre, Ensitide builds on decades of scientific research at UT Southwestern. Several years ago, researchers Michael Brown, MD, and Joseph Goldstein, MD, identified LDL receptors on liver cells that help remove LDL cholesterol from the bloodstream. Their discovery won the Nobel Prize in Physiology or Medicine in 1985 and paved the way for statins, the most widely used cholesterol-lowering drugs today.
Subsequently, results from the Dallas Heart Study at UTSW, led by Helen Hobbs, MD, and Jonathan Cohen, PhD, revealed that some people are born with low LDL cholesterol due to genetic changes that reduce production of the PCSK9 protein. This protein limits the number of LDL receptors on liver cells, making it difficult for the body to remove cholesterol. This insight led to the development of injectable PCSK9 inhibitors, including monoclonal antibodies and RNA-based therapies. Drugs such as evolocumab and alirocumab can lower LDL cholesterol by about 60%.
Why existing treatments are underutilized
Although these injectable treatments are highly effective, they are not commonly used in daily care. Dr. Navarre noted that early challenges included high costs and insurance barriers. Although these problems have improved, many doctors are still hesitant to prescribe them. One possible reason is that these drugs need to be administered as an injection rather than as a pill.
How Enlicitide works
Enlicitide targets the same PCSK9 pathway as these injectable drugs, binding to proteins in the bloodstream to help the body remove LDL cholesterol more efficiently. The main difference is that ensitide is taken orally once a day, making it an easier option for patients.
Clinical trial results show 60% reduction in LDL
The Phase 3 trial included 2,909 participants who had atherosclerosis or were considered at risk due to related health conditions. Approximately two-thirds received ensitide and the remainder received a placebo. Although most participants were already taking statins, their average LDL cholesterol level remained at 96 milligrams per deciliter (mg/dl), well above the recommended goal of 70 mg/dl for people with atherosclerosis and 55 mg/dl for people at risk for atherosclerosis.
“The study population reflects what is seen in clinical practice,” Dr. Navarre said. “Even the highest-strength statins are often not enough to help people reach their cholesterol goals.”
After 24 weeks, patients who took Ensitide were found to have lowered their LDL cholesterol by about 60% compared to those who took a placebo. The drug also lowered other important markers associated with cardiovascular disease, including non-HDL lipoprotein cholesterol, apolipoprotein B, and lipoprotein (a). These improvements were maintained through 1 year of follow-up.
“These reductions in LDL cholesterol are the largest ever achieved with an oral drug since the development of statins,” Dr. Navar said.
what happens next
Another clinical trial is already underway to determine whether these reductions in cholesterol lead to fewer heart attacks and strokes.
Dr. Brown is a Regents Professor and holds the Paul J. Thomas Chair in Medicine and the WA (Monty) Moncrief Distinguished Chair in Cholesterol and Atherosclerosis Research. Dr. Goldstein is a Regents Professor and holds the Julie and Louis A. Beauchard, Jr. Distinguished Chair in Biomedical Research and the Paul J. Thomas Chair in Medicine. Dr. Hobbs holds the Dallas Heart Bowl Chair in Heart Disease Research and is a member of the Harold C. Simmons Comprehensive Cancer Center. Dr. Cohen holds the C. Vincent Prothro Distinguished Chair in Human Nutrition Research.
This research was funded by Merck Sharp & Dohme, a subsidiary of Merck.
Dr. Navarre has received consulting fees from Merck for portions of this research. She also received compensation for other consulting work from Merck and other pharmaceutical companies that make lipid-lowering drugs (as revealed in the study).
