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.
Source: Experimental pill dramatically reduces ‘bad’ cholesterol – Scents of Science
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