Results from Merck’s PCSK9 pill suggest a future of ultra-low cholesterol

Merck, the company that brought statins to market nearly 40 years ago, has a new, highly effective pill that can lower dangerous LDL cholesterol levels to levels almost never seen in adults.

The new pill Enlicitide blocks a liver protein, PCSK9, that slows the body’s ability to excrete cholesterol. Because most PCSK9 is blocked, LDL levels fall and the rate of heart attacks and strokes in high-risk patients drops by up to 20 percent in the first year.

At least six million adults in the United States are eligible for medications that block PCSK 9.

The aim is to make the pill affordable, said Merck’s head of research. It would be an alternative to expensive biweekly or monthly injections of monoclonal antibodies that do the same thing. But only about 1 percent of eligible patients take the shots, which include Regeneron and Sanofi’s Praluent and Amgen’s Repatha. Many patients don’t want to inject themselves, and health insurance companies are putting up barriers to payment, cardiologists say. The drugs’ list prices are more than $500 per month.

On Saturday, at a meeting of the American Heart Association, Merck will report the results of a 24-week study of 2,912 people who had suffered or were at risk of a heart attack, stroke or other cardiovascular event. They were randomly assigned to receive enlicitide or a placebo. Those who took Enlicitide lowered their LDL levels by up to 60 percent, the same level as the injections.

There was no difference in side effects between those who took the pill and those who took a placebo.

On Sunday, the company will announce the results of a smaller study involving people with a genetic disorder, familial hypercholesterolemia, that causes high LDL levels.

Multiple studies over the years have shown that the lower the LDL level, the better – heart attack and stroke rates go down as LDL levels go down. And having a surprisingly low LDL level, even in the teens or 20s, doesn’t seem to have any downside. In adults who are not taking cholesterol-lowering medication, the values ​​are usually over 100.

“Lower is definitely better,” said Dr. Daniel Soffer, a cardiologist at the University of Pennsylvania.

When the injected drugs were approved a decade ago, it seemed that the PCSK9 protein might be “an obvious target” for a pill, Dr. Christie Ballantyne, principal investigator for Merck’s clinical trials and director of the Center for Cardiometabolic Disease Prevention at Baylor College of Medicine in Texas. But, said Dr. Ballantyne, chemists told him it was impossible.

The problem was that to block PCSK9, chemists had to find a substance that would attach to the same large flat surface of the PCSK9 protein as antibodies in injectable drugs. At the cellular level, antibodies are huge. A small molecule, like those found in most pills, would be far too small.

Merck’s solution, after a decade of research, was to create a circle of peptides one-hundredth the size of an antibody but larger than a typical small molecule delivered in pills.

This method, said Dr. Dean Li, president of Merck Research Laboratories, could enable researchers to create pills that could replace many other injectable drugs.

Dr. Li pointed out that pills are much cheaper to produce and transport than injectables, which need to be kept refrigerated. He said the goal is to keep the price of the PCSK9 pill low so it can be used widely in the United States and elsewhere. He wants patients to think of taking a PCSK9 pill as “no different than aspirin,” or, as he said, a standard blood pressure medication.

“The dream is to democratize PCSK9,” he said. “This dream has the possibility of coming true.”

An affordable pill that is taken daily and has the same effect as the injected drugs “can be a game-changer,” Dr. Christopher Cannon, a cardiologist at Brigham and Women’s Hospital in Boston who advises several pharmaceutical companies, but not Merck.

Dr. David Maron, a preventative cardiologist at Stanford University, said: “If they price it so that people can afford it, it will make a big difference” to the millions of people at risk of heart attack and stroke. “This is really important progress,” he said.

AstraZeneca is also working on a PCSK9 pill, Dr. Maron, who is part of an independent group of experts monitoring the safety of this drug in clinical trials.

There is still more to be done. Merck is currently conducting a large study of more than 14,500 people to confirm that lowering LDL cholesterol leads to fewer heart attacks and strokes and fewer cardiovascular deaths.

Merck plans to submit an application to the Food and Drug Administration to market enlicitide in early 2026 and hopes to bring the drug to market in 2027.

Dr. Cannon is definitely looking forward to it.

“I see this as the future,” he said.