Genetic Connections: Rare Mutation Ignites Race for Cholesterol Drug

Her cholesterol was astoundingly low. Her low-density lipoprotein, or LDL, the form that promotes heart disease, was 14, a level unheard-of in healthy adults, whose normal level is over 100.

The reason was a rare gene mutation she had inherited from both her mother and her father. Only one other person, a young, healthy Zimbabwean woman whose LDL cholesterol was 15, has ever been found with the same double dose of the mutation.

The discovery of the mutation and of the two women with their dazzlingly low LDL levels has set off one of the greatest medical chases ever. It is a fevered race among three pharmaceutical companies, Amgen, Pfizer and Sanofi, to test and win approval for a drug that mimics the effects of the mutation, drives LDL levels to new lows and prevents heart attacks. All three companies have drugs in clinical trials and report that their results, so far, are exciting.

“This is our top priority,” said Dr. Andrew Plump, the head of translational medicine at Sanofi. “Nothing else we are doing has the same public health impact.”

Dr. Gary H. Gibbons, the director of the National Heart, Lung, and Blood Institute, estimates that even if the drugs were expensive and injected as many as two million Americans might be candidates. But if they could eventually be made affordable and in pill form — two very big ifs — they might be used by one in four adults, he said.

Despite major gains over the past half-century, heart disease remains the leading killer of Americans, causing nearly 600,000 deaths a year. Statins, the cholesterol-lowering drugs that went on the market in 1987, were a huge breakthrough, but far from a panacea.

The companies and many heart researchers hope they are closing in on a blockbuster, buoyed by success with preliminary studies. But Dr. Gibbons cautioned that critical large-scale studies that would tell whether the drugs actually prevent heart attacks and deaths are only starting.

“That will show if they are a game changer,” he said.

So far, people with stubbornly high cholesterol levels who are taking the drugs in preliminary studies have seen their LDL levels plunging from levels well over 100 to 50, 40, or even lower. Like insulin for diabetes, the drugs are injected, but they are taken once or twice a month.

Dr. Barry Gumbiner, who is directing Pfizer’s studies, said the company had to decide whether to set a floor for patients’ LDL levels. Pfizer is interrupting treatment when LDL levels reach 25 or lower. The people seemed fine, but the company got nervous.

“There is not a lot of experience treating people to LDL levels this low,” Dr. Gumbiner said.

And there is another concern: cost. Each company’s drug is a biologic, a so-called monoclonal antibody made in living cells at an enormous expense, like some new cancer drugs that are already straining the medical system. Amgen plans to make metric tons of its drug, much more, the company says, than any other biologic.

Insurers generally pay for drugs approved by the Food and Drug Administration, and the number who might benefit from these cholesterol drugs dwarfs those who are helped by the biologic cancer drugs.

If the drugs come into use, researchers are asking, can cholesterol go too low?

The data point to increasing benefits with lower and lower LDL levels, said Dr. Daniel J. Rader, a cholesterol researcher at the University of Pennsylvania and a consultant for Sanofi on its drug.

“If I had coronary disease, I would definitely try to drive my LDL to well below 50,” Dr. Rader said.

But with LDL levels falling so low in studies, Dr. Gibbons said, “We are in uncharted territory.”

Seeking a Mutation

The story of how these drugs came about began a decade ago. French researchers published a short note in the journal Nature Genetics reporting on three generations of a family with astonishingly high LDL levels — up to 466 — and a strong history of heart disease. Cholesterol, a yellow waxy substance that accumulates in clogged arteries, had piled up in their bodies. Some had cholesterol-laden nodules in their tendons that looked like bumps under the skin. The result was heart attacks, strokes and deaths from heart disease at an early age.

The cause of the family’s misfortune turned out to be a mutation in a gene called PCSK9, whose function was unknown.

F.D.A. Approves Merck’s Combination Drug to Reduce Cholesterol

The drug pairs Merck’s Zetia, which lowers low-density lipoprotein (LDL or “bad cholesterol”) with the generic version of Lipitor, the best-selling statin made by Pfizer that lost its patent protection in 2011.

Although the combination drug, to be called Liptruzet, was shown in a clinical trial to reduce LDL cholesterol more than patients who took Lipitor alone, the company said Liptruzet did not reduce patients’ chances of developing heart disease. That fact troubled some cardiologists, who questioned why it was approved.

“This is extremely surprising and disturbing,” said Dr. Steven E. Nissen, chairman of the department of cardiovascular medicine at the Cleveland Clinic.

Cardiologists have long questioned the value of Zetia and Vytorin, which combined Zetia with an older statin, Zocor. They had been on the market for a decade, but had not been shown to reduce the risk of heart disease.

A clinical trial of more than 18,000 patients is assessing whether Vytorin significantly reduces heart attacks, strokes and heart-related deaths and is expected to conclude in 2014. In March, an independent monitoring board let the trial continue, suggesting that no significant safety concerns had come up. Still, Dr. Nissen said he was skeptical that the trial would show that the drugs were effective.

Morgan Liscinsky, an F.D.A. spokeswoman, said high levels of LDL cholesterol were a known risk factor for heart disease. “Liptruzet is a combination of two currently marketed drugs that effectively lower elevated levels of LDL cholesterol,” she said. The F.D.A. rejected Merck’s application for the drug last year, and the company said at the time that the agency requested more information.

Merck said Liptruzet was a good option for patients who were not successful in lowering their bad cholesterol. “A significant percentage of patients are unable to lower their LDL cholesterol to recommended levels despite treatment,” Dr. Peter H. Jones, an adviser to Merck and an associate professor of medicine at Baylor College of Medicine, said in a news release.

Liptruzet is meant to be taken once a day and will be sold in doses of 10 milligrams of Zetia, in addition to 10, 20, 40 or 80 milligrams of Lipitor, known as atorvastatin. Merck’s list price will be $5.50 a pill. A company spokeswoman did not say whether insurance companies were planning to cover the drug, but said Merck “intends to be competitive in managed care to ensure wide access to Liptruzet.”

Sales of Vytorin and Zetia have fallen since 2007, when they brought in a combined $5 billion, but they are still among Merck’s top-selling drugs. In 2012, Zetia brought in $2.6 billion and Vytorin $1.8 billion, according to company filings.