She was a 32-year-old aerobics instructor from a Dallas suburb – healthy, college-educated, with two young children. Nothing out of the ordinary, except one thing.
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 Gibbons, the director of the National Heart, Lung, and Blood Institute, estimates that even if the drugs were expensive and injected, as many as 2 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.
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," 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 Rader, a University of Pennsylvania cholesterol researcher and a consultant for Sanofi.
"If I had coronary disease, I would definitely try to drive my LDL to well below 50," Rader said.
But with LDL levels falling so low in studies, Gibbons said, "We are in uncharted territory."
The story of how these drugs came about began a decade ago. French researchers published a short note in 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.
Soon, researchers discovered that the gene slowed the body's ability to rid itself of LDL. In the family studied by the French researchers, the mutated gene no longer worked properly and led to soaring cholesterol levels.
That gave Jonathan Cohen and Dr. Helen Hobbs of the University of Texas Southwestern Medical Center in Dallas an idea. If a mutation in PCSK9 leads to high LDL levels, perhaps there were defects that did the opposite – led to very low levels of LDL and protected against heart disease.
They found what they were looking for in data from a federal study. About 2.5 percent of blacks – but not whites – in the study had a single mutated PCSK9 gene that no longer functioned. About 3.2 percent of whites had a less powerful mutation that hampered the gene but did not destroy it.
Since people have two copies of every gene, one inherited from each parent, those with the newly discovered mutations did not have two mutated genes like the aerobics instructor but instead had one fully functioning PCSK9 gene and one that was disabled. Still, the impact was clear. Blacks ended up with LDL levels that were 28 percent lower than normal, averaging 100 instead of 138. Whites with the less powerful mutation had LDL levels that were about 15 percent lower.
This led scientists to search for people who had a mutated gene from both parents. Cohen and Hobbs searched their data for a mother and father who both carried a mutation. They found one such couple and tested their daughter in 2006. She was the aerobics instructor with the rare double inheritance. The investigators are still in contact with her and say she remains healthy, but she declined to be interviewed.
Around the same time, South African researchers began their own search for those who have two copies of the gene and found a healthy young woman at a maternity clinic in Zimbabwe. The investigators no longer know her whereabouts.
But those two young women showed that people could be healthy and thrive with very low LDL cholesterol levels.
Then came the hard part: making a drug to create the effects of the mutations. The drug companies were transfixed by the idea, and each wanted to be the first to market it.
Amgen has readied three factories, in Colorado, Puerto Rico and Rhode Island, to make its drug. It is anticipating production on a scale never attempted before with a monoclonal antibody, a costly wager for a drug still being tested.
The companies want to be ready with large quantities of their versions of the drug if they are approved.
As their factories were starting to produce the drugs, the companies began recruiting patients who were worried enough about their LDL levels to inject themselves with an experimental substance.
David Mayse, 60, who lives in South Point, Ohio, was 49 when he had his first heart attack while at work in a paper recycling plant.
His doctor plied him with four different drugs to lower his cholesterol, to little avail. Then Mayse had another heart attack and bypass surgery.
His doctor sent him to a cardiologist who called his cholesterol levels "outrageous" and asked Mayse if he would enter a clinical trial.
"I was willing to try anything at that point," Mayse said.
In February 2012, he saw Dr. Evan Stein, who heads the Metabolic and Atherosclerosis Research Center in Cincinnati. Mayse's LDL was 160 even though he was taking Vytorin, a combination of a statin and another drug to lower LDL levels.
Mayse enrolled in a study for Amgen's experimental drug. His LDL fell to 42.