No more than a few hundred U.S. children have a rare disease characterized by ultrahigh levels of bad cholesterol.

Yet to the giant drugmaker AstraZeneca, this small group could be worth billions of dollars.

The company is making a bold attempt to fend off impending generic competition to its best-selling drug, the anti-cholesterol pill Crestor, by getting it approved to treat the rare disease. In an unusual legal argument, the company says Crestor is entitled to seven years of additional market exclusivity under the Orphan Drug Act, a three-decade-old law that encourages pharmaceutical companies to develop treatments for rare diseases.

Critics say AstraZeneca is trying to abuse the law, since the overwhelming use of Crestor is for treating adults with high cholesterol, not children with the rare disease.

“This represents a deviation from the intent of the Orphan Drug Act,” said Dr. Martin A. Makary, a professor of health policy at Johns Hopkins Medical School. “It is now being used to dominate the market with retrofitted indications.”

Crestor, a cholesterol-lowering statin, was prescribed 20.3 million times in the United States last year, the second-most of any brand-name drug after Synthroid, a thyroid medicine, according to the prescription tracker IMS Health. The drug, also known as rosuvastatin calcium, is scheduled to lose patent protection on July 8, potentially exposing it to an onslaught of generic competition.

The introduction of generics would weigh heavily on AstraZeneca’s bottom line. Crestor is the company’s best-selling drug, accounting for $5 billion of its $23.6 billion in product sales last year. About $2.8 billion in sales were in the United States, where the retail price is about $260 a month, according to GoodRx.com.

The chain of events leading up to the current controversy began in late May, when AstraZeneca won approval of Crestor to treat children with the rare disease, homozygous familial hypercholesterolemia, or HoFH. That approval gave Crestor market exclusivity for seven years, though it applies only to that disease.

One implication is that detailed prescribing information about using the drug for the rare disease cannot be included on the label of generic versions for seven years. However, the Food and Drug Administration can in theory allow generics on the market for other uses, such as treating high cholesterol in adults.

Yet AstraZeneca immediately petitioned the FDA, arguing that if the correct dose for children with HoFH could not be on the generic label, then it would be illegal and dangerous to approve any generic versions for any use at all. That is because doctors might still prescribe the generic for children with HoFH and choose the wrong dose, posing “substantial safety and efficacy risks.”

Michele Meixell, a spokeswoman for AstraZeneca, said the company pursued the new use of Crestor as “part of our standard practice to address unmet needs.” She said the Orphan Drug Act “provides exclusivity as an incentive for pharmaceutical companies to develop products to help address the needs of an underserved patient population.”

It is far from certain that AstraZeneca’s argument will succeed, and it is not known when the FDA will decide. One response might be for the agency to approve generic versions of Crestor on schedule, on July 8.

Spectrum Pharmaceuticals lost a lawsuit this month after trying in a similar way to protect its cancer drug Fusilev from generic competition.

Otsuka Pharmaceutical recently tried a similar tactic to shield its big-selling antipsychotic, Abilify, from generic competition by getting it approved for a rare disease. The FDA approved generics in April and its decision was upheld in court.

Perhaps the most famous case was when Bristol-Myers Squibb tried for three extra years of protection from generics for Glucophage, its big-selling drug for adult-onset diabetes, by getting it approved to treat the relatively few children with that disease. Outraged members of Congress, calling the move an abuse of the system, amended the law in 2002 to eliminate what came to be called the Glucophage loophole.

But Otsuka, in its recent court case, argued that lawmakers at that time did not explicitly mention orphan exclusivity as a loophole to be closed. The U.S. District Court judge hearing the case in Maryland, George Hazel, dismissed that argument.

“It would defy logic,” he wrote, “to believe that in enacting this measure to prevent a three-year exclusivity from becoming a ‘fundamental abuse of the system’ that harmed consumers, Congress nonetheless intended to permit the seven-year exclusivity Otsuka seeks here.”

In its petition to the FDA, AstraZeneca argues that the FDA was legally incorrect in the Otsuka case.

Kurt Karst, a director of the Washington law firm Hyman, Phelps & McNamara and principal author of the FDA Law Blog, said, “Given the Otsuka precedent, it’s going to be an uphill battle” for AstraZeneca. He predicted that the company would sue the FDA if its request were denied.

While AstraZeneca has been studying use of Crestor for pediatric conditions for some years, it began a clinical trial for children 6-17 years old with HoFH only in 2014. About 300-1,000 people in the United States have the disease, which involves two deleterious mutations, one from each parent, said Katherine Wilemon, president of the FH Foundation, an advocacy group. She said some people with the disease suffer heart attacks when they are only 5 years old.

Michelle Watts of Hagerstown, Md., said that she and her husband, Jason, both have high cholesterol, but, “We had no idea that we could both carry a gene and there’s the possibility of us giving it to our children.”

Their 7-year-old daughter, Avery, has HoFH and already has some narrowing of the arteries. She takes a generic statin and Zetia, another anti-cholesterol pill. Every two weeks, the family drives three hours each way for a treatment similar to dialysis, in which Avery’s blood is run through a machine that cleanses it of cholesterol.

The Watts, who both use Crestor to treat their own high cholesterol, declined to comment on AstraZeneca’s move, saying they did not know enough about it.

AstraZeneca’s trial involved only 14 children and tested a single dose of Crestor, according to the company’s petition. After six weeks of treatment, those who took Crestor had a bigger decline in LDL, or bad cholesterol, than those receiving a placebo. This result was expected, in that statins like Crestor are already a cornerstone of treatment for such children.

Dr. Sidney M. Wolfe, founder and senior adviser of the Public Citizen health research group, said that if AstraZeneca was interested in that rare disease, “They could have done it a long time ago, not right before midnight when it is about to turn into a pumpkin.”

One generic version of Crestor, sold by Allergan, reached the market in May under a patent litigation settlement with AstraZeneca. But drug prices do not typically plummet until multiple generics are on the market.

The issue of using orphan diseases to give drugs extended protection from generic competition is playing out on a bigger stage as well. A broad pharmaceutical policy bill passed by the House of Representatives last year, called the 21st Century Cures Act, would give six extra months of protection from generic competition if an already marketed drug gets approved for an orphan disease.

Max G. Bronstein, a senior director at the EveryLife Foundation for Rare Diseases, an advocacy group, said the measure was backed by dozens of patient groups because “repurposing” existing drugs is a quicker and less costly way to get medicines approved for rare diseases than is developing totally new drugs.

But Public Citizen predicted that the provision could add up to $12 billion to the nation’s drug bill over 10 years because “cheaper generic versions of drugs will be inaccessible to patients with much more common, nonorphan diseases for an additional six months.”

The measure has not been passed by the Senate. Advocates hope it will be added as an amendment to the Senate counterpart of the broader legislation.

© 2016 The New York Times Company