New Drug Approval Reflects Decades of Effort

March 17, 2015, was a special day for Cincinnati Children's scientists James Heubi, MD, and Kenneth Setchell, PhD.

That was the day the US Food and Drug Administration approved a new drug called Cholbam for the treatment of defects in bile acid metabolism. That day heralded a brighter future for children with a rare and potentially deadly condition while marking the culmination of a 25-year journey through the drug development process.

"It is a dream come true in many ways," Setchell says. "It's not often that one can see a discovery move all the way from bench to approved medication."

The new medication is exciting because it gives children born with bile acid metabolic defects the opportunity to grow up while taking nothing more than a daily pill versus joining a waiting list and hoping to receive a complex and highly invasive liver transplant. However, the length of time it required to win regulatory approval for the treatment also illustrates how difficult drug development can be.

Solving a mystery

Bile acid metabolic defects are quite rare. Setchell and Heubi estimate they occur only once in every 80,000 births. Back in the 1970s, medical experts in the US and Europe had no explanation for why these infants and children were dying.

Some patients with these defects quickly showed signs of jaundice as newborns. Some failed to grow. Others suffered bleeding, rickets and other symptoms that indicated dangerous vitamin deficiencies. The only hope many of these children had was to receive a liver transplant – a procedure that was not common for children in those years and not available at all to infants.

Heubi, who began practicing as a pediatric gastroenterologist at Cincinnati Children's in 1979, recalls the frustration of having so few options.

"Many of these children were labeled as having 'neonatal hepatitis.' We knew they had progressive liver disease, but we had no knowledge about the underlying causes," Heubi says. "We suspected that a genetic cause was involved, but we lacked the technology to find it."

Enter Setchell, an expert in the use of mass spectrometry, who began his career in 1970 in the United Kingdom at the London-based Medical Research Council. Setchell had developed techniques for analyzing the metabolic profile of steroids and bile acids, which he used to study blood and urine samples from children with liver disease of unknown cause.

In 1981, testing revealed the first patient to be identified with liver disease stemming from a defect in bile acid production. In 1984, Cincinnati Children's recruited Setchell to launch a mass spectrometry research center, where he began to work closely with Heubi to continue the bile acid research.

Perfecting a treatment

In healthy children, the liver produces bile acids from breaking down cholesterol by a complex, 17-step pathway. The bile acids are essential to keep the liver functioning and to allow toxins to be removed from the body. When there is a block in this pathway, the liver produces abnormal bile acids that are very damaging to the liver and that prevent bile from flowing. Children with defective bile acid production then accumulate toxins, which leads to liver damage and can result in premature death.

Heubi and Setchell discovered that adding cholic acid to the diet would suppress the production of toxic chemicals in the liver while stimulating the bile acid flow needed to absorb key vitamins and fat. These findings helped win initial permission from the FDA to provide cholic acid to children as an investigational drug.

For many years, the team worked with various suppliers to custom-make batches of cholic acid while the children were followed as part of a long-running clinical trial. Some of the earliest patients have now been successfully treated for more than 20 years.

But converting the lab-made treatment into an approved medication turned out to be more complex than anyone expected. "The regulatory hurdles were extreme, to say the least," Heubi says.

As suppliers came and went, the scientists decided to launch a spin-off company* to assure continued production of the treatment. They later learned they had to launch a new, more formal clinical trial to gather data that would satisfy evolving FDA standards. It also took five years for the new company to demonstrate it could produce cholic acid according to all regulatory purity standards.

Finally, the product - now named Cholbam - became the first FDA-approved medication in its class. And thus, Heubi and Setchell joined a rare group of pediatric researchers who have both defined a disease and established a novel treatment for it.

Continuing the work

Since those early days, Heubi has become director of the Clinical Translational Research Center at Cincinnati Children's. He also serves as associate dean of Clinical and Translational Research and director of the Center for Clinical and Translational Science and Training at the University of Cincinnati College of Medicine. Setchell now directs a much-expanded Mass Spectrometry Core in the Division of Pathology at Cincinnati Children's, which continues to study metabolism in liver disease, cancer and nutrition with an emphasis on cholesterol, steroids, bile acids and lipids, while also providing precise tracking of dose levels for immunosuppressants, pain medications and detecting drugs of abuse.

Since the mid-1980s, hospitals around the world have sent more than 13,500 samples from children with unexplained liver disease to Cincinnati Children's for bile acid analysis. "Fifteen to 30 samples arrive every 10 days," Setchell says.

Over the years, these tests have identified about 270 children with hereditary bile acid defects, saving many lives and avoiding several potentially risky liver transplants. And since that first case, genetic defects have been identified in nine of the 17 enzymes known to be involved in producing bile acids. The first six of these defects were discovered by Setchell and Heubi at Cincinnati Children's.

*Cholbam is marketed by Retrophin Inc. under a license from Asklepion Pharmaceuticals LLC. Heubi is chief medical officer and Setchell is chief scientific officer for Asklepion. These interests have been fully disclosed to Cincinnati Children's and an agreement is in place to manage any potential conflicts arising from this arrangement.