From lab to pharmacy: IU researchers' discovery leads to new drug to treat rare bone disease

Medical scientists may toil for decades pursuing that holy grail of a discovery that could actually change people’s lives. Many never live to see that breakthrough.

Two Indiana University School of Medicine researchers recently joined the select group of scientists to see their work move from the laboratory into the clinic, when the Food and Drug Administration last month approved a drug based on findings in their lab that will be used to treat a rare bone disease.

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Each year about 175 university faculty contact the university’s Innovation and Commercialization office with innovation disclosures, ideas that they think have commercial potential, said David Wilhite, the office’s director. If the office confirms that such a potential exists, its staff starts looking for potential partners who might want to take that idea and develop.

Once an industry partner is found — if a partner is found – that discovery still needs to go through further development and often years of clinical trials to show that it both works and is safe.

So success stories like this one are few and far between.

“It’s so exciting on so many levels that the inventors are here,” Wilhite said. “It’s quite an example that this can be done in Indiana. It’s really exciting to see how a career’s worth of research paid off in helping patients.”

Debbie Moore counts her son Colton among the patients who have benefited.

Both Moore and Colton, who is 12, have a disease known as X-linked hypophosphatemia, or XLH, found in about one in 20,000 people. People with this genetic disease lack sufficient levels of phosphate, a mineral needed in bone formation, in their bodies. Low levels of phosphate cause a person to develop rickets, bowed legs, as well as tooth abscesses, so those with this condition rarely reach a typical height in adulthood and often experience bone pain.

When Moore, now 46, was 18 months old, she was diagnosed with the disease at Riley Children's Hospital. She wore braces and corrective shoes as a child but her legs still grew increasingly bowed. She had to have multiple surgeries starting at age 12 and by the time she graduated high school, she relied on a wheelchair to get around. Her dream of being a nurse was crushed.

Although a new mutation had caused Moore’s disease — no one else in her family had the condition — she knew that if she had children, there would be a 50-50 chance they would inherit it. At 16 months, her only child Colton was also diagnosed as well.

Early in Colton’s life, Moore braced herself for him to have a trajectory similar to her own with the disease. But four years ago, he entered a trial for the drug burosumab, based on discoveries made in the lab of the doctor who was treating Moore for the condition.

About a year into the trial, Colton’s legs, which had been bowed and would have required surgery, started straightening on their own. Now, for the first time in his life, Colton has free reign to try whatever sport he wants and there’s no surgery in his future.

“It’s amazing,” said Moore, who lives in Peru. “This has given us such a hope that the world is open for him.”

Three decades ago when Dr. Michael Econs saw his first patient with XLH, he had little such hope to offer. Standard therapy consisted of high doses of vitamin D and phosphorus to boost the person’s levels multiple times a day. While the regimen was not perfect and could cause kidney problems, it was better than going untreated.

At Duke University at the time, Econs was looking for a research project. He committed himself to learning about XLH, which would allow him to meld an interest in molecular biology and patient care.

“Some physicians when they see patients where there aren’t good therapies… decide we’re going to get involved and do some science to try to change things,” he said.

That first discovery came in 1995 as part of a team that pinpointed the genetic mutation behind XLH, but it was not clear how that led to the disease.

Two years later Econs moved to IU, where he is now chief of the Division of Endocrinology and Metabolism. He and another new IU hire Kenneth White, now the David D. Weaver professor of genetics, continued to delve even farther into the mysteries of XLH.

Knowing that XLH tends to run in families, White and Econs turned to patients who had it and their relatives for assistance. They would go to family reunions, in Ohio, North Carolina, and elsewhere to take blood and urine samples from those affected and those not to help determine which gene was responsible for the condition.

Within a few years, their work led to the revelation that mutations in a specific gene signals the body to make too much Fibroblast growth factor-23, or FGF23, which in turn in a hormone tells the body when to dump phosphorus into the urine. Excess FGF23, therefore, results in a scarcity of phosphorus in the body.

It was this discovery that Econs took to the university’s innovation office. While proposals can come from across the university, about 75 percent of proposals that the office handles originate at the medical school, Wilhite said.

Of the 175 proposals, the office licenses about 40 each year on average, although last year, a banner year, there were 62. About 10 of those licensed involve start-up companies, Wilhite said.

Only the unique ideas with the greatest shot of making it get chosen, he added.

“Some of those we have to pump the brakes right away because we have a limited budget and have to choose which ones have the highest potential,” he said.

In 2002, Econs' and White’s idea was licensed to a Japanese company, Kyowa Hakko Kirin Co., Ltd. That company started preliminary trials on the drug that would later be called burosumab. Now sold under the name Crysvita, the injectable drug blocks excess FGF23, which allows the body to maintain normal levels of phosphorus.

Eleven years later, a California-based firm Ultragenyx collaborated with Kirin to start the clinical trials in humans that would eventually bring the drug to market.

“It’s an amazing discovery of something so fundamental that tells us how much we think we know but how little we know about how the body works,” said Dr. Emil Kakkis, Ultragenyx chief executive officer and president, who as a doctor had treated patients with XLH. “We wanted to be part of it.”

IU does not provide details of its licensing agreements but Wilhite said there is potential for the university’s agreement to bring some financial benefit to the university. Faculty “inventors” and their labs whom his office assists can also benefit financially from discoveries, he said.

Faculty are not required to participate in commercialization of ideas and discoveries nor is that included in the tenure calculation, he said.

After all that work, Econs could not be involved with the clinical trials of burosumab, as that would be a conflict of interest.  Other IU doctors, however, could participate so patients Econs knew could benefit.

“Ken and I brought the ball up the field to get to the red zone and then once we got to the red zone, I got pulled out and a younger quarterback got put in,” he said, with a laugh as White chimed in, “But we scored a touchdown, which was good for the patients.”

Call IndyStar staff reporter Shari Rudavsky at (317) 444-6354. Follow her on Facebook and on Twitter.