Research Breakthroughs

IU School of Medicine faculty members Michael Econs, MD, and Kenneth White, PhD, have made seminal discoveries elucidatating the underlying causes of hereditary hypophosphatemic rickets, phosphate-wasting bone disorders that result in skeletal deformities, pain and other complications.

Their research has formed the basis of new treatments for both X-linked hypophosphatemia (XLH), the most common type of hereditary hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets (ADHR), an ultra-rare form of the disorder.

The research spans 30 years and involves multiple breakthroughs:

Dr. Econs is part of a team that discovers that XLH is linked to a mutation on the PHEX gene, though it is unclear exactly how the genetic mutation causes the disease. Their findings are published in Nature Genetics.

Drs. Econs and White, and an international consortium of investigators, determine that ADHR is caused by a mutation on the FGF23 gene. They determine that the mutation prevents destruction of the FGF23 hormone, which regulates phosphate in the blood. The mutation causes high levels of FGF23, which prompts the body to excrete excessive amounts of phosphate in the urine.

The FGF23 discovery is published in Nature Genetics.

Drs. White, Econs, and coworkers publish information demonstrating that tumors that cause tumor-induced osteomalacia produce large quantities of FGF23.

Indiana University Innovation and Commercialization Office licenses the FGF23 discovery to Kyowa Hakko Kirin Co. KHK goes on to isolate an antibody that targets FGF23 in blood. The “soaking up” and neutralization of FGF23 by the antibody allows patients to maintain adequate phosphate levels by restoring kidney phosphate reabsorption.

Working with a large international consortium Drs. Econs and White determine that patients with tumor induced osteomalacia and XLH have high levels of FGF23, thereby resulting in low blood phosphate levels.

The first dose of burosumab is delivered to a patient at Indiana University in a trial with Drs. Munro Peacock and Erik Imel.

Phase I/II study of the drug burosumab in XLH are undertaken by Kyowa Hakko Kirin Co in the US and Canada.

Ultragenyx Pharmaceutical Inc. becomes engaged.

The first paper about the effects of burosumab in patients with XLH is published. Imel is one of the authors.

The FDA approves burosumab after clinical trials demonstrate that it normalizes blood phosphate thereby improving rickets and lower-limb deformity of the legs in children, and bone healing, fracture resolution and osteomalacia in adults. It is the first treatment that targets the underlying cause of XLH.

Research related to hypophosphatemic rickets, FGF23 and metabolic bone disorders continues at IU School of Medicine.

Drs. Econs and White revealed in recent studies that iron plays an important role in regulating FGF23 levels in patients with ADHR, the ultra-rare variant of the disease. Dr. Econs launched a National Institutes of Health (NIH) funded clinical trial in 2014 to study the use of oral iron to restore the ability of patients with ADHR to conserve phosphate. Though ongoing, the iron therapy study is extraordinarily promising and in some cases has allowed for a complete remission.

Of note, the vast majority of the work cited above was funded by the NIH, particularly the National Institute of Arthritis Musculoskeletal and Skin Diseases and the National Institute of Diabetes, Digestive, and Kidney Disease. These institutes funded the precompetitive work that was necessary before a company could get involved developing a drug. In addition, Econs has received continuous philanthropic support from the Scottish Rite of Indianapolis Foundation since joining the IU School of Medicine faculty in 1997.