Advances in medical care often take a long and winding path from a new laboratory discovery to the patient bedside. So it is particularly gratifying as a physician-scientist when you have the opportunity to offer your patients a new treatment that came about in part from research in your own laboratory.
For MassGeneral for Children’s Harald Jueppner, MD, one such gratifying moment came earlier this spring, when the FDA approved burosumab (Crysvita®) as a new treatment for X-linked hypophosphatemia (XLH).
XLH is a genetic disorder caused by mutations in PHEX, a gene located on the X-chromosome. Impaired PHEX function in osteocytes, cells buried deep within bones, leads to excessive loss of phosphate into the urine, ultimately causing extremely low blood phosphate levels.
Phosphate is a mineral important for several functions in the cell and for proper growth and development of the bones.
In children, insufficient phosphate causes rickets—a growth plate abnormality that leads to bowing of the legs, often requiring multiple surgeries to correct. Insufficient phosphate in childhood is also linked to poor growth.
In adults, low blood phosphate causes osteomalacia—poorly mineralized and weak bones—which can result in generalized bone pain as well as fractures. However, how mutations in PHEX cause renal phosphate wasting remained a mystery for many years.
Previous Treatment Options
Until this spring, the only treatment for XLH was multiple daily doses of oral phosphate, up to 6 times daily, and a form of activated vitamin D called calcitriol.
Successful treatment requires good adherence to this tough medication schedule to ensure that blood phosphate levels do not drop too much, which is not always easy with young children. In addition, treatment with oral phosphate and calcitriol does not address the full range of problems associated with XLH.
“Treatment with phosphate and calcitriol can help prevent rickets and bowing, but one main problem has remained, namely that the kids with XLH don’t grow normally,” Jueppner explains.
The Path to Discovery
In the early 2000s, researchers in the USA and in Japan discovered a new hormone, called fibroblast growth factor 23 (FGF23), which promotes urinary phosphate wasting. Dr. Jueppner recognized that several rare conditions of low phosphate, including XLH, might be caused by abnormal FGF23 action.
His laboratory thus developed a blood test to measure circulating FGF23 and, in a landmark New England Journal of Medicine publication, showed that both XLH and another rare bone disorder, tumor-induced osteomalacia, are both caused by elevations in FGF23.
Based on this newly discovered, precise understanding of the molecular mechanism of XLH, two pharmaceutical companies, Ultragenyx and Kyowa Kirin, together developed burosumab (Crysvita), a monoclonal antibody that binds to and blocks the actions of FGF23. While Jueppner is not connected to either company, his research establishing the role of FGF23 in the pathophysiology of XLH provided the framework for the development of this medication.
The FDA’s approval of Crysvita was supported by a study of 52 pediatric patients, aged 5 to 12 years, demonstrating that the medication increased phosphorus levels in the blood, substantially healed rickets and accelerated growth. A second study of 13 patients aged 1 to 4 years showed similar positive results. The new antibody marks a change in treatment strategy for patients with XLH.
While it is too soon to know if burosumab will help XLH patients attain an adult height that is closer to the normal average, preliminary data suggests that it may help with growth, Jueppner says.
In addition, from a physiologic perspective, targeting the abnormal protein rather than trying to simply replace phosphate losses may prevent some of the side effects commonly observed with the previous oral therapy.
The new treatment is given as an injection once every two weeks in children, and once every month in adults.
The one drawback is the price tag, currently about $160,000 per year. Jueppner is hopeful the cost of the treatment will come down over time.
He also believes that if the medication can reduce the need for surgical interventions to correct bowing, help XLH patients grow to a normal height, and prevent kidney complications down the line, the long-term benefits will be worth the expense.
A New Treatment Option
With the FDA’s approval this spring, Jueppner and Deborah Mitchell, MD, and other colleagues who see patients in the Pediatric Bone and Mineral Metabolism Disorders Clinic at MGHfC, are now able to offer this medication to their patients with XLH, some of whom have been treated at MGHfC for several decades.
“It’s gratifying,” he says. “When we first showed that XLH patients have elevated FGF23 levels, we thought it was a nice finding explaining their phosphate-wasting, but didn’t spend much time thinking about it subsequently, largely because the pharmaceutical industry did not appear to be interested in finding a new treatment for a rare disease. However, looking back, it was actually a very important discovery.”
- See Dr. Jueppner’s clinical profile
- Pediatric Bone and Mineral Metabolism Disorders Clinic
- X-linked hypophosphatemia (NIH’s Genetic and Rare Diseases Information Center)
About the Mass General Research Institute
Massachusetts General Hospital is home to the largest hospital-based research program in the United States. Research at Mass General takes place in over 30 departments, centers and institutes and is supported by federal and state funding, foundations, industry partners and philanthropic donations.