FGF23 Inhibitor Effective in Rare Inherited Form of Rickets

Pam Harrison

October 29, 2018

SAN DIEGO — For adults with X-linked hypophosphatemia (XLH), a rare inherited form of rickets, a monthly dose of burosumab (Crysvita, Kyowa Hakko Kirin and Ultragenyx Pharmaceutical) can normalize phosphorous levels and enhance bone mineralization, results from a randomized phase 3 trial indicate.

"In adult patients with XLH, there are no established guidelines for therapy," Farzana Perwad, MD, from the University of California, San Francisco, told Medscape Medical News.

And there is no standard of care either, she noted. When patients experience significant pain and hypophosphatemia, they are sometimes prescribed phosphate and vitamin D supplements, but sometimes they are treated just with pain medication.

Burosumab is "a promising new therapeutic approach to improve skeletal disease in adults with XLH," Perwad explained. The drug increased serum phosphorus levels to within the normal range and healed both active fractures and pseudofractures, she reported here at Kidney Week 2018.

Renal Phosphate Wasting

XLH is characterized by hypophosphatemia due to renal phosphate wasting, which leads to rickets in children and osteomalacia in adults.

Excessive levels of fibroblast growth factor 23 (FGF23) in the blood act on the kidneys to inhibit production of the 1,25 dihydroxyvitamin D, the active metabolite of vitamin D, and inhibit phosphate resorption. Both of these actions lower serum phosphorous and cause defective mineralization and delayed ossification of bone.

By inhibiting serum FGF23 levels, burosumab, a human monoclonal antibody, increases the production of 1,25 dihydroxyvitamin D in the kidney, boosts serum phosphorous levels, and improves skeletal mineralization.

In their double-blind study, Perwad and her colleagues assessed 134 adults with symptomatic hypophosphatemia and measurable bone pain.

Mean age in the study cohort was 40 years and 65% of the patients were women. The majority of patients had been treated with phosphate and vitamin D before enrolment in the study, primarily during their childhood years.

For the first 24 weeks of the study, 68 patients were randomized to burosumab, administered subcutaneously, every 4 weeks, and 66 were randomized to placebo. Then, at 24 weeks, patients in the placebo group crossed over and all study participants received burosumab for another 24 weeks.

The primary end point was a mean serum phosphorous level in excess of 2.5 mg/dL, which indicates that phosphorous levels have normalized, Perwad noted.

During the first 24 weeks, significantly more patients in the burosumab group than in the placebo group achieved mean serum phosphorous levels in the normal range (94% vs 8%; P < .0001). During the second 24 weeks, patients in the crossover group achieved serum phosphorous levels in the normal range.

At baseline, 70 participants had either complete or pseudofractures, but a significant proportion of those healed completely with treatment.

During the first 24 weeks, patients in the burosumab group were almost 17 times more likely than those in the placebo group to achieve full fracture resolution (43% vs 8%; odds ratio, 16.8; P < .0001). And at 48 weeks, more patients in the original burosumab group than in the crossover group had achieved fracture healing (63.1% vs 35.2%).

Beneficial Effect on Pain

The researchers also assessed patient-reported pain before and after burosumab treatment.

At baseline, almost three-quarters of patients rated their pain as at least 6 on the 10-point Brief Pain Inventory scale.

Pain scores in the original burosumab group decreased to about 8% of baseline levels at week 24 and to 13% of baseline levels at week 48. In the crossover group, there was no change in pain scores at week 24, but there was a significant decrease to approximately 15% of baseline levels at week 48.

At week 48, there were significant improvements from baseline in stiffness, measured on the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, in both groups (P < .001), and modest but significant improvements in physical function (P < .001).

There were no discontinuations in either group because of adverse effects. Most of the adverse effects were mild to moderate in severity, and rates of the most common events — injection-site and hypersensitivity reactions — were similar in the two treatment groups.

It's very exciting to see the beneficial effects of burosumab in patients with XLH, particularly in relation to pain, said session cochair Kathleen Hill Gallant, PhD, from, Purdue University in West Lafayette, Indiana.

Even though it's a rare disease, it's a big deal for patients who have it.

"Previous therapies like phosphorous supplements simply attempt to offset the profound loss of phosphate in the urine. This new drug provides a therapeutic option that addresses the elevated FGF23 levels that actually cause the disease," she told Medscape Medical News.

"XLH affects whole families, so it's really fantastic that these rare bone diseases are being researched and people are finding therapies that work," Hall Gallant explained. "Even though it's a rare disease, it's a big deal for patients who have it."

Burosumab has been approved by the US Food and Drug Administration for the treatment of X-linked hypophosphatemia in both children and adults.

This study was funded by Ultragenyx. Perwad has served on the advisory board for and received honorarium from Ultragenyx. Hill Gallant has received research funding from Chugai Pharmaceuticals.

Kidney Week 2018: American Society of Nephrology Annual Meeting: Abstract TH-OR023 Presented October 25, 2018.

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