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Burosumab reverses hypophosphatemia, rickets in children with genetic bone disease
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BOSTON — Children with X-linked hypophosphatemia treated with the monoclonal antibody burosumab for 40 weeks saw increased serum concentrations of phosphorous and decreased rickets severity, according to results of two phase 2 studies presented here.
In X-linked hypophosphatemia, or XLH, a mutation in the PHEX gene results in an excess of fibroblast growth factor 23 production that causes low serum phosphorus concentrations, leading to impaired bone growth in children and adolescents, according to Anthony Portale, MD, professor in the department of pediatrics at the University of California San Francisco.
Burosumab (Crysvita, Ultragenyx) was approved by the FDA in April for treatment of the condition.
Portale and colleagues conducted two trials. In the first, designed to evaluate safety and effective dose, 26 children aged 5 to 12 years (mean age, 8.7 years; 46% boys; 89% white; mean height z score, –1.7) were randomly assigned to receive subcutaneous burosumab either once every 2 weeks or every 4 weeks, with dose titration for the first 16 weeks up to 2 mg/kg to achieve serum phosphorous concentration just above the lower limit of normal, 3 mg/dL to 5 mg/dL.
In the second trial, 13 children aged 1 to 4 years (mean age, 2.9 years; 69% boys; 92% white; mean height z score, –1.4) received 0.8 mg/kg subcutaneous burosumab once every 2 weeks, with the dose increased to 1.2 mg/kg if needed to increase phosphorous levels.
In both trials, oral phosphate and calcitriol were discontinued. Endpoints were serum concentrations of phosphorous, 1,25(OH)2D and alkaline phosphatase, radiographic evidence of rickets, and height and safety at weeks 40 and 64.
Among the participants who received burosumab every 2 weeks, at 40 weeks the mean dose was 1 mg/dL for the older children and 0.9 mg/dL for the younger children. Serum phosphorus levels increased by a mean of 38% in the older children and by a mean of 40% in the younger group.
“In the first 16 weeks, the phosphorous levels were higher in the younger children, and we attribute that to their receiving a more effective starting dose, but also serum levels of phosphorous are higher in younger children,” Portale said.
Researchers observed statistically significant increases in 1,25(OH)2D and decreases in alkaline phosphatase in both groups.
“The alkaline phosphatase levels reflect rickets activity,” Portale said. “They decrease progressively over the course of treatment. As is typical with alkaline phosphatase, the higher levels are seen in the youngest children. The decrease in the younger group was about 40% from baseline and in the older group about 20% from baseline.”
Researchers also observed significant healing of rickets, with a 59% decrease in the mean Rickets Severity Score, to 1.8 from 2.9 at baseline. The Radiographic Global Impression of Change score also indicated substantial healing in both groups at 40 weeks., Portale said.
Adverse events were mostly mild to moderate injection site reactions except for one serious adverse event in each group. No participant developed hyperphosphatemia or discontinued the study.
Asked about improvement in quality of life for the participants, Portale said, “From my personal experience, I know that for families, administering a medication every 2 weeks is far superior to having to give multiple medicines three and four times a day. With burosumab we’ve seen significant improvement in growth and T scores in children [and] also some modest improvements in functional tests.” – by Jill Rollet
Reference:
Portale A, et al. Abstract 525. Presented at: AACE Annual Scientific and Clinical Congress; May 16-20, 2018; Boston.
Disclosure: Portale reports he has received research honoraria and support from Ultrgenyx.