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Burosumab safe, effective in children with rare form of rickets
Young children with X-linked hypophosphatemia saw significant improvements in rickets and phosphate homeostasis after 63 weeks of biweekly treatment with the monoclonal antibody burosumab, according to findings published in The Lancet Diabetes & Endocrinology.
X-linked hypophosphatemia causes low levels of phosphorus in the blood due to excess fibroblast growth factor 23 production, leading to impaired bone growth and development in children and adolescents and problems with bone mineralization throughout a person’s life. The FDA approved burosumab (Crysvita, Ultragenyx) for the treatment of X-linked hypophosphatemia in April.
“Our findings are similar to those reported in our previous trial in children aged 5 to 12 years with X-linked hypophosphatemia who received a similar therapeutic regimen and are consistent with the significant improvement in serum phosphorus concentrations with burosumab treatment in adults,” Michael P. Whyte, MD, medical-scientific director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children in St. Louis, and colleagues wrote.
In an open-label, phase 2 trial, Whyte and colleagues analyzed data from 13 children aged 1 to 4 years with X-linked hypophosphatemia who received subcutaneous burosumab (0.8 mg/kg) every 2 weeks for 64 weeks at three hospitals in the United States. Children could receive burosumab for up to an additional 96 weeks during the extension period. Conventional therapy was stopped upon enrollment.
Coprimary endpoints were safety and change from baseline to 40 weeks in fasting serum phosphorus concentrations. Secondary outcomes included change in rickets severity from baseline to 40 weeks (assessed using the Thacher Rickets Severity Score and an adaptation of the Radiographic Global Impression of Change) and recumbent length or standing height.
Before enrollment, patients received conventional therapy for a mean duration of 6 months. At baseline, all patients had fasting serum phosphorus concentrations below the normal range of 1.03 mmol/L to 1.97 mmol/L and 12 patients had a total Thacher Rickets Severity Score of at least 1.5.
From baseline through week 40, children experienced a least squares mean increase of 0.31 mmol/L in serum phosphorus level (95% CI, 0.24-0.39). At week 40, all fasting serum phosphorus concentrations were within the normal range, with a mean of 1.12 mmol/L, according to researchers.
The researchers observed improvement in rickets for all children. Total Thacker Rickets Severity Score decreased by a least squares mean of –1.7 (P < .0001) for baseline to week 40 and by a least squares mean of –2 (P < .0001) by week 64. Similarly, Radiographic Global Impression of Change score improved by a least squares mean score of 2.3 by week 40 and by a least squares mean of 2.2 at week 64 (P < .0001 for both).
Children maintained mean length or standing height z score from baseline through week 64.
All patients experienced at least one adverse event, according to researchers, including 14 treatment-related adverse events (mostly injection-site reactions) in five children. Most adverse events were considered mild to moderate, and there were no incidences of nephrocalcinosis.
The researchers noted that a key limitation during the study was a difficulty in obtaining accurate growth assessments in young children, as shown by an atypical decrease in the height of one child and the inability of another child to remain still enough for an accurate height assessment.
“Nevertheless, children in this study maintained steady growth at an age when patients with X-linked hypophosphatemia first fall below normal growth curves,” the researchers wrote. “Such limitations are addressed in our ongoing phase 3 study in children (aged 1-12 years) with X-linked hypophosphatemia that compares safety and efficacy of burosumab to conventional therapy, in which length or standing height is measured three times at each visit and is averaged to avoid error.”
In initial study data reported at the American Association of Clinical Endocrinologists in May and reported by Endocrine Today, researchers reported that children in the cohort, as well as children aged 5 to 12 years in a separate phase 2 study, also experienced increases in 1,25-hydroxyvitamin 2D and decreases in alkaline phosphatase levels, as well as improved T-scores in children and some modest improvements in functional tests. – by Regina Schaffer
Disclosures: Kyowa Kirin International and Ultragenyx Pharmaceuticals funded this study. Whyte reports he is a clinical investigator for Ultragenyx and has received grants, consultant fees and reimbursement for travel expenses from the company. Please see the study for all other authors’ relevant financial disclosures.