Research in context
Evidence before this study
X-linked hypophosphataemia, caused by loss-of-function mutations in the PHEX (phosphate-regulating endopeptidase homolog, X-linked) gene, is the most common heritable form of rickets and osteomalacia. X-linked hypophosphataemia is characterised by elevated circulating concentrations of fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting, decreased 1,25(OH)2D concentrations, skeletal deformities, impaired growth, and compromised physical functioning. Since the 1980s, conventional therapy for X-linked hypophosphataemia has consisted of multiple daily doses of oral phosphate and one or more daily doses of active vitamin D. Although this therapy might improve rickets and skeletal deformities, the response is variable. Often rickets and short stature persist, and some patients require surgical intervention for lower extremity deformities. Also, clinical complications of conventional therapy can include nephrocalcinosis and hyperparathyroidism. Burosumab, a fully human monoclonal antibody against FGF23, received approval from the US Food and Drug Administration and from Health Canada, and conditional marketing approval by the European Medicines Agency in 2018 for the treatment of X-linked hypophosphataemia (conditions of approval vary). Two paediatric, single-arm, phase 2 clinical trials have shown that inhibition of FGF23 with burosumab restores phosphate homeostasis, and improves rickets, growth, and mobility in affected 1–12-year-old children. Complications associated with conventional therapy such as nephrocalcinosis and hyperparathyroidism were not detected in those phase 2 paediatric trials of burosumab.
Added value of this study
This international, randomised, active-controlled, open-label, phase 3 trial is the first to compare the efficacy and safety of switching to burosumab versus continuing conventional therapy among 1–12-year-old children with X-linked hypophosphataemia. In this trial, burosumab resulted in greater radiographic improvement of rickets and lower extremity bowing, larger decreases in serum alkaline phosphatase activity, and greater increases in serum phosphorus, growth, and mobility than continuation of conventional therapy. These improvements occurred in children who switched from long-standing conventional therapy to burosumab, suggesting that burosumab offers a therapeutic advantage over conventional therapy. From a safety standpoint, no patient developed hyperphosphataemia or worsening nephrocalcinosis scores in either treatment group. There were no discontinuations from the study or treatment. Adverse events were more frequent with burosumab compared with conventional therapy, mostly driven by adverse events associated with injecting a subcutaneous therapeutic protein.
Implications of all the available evidence
This phase 3 trial presents the first comparison of conventional therapy with burosumab in children with X-linked hypophosphataemia, and showed the superiority of burosumab over continuation of conventional therapy for several clinical outcomes, including the correction of renal phosphate wasting. By improving rickets, long bone deformities, and linear growth, burosumab offers a promising new treatment approach for children with X-linked hypophosphataemia.