A phase 2 trial of burosumab for treatment of fibroblast growth factor-23-mediated hypophosphatemia in children and adults with fibrous dysplasia

Abstract Fibrous dysplasia (FD) is a rare disorder associated with fractures and deformities. FD lesions produce excess phosphaturic hormone fibroblast growth factor 23 (FGF23), leading to hyperphosphaturia in most patients, and hypophosphatemia in those with high FD burden. Skeletal complications are associated with both low-normophosphatemia and frank hypophosphatemia. Burosumab is approved for other forms of FGF23 excess, but there is little evidence to inform use in FD. A phase 2 study investigated the safety and efficacy of burosumab in patients with FD. The primary endpoint was the proportion of participants achieving phosphate levels within the mid to upper part of the normal range (age and sex-adjusted Z-score –1 to +2). 12 participants (7 children, 5 adults) received burosumab for 48 weeks. Median phosphate Z-score increased from −2.88 (1.65) to 0.22 (1.37), meeting the target in 100% of participants. Alkaline phosphatase levels were elevated at baseline in 8 participants [median 846 U/L (464)] and declined by 49% at week 48, representing a median decline of −364 (244.5) U/L. PROMIS questionnaires showed trends toward improvements in all domains in children; adult scores showed no identifiable trends. Two children experienced transformational mobility gains, including advancement from full-time wheelchair use to independent ambulation. Lesion biopsies showed no changes in cellularity or composition, and 18F-NaF PET/CT scans showed no changes in tracer uptake, suggesting burosumab did not adversely impact lesional activity. Adverse events were mild, and none resulted in treatment withdrawal. Burosumab treatment in patients with FD was well-tolerated, restored phosphate homeostasis, and reduced alkaline phosphatase levels. Burosumab has the potential to lead to functional improvements and ambulation gains in severely affected patients and is a valuable tool to reduce the impact of FD-related disability.