Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia

Abstract

Purpose: In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH.

Methods: After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab.

Results: Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity.

Main conclusions: In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab.

Clinicaltrials.gov: NCT02163577.

Keywords: calcitriol; growth; hypophosphatemia; osteomalacia; phosphate; rickets.

© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.

UX023-CL201 CONSORT diagram.

Figure 2.

Tanner stage at baseline and week 160.

Figure 3.

(A) Sustained improvement in serum phosphorus with burosumab—note that data from week 0 to week 64 were previously reported (13). (B) Sustained improvement in TmP/GFR with burosumab—note that data from week 0 to week 64 were previously reported (13). (C) Sustained improvement in serum 1,25(OH)2D with burosumab—note that data from week 0 to week 64 were previously reported (13).

Figure 4.

(A) RSS total score decreased from baseline indicating improved rickets. (B) RGI-C global score increased indicating improved rickets. (C) Sustained healing of rickets in an 8-year-old boy. (D) RGI-C lower limb deformity score increased indicating improvement throughout the study. (E) Sustained improvement in serum alkaline phosphatase (ALP) with burosumab—note that data from week 0 to week 64 were previously reported (13).

Figure 5.

(A) Change in standing height z-score from baseline. (B) Change in percent of predicted 6MWT from baseline (least square mean ± SE). (C) POSNA-PODCI normative score (mean ± SE).

Figure 6.

(A) No clinically meaningful changes in serum calcium. (B) No clinically meaningful changes in 24-hour urine calcium excretion. (C) No clinically meaningful changes in serum PTH (iPTH).