Burosumab vs Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Subgroup Analysis by Dose Level

Abstract

Context: In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional therapy with active vitamin D and phosphate.

Objective: We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy.

Methods: Conventional therapy dose groups were defined as higher-dose phosphate [greater than 40 mg/kg] (HPi), lower-dose phosphate [40 mg/kg or less] (LPi), higher-dose alfacalcidol [greater than 60 ng/kg] or calcitriol [greater than 30 ng/kg] (HD), and lower-dose alfacalcidol [60 ng/kg or less] or calcitriol [30 ng/kg or less] (LD).

Results: At week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomly assigned to burosumab vs conventional therapy for all prebaseline dose groups: HPi (+1.72 vs +0.67), LPi (+2.14 vs +1.08), HD (+1.90 vs +0.94), LD (+2.11 vs +1.06). At week 64, the RGI-C for rickets was also higher in children randomly assigned to burosumab (+2.06) vs conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase (ALP) also decreased in the burosumab-treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses.

Conclusion: Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum ALP more than continuing either higher or lower doses of phosphate or active vitamin D.

Trial registration: ClinicalTrials.gov NCT02915705.

Keywords: FGF23; X-linked hypophosphatemia; XLH; active vitamin D; burosumab; oral phosphate; rickets.

Figure 1.

A, Mean Radiographic Global Impression of Change (RGI-C) rickets and lower-limb deformity score with burosumab vs conventional therapy stratified by prebaseline doses of oral phosphate using published dose thresholds. B, Mean RGI-C rickets and lower-limb deformity score with burosumab vs conventional therapy stratified by prebaseline doses of active vitamin D using published dose thresholds. C, Mean (SE) RGI-C rickets and lower-limb deformity scores with burosumab vs on-study doses of phosphate using published dose thresholds. D, Mean (SE) RGI-C rickets and lower-limb deformity scores with burosumab vs on-study doses of active vitamin D using published dose thresholds. Number above error bar is the mean; error bar denotes SE; number within column is number of patients contributing to the result shown.

Figure 2.

A, Mean (SE) percentage of the upper limit of normal for alkaline phosphatase (ALP) stratified by prebaseline dose of oral phosphate (left panel) and active vitamin D (right panel). B, Mean (SE) serum parathyroid hormone (iPTH) stratified by prebaseline dose of oral phosphate (left panel) and active vitamin D (right panel). Symbol represents mean for each time point; error bar denotes SE.

Figure 3.

Mean (SE) percentage of the upper limit of normal for alkaline phosphatase (ALP) with burosumab vs on-study higher (HPi)/lower dose phosphate (LPi) and on-study higher (HD)/lower dose active vitamin D (LD). Symbol represents mean for each time point; error bar denotes SE.

Figure 4.

Mean (SE) serum parathyroid hormone (iPTH) with burosumab and conventional therapy by on-study doses of phosphate (left panel) and active vitamin D (right panel). Symbol represents mean for each time point; error bar denotes SE.