Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia

Abstract

Context: Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown.

Objective: This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH.

Methods: This post hoc analysis of a 64-week, open-label, randomized controlled study took place at 16 academic centers. Sixty-one children aged 1 to 12 years with XLH (younger, n = 26; older, n = 35) participated. Children received burosumab starting at 0.8 mg/kg every 2 weeks (younger, n = 14; older, n = 15) or continued Pi/D individually titrated per recommended guidelines (younger, n = 12; older, n = 20). The main outcome measure included the least squares means difference (LSMD) in Radiographic Global Impression of Change (RGI-C) rickets total score from baseline to week 64.

Results: The LSMD in outcomes through 64 weeks on burosumab vs conventional therapy by age group were as follows: RGI-C rickets total score (younger, +0.90; older, +1.07), total Rickets Severity Score (younger, -0.86; older, -1.44), RGI-C lower limb deformity score (younger, +1.02; older, +0.91), recumbent length or standing height Z-score (younger, +0.20; older, +0.09), and serum alkaline phosphatase (ALP) (younger, -31.15% of upper normal limit [ULN]; older, -52.11% of ULN). On burosumab, dental abscesses were not reported in younger children but were in 53% of older children.

Conclusion: Burosumab appears to improve outcomes both in younger and older children with XLH, including rickets, lower limb deformities, growth, and ALP, compared with Pi/D.

Trial registration: ClinicalTrials.gov NCT02915705.

Keywords: X-linked hypophosphatemia; burosumab; children; fibroblast growth factor 23; rickets.

Figure 1.

Mean (SD) A, serum phosphorus; B, TmP/GFR; C, 1,25(OH)₂D; D, 25(OH)D; E, alkaline phosphatase; and F, plasma iPTH from study weeks 0 to 64 in children younger than 5 and aged 5 years and older who received Pi/D or burosumab every 2 weeks. Dashed lines indicate the LLN for serum phosphorus (3.2-6.1 mg/dL), TmP/GFR (3.4-5.8 mg/dL), the LLN and ULN for 1,25(OH)₂D (25.8-101.5 pg/mL), the 25(OH)D status benchmarked to 20 ng/mL, the ULN for alkaline phosphatase, and the ULN for plasma iPTH (14-72 pg/mL). Alkaline phosphatase is shown as the percentage of the ULN for age and sex, and the ULN is labeled as 100%, calculated from the following normal ranges: girls aged 1 to 4 years, 317 U/L; girls aged 4 to 7 years, 297 U/L; girls aged 7 to 10 years, 325 U/L; girls aged 10 to 15 years, 300 U/L; boys aged 1 to 4 years, 383 U/L; boys aged 4 to 7 years, 345 U/L; boys aged 7 to 10 years, 309 U/L; and boys aged 10 to 15 years, 385 U/L. For PTH, the dashed line indicates the upper limit of the normal for range (14-72 pg/mL). 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; iPTH, intact parathyroid hormone; LLN, lower limit of normal; Pi/D, phosphate salts and active vitamin D; TmP/GFR, tubular maximum for phosphate reabsorption per glomerular filtration rate; ULN, upper limit of normal.

Figure 2.

Rickets, lower limb deformity, and growth evaluations in children younger than 5 and 5 years and older who received conventional therapy or burosumab. A, RGI-C rickets total score at study week 64. RGI-C scale: +3.0, complete healing; +2.0, substantial healing; +1.0, minimal healing; 0, unchanged. B, Total RSS at baseline and study week 64. C, RGI-C lower limb deformity score at study week 64. D, Least squares mean (SE) change from baseline to study weeks 24, 40, and 64 in standing height Z-score. LS, least squares; RGI-C, Radiographic Global Impression of Change; RSS, Rickets Severity Score. In panels A to C, diamonds indicate means, horizontal lines indicate medians with ranges, and empty circles indicate outliers.

Figure 3.

Knee radiographs showing rickets improvement in children younger than 5 and 5 years and older on conventional therapy or burosumab. Baseline and week 64 knee radiographs and total RSS scores in A, a 1.8-year-old girl who received Pi/D; B, a 1.0-year-old girl who received burosumab; C, an 11.9-year-old boy who received Pi/D;, and D, in a 12.5-year-old boy who received burosumab. Pi/D, phosphate salts and active vitamin D; RSS, Rickets Severity Score.

Figure 4.

Radiographs showing improvement in lower limb deformity in children younger than 5 and 5 years and older on conventional therapy or burosumab. Baseline and week 64 knee radiographs and baseline to week 64 RGI-C lower limb deformity scores of A, a 1.8-year-old girl who received Pai/D; B, a 1.0-year-old girl who received burosumab; C, a 11.9-year-old boy who received Pi/D; and D, a 12.5-year-old boy who received burosumab. Pi/D, phosphate salts and active vitamin D; RGI-C, Radiographic Global Impression of Change.