Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period

Abstract

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.

Keywords: FGF23; burosumab; phosphate; rare disease; x-linked hypophosphatemia.

Graphical Abstract

Figure 1

Disposition through week 88 of the extension period.

Figure 2

Rickets and bone health evaluations in children with available radiographic assessments through week 88. (A) RGI-C rickets total score at weeks 40, 64, and 88. (B) Total RSS at baseline and weeks 40, 64, and 88. (C) RGI-C lower limb deformity score at weeks 40, 64, and 88. RSS, Rickets Severity Score.

Figure 3

Knee radiographs showing rickets improvement with burosumab treatment. Shown are knee RSS scores and radiographs at baseline and at weeks 40, 64, and 88 in a 2.9-year-old girl in the burosumab continuation group (A) and in a 3.5-year-old girl in the conventional therapy to burosumab crossover group (B). RSS, Rickets Severity Score.

Figure 4

Radiographs showing improvement in lower limb deformity with burosumab treatment. Shown is the lower limb deformity RGI-C at baseline and at weeks 40, 64, and 88 in a 2.9-year-old girl in the burosumab continuation group (A) and in a 3.5-year-old girl in the conventional therapy to burosumab crossover group (B). LLD, lower limb deformity; NA, not applicable; RGI-C, Radiographic Global Impression of Change.

Figure 5

Mean (SD) serum alkaline phosphatase (A), serum phosphorus (B), TmP/GFR (C), serum 1,25(OH)₂D (D), serum 25(OH)D (E), and plasma intact parathyroid hormone (F) in children with available radiographic assessments through week 88. Dashed lines indicate the upper limit of normal for alkaline phosphatase, the lower limit of normal for serum phosphorus (3.2–6.1 mg/dL), the lower limit of normal for TmP/GFR (3.4–5.8 mg/dL), the lower and upper limits of normal for serum 1,25(OH)₂D (25.8–101.5 pg/mL), the 25(OH)D status benchmarked to 20 ng/mL, and the lower and upper limits of normal for serum intact parathyroid hormone (14.0–72.0 pg/mL). Alkaline phosphatase is shown as the percent of ULN for age and sex, and the ULN is labeled as 100%, calculated from the following normal ranges: girls 1–4 years, 317 U/L; girls 4–7 years, 297 U/L; girls 7–10 years, 325 U/L; girls 10–15 years, 300 U/L; boys 1–4 years, 383 U/L; boys 4–7 years, 345 U/L; boys 7–10 years, 309 U/L; and boys 10–15 years, 385 U/L. For iPTH, the dashed line indicates the upper limit of the normal range (14–72 pg/mL). 1,25(OH)₂D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; AP, alkaline phosphatase; iPTH, intact parathyroid hormone; TmP/GFR, tubular maximum for phosphate reabsorption per glomerular filtration rate.

Figure 6

Mean (SD) change from baseline to 88 in recumbent length and standing height Z-score (A), growth velocity Z-score (B), and the percentage of predicted distance walked in the 6MWT (C). 6MWT, 6-minute walk test.