Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial

Abstract

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.

Funding: Ultragenyx Pharmaceutical and Kyowa Kirin International.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Trial Profile

The most common reason for screen failure was a total Rickets Severity Score PHEX mutation or variant of unknown significance in the patient or a family member with appropriate X-linked inheritance, height ≥50% based on country-specific norms, parathyroid hormone level > >19 pmol/L (180 pg/mL), unwilling to complete all aspects of the study, unwilling to provide consent/assent, insufficient duration of prior conventional therapy, serum creatinine above the age-adjusted reference range, and serum 25(OH)D <16 ng/mL. Patients could be ineligible for more than one reason.

Figure 2.. Improvement in Rickets Severity (Primary Endpoint) and Lower Limb Bowing

Data in panels A, B, and C are mean ± standard deviation. *paThe upper limit of normal for alkaline phosphatase varies by sex and age: females – 1–4 years-old 317 U/L, 4–7 years-old 297 U/L, 7–10 years-old 325 U/L, 10–15 years-old 300 U/L; Males – 1–4 years-old 383 U/L, 4–7 years-old 345 U/L, 7–10 years-old 309 U/L, 10–15 years-old 385 U/L (provided by Covance laboratories).

Figure 3.. Serum Phosphorus, TmP/GFR, and 1,25(OH)2D

Data are expressed as mean ± standard deviation; some post-baseline values are slightly offset from the actual treatment week to avoid overlapping error bars. Assessments at Weeks 1, 2, and 33 only occurred in the burosumab group to measure peak dose effect. Due to the difficulty of collecting urine samples from young children, the number of patients included in TmP/GFR assessments at different time points ranged from 27–30 for conventional therapy and 22–23 for burosumab. *paNormal (or target) ranges provided by Covance laboratories.

Figure 4.. Height and Mobility

Data are expressed as mean change from baseline ± standard deviation; some post-baseline values are slightly offset from the actual treatment week to avoid overlapping error bars. Recumbent length/standing height Z-score was assessed in all enrolled patients. 6MWT was assessed in patients >5 years-old and able to complete the test (conventional therapy n=20, burosumab n=13). *p