Elsevier

The Lancet

Volume 393, Issue 10189, 15–21 June 2019, Pages 2416-2427
The Lancet

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

https://doi.org/10.1016/S0140-6736(19)30654-3Get rights and content

Summary

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.

Introduction

X-linked hypophosphataemia, caused by loss-of-function mutations in the PHEX (phosphate-regulating endopeptidase homolog, X-linked) gene, is the most common genetic cause of rickets.1, 2 This disease is characterised by elevated concentrations of fibroblast growth factor 23 (FGF23) in the blood, leading to renal phosphate wasting, and decreased serum 1,25(OH)2D. Resulting hypophosphataemia and defective bone mineralisation cause rickets, osteomalacia, skeletal deformities, and short stature that persist into adulthood, along with impaired physical functioning and musculoskeletal pain.

Since the 1980s, conventional therapy for X-linked hypophosphataemia has entailed multiple daily doses of oral phosphate and one or more daily doses of active vitamin D.3, 4 This therapy is associated with variable improvement in clinical features of X-linked hypophosphataemia, and is complicated by safety risks, including nephrocalcinosis and hyperparathyroidism.1, 5 Conventional therapy can be burdensome, especially for children, with frequent dosing, gastrointestinal side-effects, and careful repeated monitoring so that appropriate dose adjustments can be made to avoid complications.

Research in context

Evidence before this study

X-linked hypophosphataemia, caused by loss-of-function mutations in the PHEX (phosphate-regulating endopeptidase homolog, X-linked) gene, is the most common heritable form of rickets and osteomalacia. X-linked hypophosphataemia is characterised by elevated circulating concentrations of fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting, decreased 1,25(OH)2D concentrations, skeletal deformities, impaired growth, and compromised physical functioning. Since the 1980s, conventional therapy for X-linked hypophosphataemia has consisted of multiple daily doses of oral phosphate and one or more daily doses of active vitamin D. Although this therapy might improve rickets and skeletal deformities, the response is variable. Often rickets and short stature persist, and some patients require surgical intervention for lower extremity deformities. Also, clinical complications of conventional therapy can include nephrocalcinosis and hyperparathyroidism. Burosumab, a fully human monoclonal antibody against FGF23, received approval from the US Food and Drug Administration and from Health Canada, and conditional marketing approval by the European Medicines Agency in 2018 for the treatment of X-linked hypophosphataemia (conditions of approval vary). Two paediatric, single-arm, phase 2 clinical trials have shown that inhibition of FGF23 with burosumab restores phosphate homeostasis, and improves rickets, growth, and mobility in affected 1–12-year-old children. Complications associated with conventional therapy such as nephrocalcinosis and hyperparathyroidism were not detected in those phase 2 paediatric trials of burosumab.

Added value of this study

This international, randomised, active-controlled, open-label, phase 3 trial is the first to compare the efficacy and safety of switching to burosumab versus continuing conventional therapy among 1–12-year-old children with X-linked hypophosphataemia. In this trial, burosumab resulted in greater radiographic improvement of rickets and lower extremity bowing, larger decreases in serum alkaline phosphatase activity, and greater increases in serum phosphorus, growth, and mobility than continuation of conventional therapy. These improvements occurred in children who switched from long-standing conventional therapy to burosumab, suggesting that burosumab offers a therapeutic advantage over conventional therapy. From a safety standpoint, no patient developed hyperphosphataemia or worsening nephrocalcinosis scores in either treatment group. There were no discontinuations from the study or treatment. Adverse events were more frequent with burosumab compared with conventional therapy, mostly driven by adverse events associated with injecting a subcutaneous therapeutic protein.

Implications of all the available evidence

This phase 3 trial presents the first comparison of conventional therapy with burosumab in children with X-linked hypophosphataemia, and showed the superiority of burosumab over continuation of conventional therapy for several clinical outcomes, including the correction of renal phosphate wasting. By improving rickets, long bone deformities, and linear growth, burosumab offers a promising new treatment approach for children with X-linked hypophosphataemia.

In 2018, burosumab (a fully human monoclonal antibody against FGF23) received approval from the US Food and Drug Administration and Health Canada, and received European Medicines Agency conditional marketing approval for the treatment of X-linked hypophosphataemia (approval conditions vary).6, 7 In a previous phase 2 trial in 5–12-year-old children with X-linked hypophosphataemia, burosumab normalised serum phosphorus concentrations, reduced rickets severity, and improved growth and physical functioning.8 Burosumab also increased serum phosphorus concentrations and improved rickets and lower extremity bowing in 1–4-year-old children with X-linked hypophosphataemia in another phase 2 trial.9 Both trials had an acceptable safety profile. Here, we present the results from the first active-controlled phase 3 trial comparing the efficacy and safety of continuing conventional therapy versus switching to burosumab in 1–12-year-old children with X-linked hypophosphataemia who had previously been treated with conventional therapy.

Section snippets

Study design

This open-label, randomised, active-controlled, phase 3 trial compared the efficacy and safety of burosumab with conventional therapy for X-linked hypophosphataemia. Eligible patients were randomly assigned to receive subcutaneous burosumab or conventional therapy at 16 clinical sites: five in the USA, three in Japan, three in Canada, two in the UK, one in Sweden, one in South Korea, and one in Australia. The clinical sites were academic health centres with substantial experience in treatment

Results

Recruitment took place between Aug 3, 2016, and May 8, 2017. Of the 122 patients screened, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) were randomly assigned to receive burosumab (figure 1). No patients discontinued treatment and all patients received at least one dose of treatment and therefore were included in the analyses.

Consistent with enrolment criteria and despite previous receipt of conventional therapy, patients

Discussion

We report the first randomised, active-controlled, phase 3 trial of burosumab in children with X-linked hypophosphataemia. Switching patients from conventional therapy to burosumab normalised phosphate homeostasis and improved rickets, serum alkaline phosphatase, growth, bowing, and mobility in 1–12-year-old children with X-linked hypophosphataemia. Although rickets and bowing assessments at week 40 and 64 showed some improvements with conventional therapy, improvements with burosumab were

Data sharing

Requests for individual de-identified participant data will be reviewed for at least 12 months after study completion to researchers providing methodologically sound proposals that are in accordance with our data sharing policy listed on the Ultragenyx Pharmaceutical website.

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