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Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial
Department of Medicine and Department of Pediatrics, Indiana University School of Medicine, Indianapolis IN, USA.
Shriners Hospital for Children — Canada, McGill University, Montreal QC, Canada.
Shriners Hospitals for Children — St Louis, St Louis MO, USA.
The University of Sydney Children's Hospital Westmead Clinical School, The Children's Hospital at Westmead, Westmead, NSW, Australia; Department of Endocrinology, The Children's Hospital at Westmead, Westmead NSW, Australia.
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2019 (English)In: The Lancet, ISSN 0140-6736, E-ISSN 1474-547X, Vol. 393, no 10189, p. 2416-2427Article in journal (Refereed) Published
Abstract [en]

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 endopep-tidase 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. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Place, publisher, year, edition, pages
Elsevier, 2019. Vol. 393, no 10189, p. 2416-2427
National Category
General Practice Pediatrics
Identifiers
URN: urn:nbn:se:oru:diva-75226DOI: 10.1016/S0140-6736(19)30654-3ISI: 000471758200039PubMedID: 31104833Scopus ID: 2-s2.0-85067187146OAI: oai:DiVA.org:oru-75226DiVA, id: diva2:1339149
Note

Funding Agencies:Ultragenyx Pharmaceutical  

Kyowa Kirin International  

Available from: 2019-07-26 Created: 2019-07-26 Last updated: 2019-07-26Bibliographically approved

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