TY - JOUR
T1 - Burosumab versus conventional therapy in children with X-linked hypophosphataemia
T2 - a randomised, active-controlled, open-label, phase 3 trial
AU - Imel, Erik A.
AU - Glorieux, Francis H.
AU - Whyte, Michael P.
AU - Munns, Craig F.
AU - Ward, Leanne M.
AU - Nilsson, Ola
AU - Simmons, Jill H.
AU - Padidela, Raja
AU - Namba, Noriyuki
AU - Cheong, Hae Il
AU - Pitukcheewanont, Pisit
AU - Sochett, Etienne
AU - Högler, Wolfgang
AU - Muroya, Koji
AU - Tanaka, Hiroyuki
AU - Gottesman, Gary S.
AU - Biggin, Andrew
AU - Perwad, Farzana
AU - Mao, Meng
AU - Chen, Chao Yin
AU - Skrinar, Alison
AU - San Martin, Javier
AU - Portale, Anthony A.
N1 - Funding Information:
The following authors served as clinical investigators for one or more studies (including this study) sponsored by Ultragenyx Pharmaceutical in partnership with Kyowa Kirin International: EAI, FHG, MPW, CFM, LMW, ON, JHS, RP, NN, HIC, PP, ES, WH, KM, HT, GSG, AB, FP, and AAP. EAI, LMW, NN, FP, and AAP have received honoraria for serving as an advisory board member or for lectures from Ultragenyx Pharmaceutical. WH has received honoraria, consulting fees, and travel support from Ultragenyx Pharmaceutical and research funding, honoraria, and travel support from Kyowa Kirin International. RP has received personal fees from Ultragenyx Pharmaceutical and Kyowa Kirin International, as well as non-financial support from Kyowa Kirin Interational. PP has received research funding from Amgen and Shire and is an employee of Ascendis Pharma (as of May 1, 2019). FHG has received research funding from Amgen and Mereo-Biopharma. MPW has received research grants from Ultragenyx Pharmaceutical. GSG has received consulting fees from Ultragenyx Pharmaceutical. MM, AS, and JSM are employees and stockholders of Ultragenyx Pharmaceutical (as of May 1, 2019) and C-YC was an employee and stockholder (until April 19, 2019). JSM is the co-inventor of a patent application with Ultragenyx Pharmaceutical.
Funding Information:
At Birmingham Children's Hospital, the research was done at the National Institute for Health Research/Wellcome Trust Clinical Research Facility. The views expressed are those of the authors and not necessarily those of the National Health Service, the National Institute for Health Research, or the Department of Health. At Indiana University, the research was done at the Indiana Clinical and Translational Sciences Institute, funded in part by UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical and Translational Sciences Award. The content of this Article is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Catherine Woods, an employee of Ultragenyx Pharmaceutical, provided medical writing support. We thank the patients, their families, and study site personnel who made the clinical trial possible: Tom Thacher, Anna Frid, Marian Hart, Valerie Wollberg, Vinieth N Bijanki, Amy Reeves, Nasrin Khan, Lynn MacLeay, Marika Page, Vrinda Saraff, Nick Shaw, Melissa Fang, Julie Kwon, Daniel Schrader, Erfan Jaberiyanfar, Margo Black, and Michaela Durigova.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/6/15
Y1 - 2019/6/15
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85067187146&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(19)30654-3
DO - 10.1016/S0140-6736(19)30654-3
M3 - Article
C2 - 31104833
AN - SCOPUS:85067187146
VL - 393
SP - 2416
EP - 2427
JO - The Lancet
JF - The Lancet
SN - 0140-6736
IS - 10189
ER -