Burosumab versus conventional therapy in children with X-linked hypophosphataemia

a randomised, active-controlled, open-label, phase 3 trial

Erik Imel, Francis H. Glorieux, Michael P. Whyte, Craig F. Munns, Leanne M. Ward, Ola Nilsson, Jill H. Simmons, Raja Padidela, Noriyuki Namba, Hae Il Cheong, Pisit Pitukcheewanont, Etienne Sochett, Wolfgang Högler, Koji Muroya, Hiroyuki Tanaka, Gary S. Gottesman, Andrew Biggin, Farzana Perwad, Meng Mao, Chao Yin Chen & 3 others Alison Skrinar, Javier San Martin, Anthony A. Portale

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2416-2427
Number of pages12
JournalThe Lancet
Volume393
Issue number10189
DOIs
StatePublished - Jun 15 2019

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Rickets
Group Psychotherapy
Therapeutics
PHEX Phosphate Regulating Neutral Endopeptidase
Research Personnel
Safety
X-Linked Genes
Growth
Least-Squares Analysis
Serum
Vitamin D
Biochemistry
Phosphorus
Lower Extremity
Fasting
Phosphates
Monoclonal Antibodies
Pediatrics
Mutation
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Burosumab versus conventional therapy in children with X-linked hypophosphataemia : a randomised, active-controlled, open-label, phase 3 trial. / Imel, Erik; Glorieux, Francis H.; Whyte, Michael P.; Munns, Craig F.; Ward, Leanne M.; Nilsson, Ola; Simmons, Jill H.; Padidela, Raja; Namba, Noriyuki; Cheong, Hae Il; Pitukcheewanont, Pisit; Sochett, Etienne; Högler, Wolfgang; Muroya, Koji; Tanaka, Hiroyuki; Gottesman, Gary S.; Biggin, Andrew; Perwad, Farzana; Mao, Meng; Chen, Chao Yin; Skrinar, Alison; San Martin, Javier; Portale, Anthony A.

In: The Lancet, Vol. 393, No. 10189, 15.06.2019, p. 2416-2427.

Research output: Contribution to journalArticle

Imel, E, Glorieux, FH, Whyte, MP, Munns, CF, Ward, LM, Nilsson, O, Simmons, JH, Padidela, R, Namba, N, Cheong, HI, Pitukcheewanont, P, Sochett, E, Högler, W, Muroya, K, Tanaka, H, Gottesman, GS, Biggin, A, Perwad, F, Mao, M, Chen, CY, Skrinar, A, San Martin, J & Portale, AA 2019, 'Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial', The Lancet, vol. 393, no. 10189, pp. 2416-2427. https://doi.org/10.1016/S0140-6736(19)30654-3
Imel, Erik ; Glorieux, Francis H. ; Whyte, Michael P. ; Munns, Craig F. ; Ward, Leanne M. ; Nilsson, Ola ; Simmons, Jill H. ; Padidela, Raja ; Namba, Noriyuki ; Cheong, Hae Il ; Pitukcheewanont, Pisit ; Sochett, Etienne ; Högler, Wolfgang ; Muroya, Koji ; Tanaka, Hiroyuki ; Gottesman, Gary S. ; Biggin, Andrew ; Perwad, Farzana ; Mao, Meng ; Chen, Chao Yin ; Skrinar, Alison ; San Martin, Javier ; Portale, Anthony A. / Burosumab versus conventional therapy in children with X-linked hypophosphataemia : a randomised, active-controlled, open-label, phase 3 trial. In: The Lancet. 2019 ; Vol. 393, No. 10189. pp. 2416-2427.
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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.",
author = "Erik Imel and Glorieux, {Francis H.} and Whyte, {Michael P.} and Munns, {Craig F.} and Ward, {Leanne M.} and Ola Nilsson and Simmons, {Jill H.} and Raja Padidela and Noriyuki Namba and Cheong, {Hae Il} and Pisit Pitukcheewanont and Etienne Sochett and Wolfgang H{\"o}gler and Koji Muroya and Hiroyuki Tanaka and Gottesman, {Gary S.} and Andrew Biggin and Farzana Perwad and Meng Mao and Chen, {Chao Yin} and Alison Skrinar and {San Martin}, Javier and Portale, {Anthony A.}",
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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

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.

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.

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