Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period

Leanne M Ward; Wolfgang Högler; Francis H Glorieux; Anthony A Portale; Michael P Whyte; Craig F Munns; Ola Nilsson; Jill H Simmons; Raja Padidela; Noriyuki Namba; Hae Il Cheong; Etienne Sochett; Koji Muroya; Hiroyuki Tanaka; Pisit Pitukcheewanont; Gary S Gottesman; Andrew Biggin; Farzana Perwad; Angel Chen; John Lawrence Merritt II; Erik A Imel

doi:10.1093/jbmrpl/ziad001

Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period

Leanne M Ward^*, Wolfgang Högler, Francis H Glorieux, Anthony A Portale, Michael P Whyte, Craig F Munns, Ola Nilsson, Jill H Simmons, Raja Padidela, Noriyuki Namba, Hae Il Cheong, Etienne Sochett, Koji Muroya, Hiroyuki Tanaka, Pisit Pitukcheewanont, Gary S Gottesman, Andrew Biggin, Farzana Perwad, Angel Chen, John Lawrence Merritt IIErik A Imel

^*Corresponding author for this work

Metabolism and Systems Research

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Abstract

In a randomized, open-label phase 3 study of 61 children aged 1–12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64–88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.

Original language	English
Article number	ziad001
Number of pages	14
Journal	JBMR Plus
Volume	8
Issue number	1
DOIs	https://doi.org/10.1093/jbmrpl/ziad001
Publication status	Published - 4 Jan 2024

Bibliographical note

Funding:
This study was sponsored and funded by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc. Medical writing support was provided by Ben Scott, PhD (Scott Medical Communications, LLC) and was funded by Ultragenyx Pharmaceutical Inc. Additional editorial support was provided by Jamie Ziobro, an employee and shareholder of Ultragenyx Pharmaceutical Inc. 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. In Montreal and St. Louis, the work was also supported by the Shriners of North America. Dr. Ward is supported by a Tier 1 (Senior) Research Chair in Pediatric Bone Disorders from the University of Ottawa and Children’s Hospital of Eastern Ontario Research Institute. 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.

Keywords

burosumab
FGF23
x-linked hypophosphatemia
rare disease
phosphate

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Ward, L. M., Högler, W., Glorieux, F. H., Portale, A. A., Whyte, M. P., Munns, C. F., Nilsson, O., Simmons, J. H., Padidela, R., Namba, N., Cheong, H. I., Sochett, E., Muroya, K., Tanaka, H., Pitukcheewanont, P., Gottesman, G. S., Biggin, A., Perwad, F., Chen, A., ... Imel, E. A. (2024). Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period. JBMR Plus, 8(1), Article ziad001. https://doi.org/10.1093/jbmrpl/ziad001

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title = "Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period",

abstract = "In a randomized, open-label phase 3 study of 61 children aged 1–12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64–88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.",

keywords = "burosumab, FGF23, x-linked hypophosphatemia, rare disease, phosphate",

author = "Ward, {Leanne M} and Wolfgang H{\"o}gler and Glorieux, {Francis H} and Portale, {Anthony A} and Whyte, {Michael P} and Munns, {Craig F} and Ola Nilsson and Simmons, {Jill H} and Raja Padidela and Noriyuki Namba and Cheong, {Hae Il} and Etienne Sochett and Koji Muroya and Hiroyuki Tanaka and Pisit Pitukcheewanont and Gottesman, {Gary S} and Andrew Biggin and Farzana Perwad and Angel Chen and {Lawrence Merritt II}, John and Imel, {Erik A}",

note = "Funding: This study was sponsored and funded by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc. Medical writing support was provided by Ben Scott, PhD (Scott Medical Communications, LLC) and was funded by Ultragenyx Pharmaceutical Inc. Additional editorial support was provided by Jamie Ziobro, an employee and shareholder of Ultragenyx Pharmaceutical Inc. 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. In Montreal and St. Louis, the work was also supported by the Shriners of North America. Dr. Ward is supported by a Tier 1 (Senior) Research Chair in Pediatric Bone Disorders from the University of Ottawa and Children{\textquoteright}s Hospital of Eastern Ontario Research Institute. 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.",

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doi = "10.1093/jbmrpl/ziad001",

language = "English",

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Ward, LM, Högler, W, Glorieux, FH, Portale, AA, Whyte, MP, Munns, CF, Nilsson, O, Simmons, JH, Padidela, R, Namba, N, Cheong, HI, Sochett, E, Muroya, K, Tanaka, H, Pitukcheewanont, P, Gottesman, GS, Biggin, A, Perwad, F, Chen, A, Lawrence Merritt II, J & Imel, EA 2024, 'Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period', JBMR Plus, vol. 8, no. 1, ziad001. https://doi.org/10.1093/jbmrpl/ziad001

TY - JOUR

T1 - Burosumab vs conventional therapy in children with X-linked hypophosphatemia

T2 - results of the open-label, phase 3 extension period

AU - Ward, Leanne M

AU - Högler, Wolfgang

AU - Glorieux, Francis H

AU - Portale, Anthony A

AU - Whyte, Michael P

AU - Munns, Craig F

AU - Nilsson, Ola

AU - Simmons, Jill H

AU - Padidela, Raja

AU - Namba, Noriyuki

AU - Cheong, Hae Il

AU - Sochett, Etienne

AU - Muroya, Koji

AU - Tanaka, Hiroyuki

AU - Pitukcheewanont, Pisit

AU - Gottesman, Gary S

AU - Biggin, Andrew

AU - Perwad, Farzana

AU - Chen, Angel

AU - Lawrence Merritt II, John

AU - Imel, Erik A

N1 - Funding: This study was sponsored and funded by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc. Medical writing support was provided by Ben Scott, PhD (Scott Medical Communications, LLC) and was funded by Ultragenyx Pharmaceutical Inc. Additional editorial support was provided by Jamie Ziobro, an employee and shareholder of Ultragenyx Pharmaceutical Inc. 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. In Montreal and St. Louis, the work was also supported by the Shriners of North America. Dr. Ward is supported by a Tier 1 (Senior) Research Chair in Pediatric Bone Disorders from the University of Ottawa and Children’s Hospital of Eastern Ontario Research Institute. 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.

PY - 2024/1/4

Y1 - 2024/1/4

N2 - In a randomized, open-label phase 3 study of 61 children aged 1–12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64–88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.

AB - In a randomized, open-label phase 3 study of 61 children aged 1–12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64–88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.

KW - burosumab

KW - FGF23

KW - x-linked hypophosphatemia

KW - rare disease

KW - phosphate

U2 - 10.1093/jbmrpl/ziad001

DO - 10.1093/jbmrpl/ziad001

M3 - Article

SN - 2473-4039

VL - 8

JO - JBMR Plus

JF - JBMR Plus

IS - 1

M1 - ziad001

ER -

Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period

Abstract

Bibliographical note

Keywords

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