Effect of Burosumab Compared With Conventional Therapy on Younger vs Older Children With X-linked Hypophosphatemia

Leanne M Ward, Francis H Glorieux, Michael P Whyte, Craig F Munns, Anthony A Portale, Wolfgang Högler, Jill H Simmons, Gary S Gottesman, Raja Padidela, Noriyuki Namba, Hae Il Cheong, Ola Nilsson, Meng Mao, Angel Chen, Alison Skrinar, Mary Scott Roberts, Erik A Imel, Leanne M Ward, Francis H Glorieux, Michael P Whyte, Craig F Munns, Anthony A Portale, Wolfgang Högler, Jill H Simmons, Gary S Gottesman, Raja Padidela, Noriyuki Namba, Hae Il Cheong, Ola Nilsson, Meng Mao, Angel Chen, Alison Skrinar, Mary Scott Roberts, Erik A Imel

Abstract

Context: Younger age at treatment onset with conventional therapy (phosphate salts and active vitamin D; Pi/D) is associated with improved growth and skeletal outcomes in children with X-linked hypophosphatemia (XLH). The effect of age on burosumab efficacy and safety in XLH is unknown.

Objective: This work aimed to explore the efficacy and safety of burosumab vs Pi/D in younger (< 5 years) and older (5-12 years) children with XLH.

Methods: This post hoc analysis of a 64-week, open-label, randomized controlled study took place at 16 academic centers. Sixty-one children aged 1 to 12 years with XLH (younger, n = 26; older, n = 35) participated. Children received burosumab starting at 0.8 mg/kg every 2 weeks (younger, n = 14; older, n = 15) or continued Pi/D individually titrated per recommended guidelines (younger, n = 12; older, n = 20). The main outcome measure included the least squares means difference (LSMD) in Radiographic Global Impression of Change (RGI-C) rickets total score from baseline to week 64.

Results: The LSMD in outcomes through 64 weeks on burosumab vs conventional therapy by age group were as follows: RGI-C rickets total score (younger, +0.90; older, +1.07), total Rickets Severity Score (younger, -0.86; older, -1.44), RGI-C lower limb deformity score (younger, +1.02; older, +0.91), recumbent length or standing height Z-score (younger, +0.20; older, +0.09), and serum alkaline phosphatase (ALP) (younger, -31.15% of upper normal limit [ULN]; older, -52.11% of ULN). On burosumab, dental abscesses were not reported in younger children but were in 53% of older children.

Conclusion: Burosumab appears to improve outcomes both in younger and older children with XLH, including rickets, lower limb deformities, growth, and ALP, compared with Pi/D.

Trial registration: ClinicalTrials.gov NCT02915705.

Keywords: X-linked hypophosphatemia; burosumab; children; fibroblast growth factor 23; rickets.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.
Figure 1.
Mean (SD) A, serum phosphorus; B, TmP/GFR; C, 1,25(OH)2D; D, 25(OH)D; E, alkaline phosphatase; and F, plasma iPTH from study weeks 0 to 64 in children younger than 5 and aged 5 years and older who received Pi/D or burosumab every 2 weeks. Dashed lines indicate the LLN for serum phosphorus (3.2-6.1 mg/dL), TmP/GFR (3.4-5.8 mg/dL), the LLN and ULN for 1,25(OH)2D (25.8-101.5 pg/mL), the 25(OH)D status benchmarked to 20 ng/mL, the ULN for alkaline phosphatase, and the ULN for plasma iPTH (14-72 pg/mL). Alkaline phosphatase is shown as the percentage of the ULN for age and sex, and the ULN is labeled as 100%, calculated from the following normal ranges: girls aged 1 to 4 years, 317 U/L; girls aged 4 to 7 years, 297 U/L; girls aged 7 to 10 years, 325 U/L; girls aged 10 to 15 years, 300 U/L; boys aged 1 to 4 years, 383 U/L; boys aged 4 to 7 years, 345 U/L; boys aged 7 to 10 years, 309 U/L; and boys aged 10 to 15 years, 385 U/L. For PTH, the dashed line indicates the upper limit of the normal for range (14-72 pg/mL). 1,25(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvitamin D; iPTH, intact parathyroid hormone; LLN, lower limit of normal; Pi/D, phosphate salts and active vitamin D; TmP/GFR, tubular maximum for phosphate reabsorption per glomerular filtration rate; ULN, upper limit of normal.
Figure 2.
Figure 2.
Rickets, lower limb deformity, and growth evaluations in children younger than 5 and 5 years and older who received conventional therapy or burosumab. A, RGI-C rickets total score at study week 64. RGI-C scale: +3.0, complete healing; +2.0, substantial healing; +1.0, minimal healing; 0, unchanged. B, Total RSS at baseline and study week 64. C, RGI-C lower limb deformity score at study week 64. D, Least squares mean (SE) change from baseline to study weeks 24, 40, and 64 in standing height Z-score. LS, least squares; RGI-C, Radiographic Global Impression of Change; RSS, Rickets Severity Score. In panels A to C, diamonds indicate means, horizontal lines indicate medians with ranges, and empty circles indicate outliers.
Figure 3.
Figure 3.
Knee radiographs showing rickets improvement in children younger than 5 and 5 years and older on conventional therapy or burosumab. Baseline and week 64 knee radiographs and total RSS scores in A, a 1.8-year-old girl who received Pi/D; B, a 1.0-year-old girl who received burosumab; C, an 11.9-year-old boy who received Pi/D;, and D, in a 12.5-year-old boy who received burosumab. Pi/D, phosphate salts and active vitamin D; RSS, Rickets Severity Score.
Figure 4.
Figure 4.
Radiographs showing improvement in lower limb deformity in children younger than 5 and 5 years and older on conventional therapy or burosumab. Baseline and week 64 knee radiographs and baseline to week 64 RGI-C lower limb deformity scores of A, a 1.8-year-old girl who received Pai/D; B, a 1.0-year-old girl who received burosumab; C, a 11.9-year-old boy who received Pi/D; and D, a 12.5-year-old boy who received burosumab. Pi/D, phosphate salts and active vitamin D; RGI-C, Radiographic Global Impression of Change.

References

    1. Carpenter TO, Shaw NJ, Portale AA, Ward LM, Abrams SA, Pettifor JM. Rickets. Nat Rev Dis Primers. 2017;3:17101.
    1. Gohil A, Imel EA. FGF23 and associated disorders of phosphate wasting. Pediatr Endocrinol Rev. 2019;17(1):17-34.
    1. Mao M, Carpenter TO, Whyte MP, et al. . Growth curves for children with X-linked hypophosphatemia. J Clin Endocrinol Metab. 2020;105(10):3243-3249.
    1. Carpenter TO. New perspectives on the biology and treatment of X-linked hypophosphatemic rickets. Pediatr Clin North Am. 1997;44(2):443-466.
    1. Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26(7):1381-1388.
    1. Linglart A, Biosse-Duplan M, Briot K, et al. . Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3(1):R13-R30.
    1. Connor J, Olear EA, Insogna KL, et al. . Conventional therapy in adults with X-linked hypophosphatemia: effects on enthesopathy and dental disease. J Clin Endocrinol Metab. 2015;100(10): 3625-3632.
    1. Beck-Nielsen SS, Mughal Z, Haffner D, et al. . FGF23 and its role in X-linked hypophosphatemia-related morbidity. Orphanet J Rare Dis. 2019;14(1):58.
    1. Imel EA, Glorieux FH, Whyte MP, et al. . Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019;393(10189):2416-2427.
    1. Mäkitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88(8):3591-3597.
    1. Quinlan C, Guegan K, Offiah A, et al. . Growth in PHEX-associated X-linked hypophosphatemic rickets: the importance of early treatment. Pediatr Nephrol. 2012;27(4):581-588.
    1. Verge CF, Lam A, Simpson JM, Cowell CT, Howard NJ, Silink M. Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med. 1991;325(26):1843-1848.
    1. Whyte MP, Fujita KP, Moseley S, Thompson DD, McAlister WH. Validation of a novel scoring system for changes in skeletal manifestations of hypophosphatasia in newborns, infants, and children: the radiographic global impression of change scale. J Bone Miner Res. 2018;33(5): 868-874.
    1. Thacher TD, Pettifor JM, Tebben PJ, et al. . Rickets severity predicts clinical outcomes in children with X-linked hypophosphatemia: utility of the radiographic Rickets Severity Score. Bone. 2019;122:76-81.
    1. Chanakul A, Zhang MYH, Louw A, et al. . FGF-23 regulates CYP27B1 transcription in the kidney and in extra-renal tissues. PLoS One. 2013;8(9):e72816.
    1. Shimada T, Hasegawa H, Yamazaki Y, et al. . FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res. 2004;19(3):429-435.
    1. Carpenter TO, Whyte MP, Imel EA, et al. . Burosumab therapy in children with X-linked hypophosphatemia. N Engl J Med. 2018;378(21):1987-1998.
    1. Whyte MP, Carpenter TO, Gottesman GS, et al. . Efficacy and safety of burosumab in children aged 1-4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial. Lancet Diabetes Endocrinol. 2019;7(3):189-199.
    1. Insogna KL, Briot K, Imel EA, et al. ; AXLES 1 Investigators. A randomized, double-blind, placebo-controlled, phase 3 trial evaluating the efficacy of burosumab, an anti-FGF23 antibody, in adults with X-linked hypophosphatemia: week 24 primary analysis. J Bone Miner Res. 2018;33(8):1383-1393.
    1. Insogna KL, Rauch F, Kamenický P, et al. . Burosumab improved histomorphometric measures of osteomalacia in adults with X-linked hypophosphatemia: a phase 3, single-arm, international trial. J Bone Miner Res. 2019;34(12):2183-2191.
    1. McKee MD, Hoac B, Addison WN, Barros NMT, Millán JL, Chaussain C. Extracellular matrix mineralization in periodontal tissues: noncollagenous matrix proteins, enzymes, and relationship to hypophosphatasia and X-linked hypophosphatemia. Periodontol 2000. 2013;63(1):102-122.
    1. Coyac BR, Falgayrac G, Penel G, et al. . Impaired mineral quality in dentin in X-linked hypophosphatemia. Connect Tissue Res. 2018;59(Suppl 1):91-96.
    1. Salmon B, Bardet C, Coyac BR, et al. . Abnormal osteopontin and matrix extracellular phosphoglycoprotein localization, and odontoblast differentiation, in X-linked hypophosphatemic teeth. Connect Tissue Res. 2014;55(Suppl 1):79-82.
    1. Dahir K, Roberts MS, Krolczyk S, Simmons JH. X-linked hypophosphatemia: a new era in management. J Endocr Soc. 2020;4(12):bvaa151.

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