Burosumab Therapy in Children with X-Linked Hypophosphatemia

Carpenter, Thomas O.; Whyte, Michael P.; Imel, Erik A.; Boot, Annemieke M.; Högler, Wolfgang; Linglart, Agnès; Padidela, Raja; Hoff, William van’t; Mao, Meng; Chen, Chao Yin; Skrinar, Alison; Kakkis, Emil; Martín, Javier San; Portale, Anthony A.

doi:10.1056/nejmoa1714641

Cited by 396 publications

(394 citation statements)

References 35 publications

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“…In adults with XLH, chronic hypophosphatemia leads to osteomalacia, fractures, pain, stiffness, decreased mobility, and an impaired quality of life. Burosumab, a monoclonal antibody against FGF23 approved for the treatment of XLH, was shown to reverse hypophosphatemia and improve clinical outcomes in both children and adults with XLH . Consistent with those published studies, the current study in adults with XLH demonstrates that 48 weeks of burosumab treatment restores phosphorus homeostasis.…”

Section: Discussionsupporting

confidence: 87%

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial

Insogna

Rauch

Kamenický

et al. 2019

Journal of Bone and Mineral Research

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102

121

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In adults with X‐linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25‐dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023‐CL304 is an ongoing, open‐label, single‐arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia‐related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, –54%, osteoid thickness, –32%, osteoid surface/bone surface, –26%, [median] mineralization lag time, –83%). Mean serum phosphorus concentration averaged across the mid‐point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment‐emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure‐related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

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Section: Discussionsupporting

confidence: 87%

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial

Insogna

Rauch

Kamenický

et al. 2019

Journal of Bone and Mineral Research

Self Cite

102

121

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“…Similar peak and trough effects occur during repeated dosing. However, with long‐term repeated dosing, the magnitude of that peak in 1,25(OH) 2 D lessens, while the peak effect on phosphate generally persists . This 1,25(OH) 2 D effect suggests that vitamin D activation is being suppressed in the pretreatment state by high FGF23 concentrations but that the cellular machinery is in place to support a rapid switch to producing 1,25(OH) 2 D. This is consistent with studies in the XLH mouse model indicating that despite high FGF23, the gene expression for the enzyme 1‐alpha hydroxylase is actually increased compared with normal mice, but the expression of the protein itself and its enzyme activity are lower than normal due to posttranscriptional or posttranslational effects .…”

Section: Therapeutic Potential Of Burosumab a Neutralizing Anti‐fgf2supporting

confidence: 78%

“…Notably, an effect found in these initial trials and in all subsequent published burosumab trials in XLH to date was that a very high peak in serum 1,25(OH) 2 D occurs approximately 3 to 7 days after the first few s.c. doses . Similar peak and trough effects occur during repeated dosing.…”

Section: Therapeutic Potential Of Burosumab a Neutralizing Anti‐fgf2mentioning

confidence: 66%

“…During this burosumab trial, improvements were also demonstrated in patient‐reported outcomes including physical functioning and stiffness scores using the Western Ontario and McMaster Osteoarthritis Index (WOMAC) scale . These improvements were generally supported by improvements in patient‐reported outcomes and functional outcomes in subsequent trials in children and adults …”

Section: Therapeutic Potential Of Burosumab a Neutralizing Anti‐fgf2mentioning

confidence: 75%

“…Two key trials were published in 2018. A phase 2 randomized open‐label trial in 52 children aged 5 to 12 years compared second weekly (Q2W) and Q4W dosing in subjects previously treated with phosphate and active vitamin D analogs . All the children stopped phosphate and vitamin D to receive burosumab.…”

Section: Therapeutic Potential Of Burosumab a Neutralizing Anti‐fgf2mentioning

confidence: 99%

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FGF23, Hypophosphatemia, and Emerging Treatments

2019

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FGF23 is an important hormonal regulator of phosphate homeostasis. Together with its co‐receptor Klotho, it modulates phosphate reabsorption and both 1α‐hydroxylation and 24‐hydroxylation in the renal proximal tubules. The most common FGF23‐mediated hypophosphatemia is X‐linked hypophosphatemia (XLH), caused by mutations in the PHEX gene. FGF23‐mediated forms of hypophosphatemia are characterized by phosphaturia and low or low‐normal calcitriol concentrations, and unlike nutritional rickets, these cannot be cured with nutritional vitamin D supplementation. Autosomal dominant and autosomal recessive forms of FGF23‐mediated hypophosphatemias show a similar pathophysiology, despite a variety of different underlying genetic causes. An excess of FGF23 activity has also been associated with a number of other conditions causing hypophosphatemia, including tumor‐induced osteomalacia, fibrous dysplasia of the bone, and cutaneous skeletal hypophosphatemia syndrome. Historically phosphate supplementation and therapy using analogs of highly active vitamin D (eg, calcitriol, alfacalcidol, paricalcitol, eldecalcitol) have been used to manage conditions involving hypophosphatemia; however, recently a neutralizing antibody for FGF23 (burosumab) has emerged as a promising treatment agent for FGF23‐mediated disorders. This review discusses the progression of clinical trials for burosumab for the treatment of XLH and its recent availability for clinical use. Burosumab may have potential for treating other conditions associated with FGF23 overactivity, but these are not yet supported by trial data. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

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A PAI‐1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D‐resistant rickets model mouse

Qian,

Ito,

Tsuji

et al. 2023

FEBS Open Bio

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Congenital fibroblast growth factor 23 (FGF23)‐related hypophosphatemic rickets/osteomalacia is a rare bone metabolism disorder characterized by hypophosphatemia and caused by genetic abnormalities that result in excessive secretion of FGF23. Hyp mice are a model of X‐linked hypophosphatemia (XLH) caused by deletion of the PHEX gene and excessive production of FGF23. The purpose of this study was to investigate the potential of TM5614 as a therapeutic agent for the treatment of congenital FGF23‐related hypophosphatemic rickets and osteomalacia in humans by administering TM5614 to Hyp mice and examining its curative effect on hypophosphatemia. After a single oral administration of TM5614 10 mg·kg−1 to female Hyp mice starting at 17 weeks of age, the serum phosphate concentration increased with a peak at 6 h after administration. ELISA confirmed that TM5614 administration decreased the intact FGF23 concentration in the blood. Expression of 25‐hydroxyvitamin D‐1α‐hydroxylase protein encoded by Cyp27b1 mRNA in the kidney was suppressed in Hyp mice, and treatment with 10 mg·kg−1 of TM5614 normalized the expression of 25‐hydroxyvitamin D‐1α‐hydroxylase protein and Cyp27b1 mRNA in the kidneys of these mice. Our data indicate that oral administration of TM5614 ameliorates hypophosphatemia in Hyp mice, suggesting that TM5614 may be an effective treatment for congenital FGF23‐related hypophosphatemic rickets and osteomalacia.

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Burosumab Therapy in Children with X-Linked Hypophosphatemia

Cited by 396 publications

References 35 publications

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial

FGF23, Hypophosphatemia, and Emerging Treatments

A PAI‐1 antagonist ameliorates hypophosphatemia in the Hyp vitamin D‐resistant rickets model mouse

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