Clinical Evidence for the Benefits of Burosumab Therapy for X-Linked Hypophosphatemia (XLH) and Other Conditions in Adults and Children

Biggin, Andrew; Munns, Craig F

doi:10.3389/fendo.2020.00338

Cited by 45 publications

(42 citation statements)

References 24 publications

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“…Accordingly, amelioration of phosphate availability has been regarded as the main therapeutic principle. With availability of Fibroblast-like Growth Factor 23 (FGF23) inhibiting therapies, normalization of phosphate levels can be achieved in most patients with profound improvement of rickets ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Persistent Lower Limb Deformities Despite Amelioration of Rickets in X-Linked Hypophosphatemia (XLH) - A Prospective Observational Study

et al. 2022

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BackgroundGait deviations, lower limb pain and joint stiffness represent key symptoms in patients with X-linked hypophosphatemia (XLH, OMIM 307800), a rare disorder of mineral homeostasis. While the pathomechanism for rickets is well understood, the direct role of PHEX (Phosphate-regulating neutral endopeptidase) deficiency in non-rachitic features including complex deformities, skull and dental affections remains unclear. FGF23-inhibiting antibody treatment can normalize serum phosphate levels and to improve rickets in XLH patients. However, linear growth remains impaired and effects on lower limb deformity and gait are insufficiently studied.AimsTo characterize and evaluate the course of lower limb deformity in a case series of pediatric XLH patients receiving Burosumab therapy.MethodsComparative assessment of planar radiographs, gait analysis, biochemical and clinical features of pediatric patients before and ≥12 months after initiation of FGF23-inhibiting was performed prospectively. Lower limb maltorsion was quantified by torsional MRI and gait analysis. Standardized deformity analysis of lower limb anteroposterior radiographs was conducted.ResultsSeven patients (age 9.0 +/-3.6 years) were eligible for this study. All patients received conventional treatment before onset of antibody treatment. Maltorsion of the femur was observed in 8/14 legs using torsional MRI (mean antetorsion 8.79°). Maltorsion of the tibia was observed in 9/14 legs (mean external torsion 2.8°). Gait analysis confirmed MRI findings with femoral external malrotation prior to and one year after onset of Burosumab therapy. Internal foot progression (intoeing gait) remained pathological in all cases (mean 2.2°). Knee rotation was pathologically internal 10/14 legs. Mean mechanical axis deviation (MAD) of 16.1mm prior to Burosumab changed in average by 3.9mm. Three children underwent guided growth procedures within the observation period. Mild postprocedural rebound of frontal axis deviation was observed under Burosumab treatment in one patient.ConclusionsThis is the first study to investigate lower limb deformity parameters quantitatively in children with XLH receiving Burosumab. One year of Burosumab therapy was associated with persistent maltorsion and frontal axis deviation (varus/valgus) despite improved rickets in this small, prospective uncontrolled study.

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Section: Introductionmentioning

confidence: 99%

Persistent Lower Limb Deformities Despite Amelioration of Rickets in X-Linked Hypophosphatemia (XLH) - A Prospective Observational Study

et al. 2022

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“…In addition, serious long-term complications from conventional therapy, such as hypercalciuria, nephrocalcinosis, hyperparathyroidism, and chronic kidney disease, necessitate frequent monitoring and dose titration. Thus, safer and more efficacious therapies that are more easily adhered to are needed ( Schindeler et al, 2020 ). In December 2019, burosumab, a recombinant fully human IgG1 monoclonal antibody that inhibits FGF23 activity, was first covered by insurance in Japan before the rest of the world for treatment of FGF23-associated hypophosphatemic osteomalacia by TIO.…”

Section: Introductionmentioning

confidence: 99%

Effects of burosumab on osteocalcin and bone mineral density in patient with 15-year history of nonremission tumor-induced osteomalacia initially treated with conventional therapy: Case report

et al. 2020

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Excess fibroblast growth factor 23 (FGF23) causes hypophosphatemic osteomalacia, which is associated with impaired bone matrix mineralization. Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by over-secretion of FGF23 from a tumor. Burosumab, a fully human monoclonal antibody with activities against FGF23, was initially approved in Japan before the rest of the world for treatment of FGF23-associated hypophosphatemic osteomalacia by TIO. We report here a patient with a 15-year history of non-remission TIO initially treated with conventional therapy who was then switched to burosumab treatment. Persistent hypophosphatemia and a relative low level of osteocalcin (bone Gla protein, BGP) compared with bone alkaline phosphatase (BAP) level, indicating poor matrix mineralization, developed during long-term conventional therapy. Repeated surgical and stereotactic body radiation treatments did not result in complete resection of the causable tumor, and bone mineral density (BMD) gradually decreased. Ultimately, burosumab treatment was administered and the serum Pi concentration immediately normalized, while both BGP and BMD also showed a good response. This is first known case report of the detailed efficacy of burosumab for nonremission TIO as an alternative to conventional therapy.

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“…Burosumab (KRN23), a fully human monoclonal antibody targeted to inhibit excess FGF23 activity, has recently been approved in several countries for the treatment of XLH [ 26-29 ]. Burosumab is administered subcutaneously (SC), every 2 weeks (for children) or every 4 weeks (for adults), and has demonstrated efficacy with an acceptable safety profile in both pediatric and adult XLH cohorts [ 30 , 31 ]. To date, data from 3 clinical trials in pediatric patients have been reported [ 32-34 ].…”

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confidence: 99%

Safety and Efficacy of Burosumab in Pediatric Patients With X-Linked Hypophosphatemia: A Phase 3/4 Open-Label Trial

Namba

Kubota

Muroya

et al. 2022

Journal of the Endocrine Society

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Objective Burosumab, an anti-fibroblast growth factor 23 antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH). We evaluated burosumab safety and efficacy in pediatric XLH patients. Methods This open-label, phase 3/4 trial of ≤124 weeks’ duration was conducted at four Japanese medical centers. Fifteen children aged 1–12 years with XLH were included. All had previously been treated with phosphorus or vitamin D. Subcutaneous burosumab was administered every 2 weeks, starting with 0.8 mg/kg, and adjusted based on serum phosphorus levels and any safety concerns (maximum 2 mg/kg). Safety assessments included the frequency of treatment-emergent adverse events (TEAEs). Efficacy of burosumab on biochemical markers, clinical markers of rickets, motor function, and growth was also evaluated. Results The average treatment duration was 121.7 weeks. Frequently reported TEAEs were nasopharyngitis (46.7%), dental caries (40.0%), and influenza (33.3%). At baseline, patients had low serum phosphorus concentrations (2.6 ± 0.3 mg/dL) and low-to-normal 1,25-dihydroxyvitamin D (1,25[OH]2D) concentrations (24.7 ± 12.7 pg/mL), which increased with burosumab treatment and were maintained during the study period. Alkaline phosphatase decreased continuously. At baseline, the mean ± standard deviation total Thacher Rickets Severity Score (RSS) was 1.3 ± 1.2, and four patients (26.7%) had an RSS ≥2.0. Mean Radiographic Global Impression of Change and RSS tended to improve, particularly in patients with higher baseline RSS. There was a trend toward increased 6-minute walk test distance. No apparent changes in growth rate were observed. Conclusions Burosumab has a good safety profile and is effective in pediatric patients with XLH.

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Clinical Evidence for the Benefits of Burosumab Therapy for X-Linked Hypophosphatemia (XLH) and Other Conditions in Adults and Children

Cited by 45 publications

References 24 publications

Persistent Lower Limb Deformities Despite Amelioration of Rickets in X-Linked Hypophosphatemia (XLH) - A Prospective Observational Study

Persistent Lower Limb Deformities Despite Amelioration of Rickets in X-Linked Hypophosphatemia (XLH) - A Prospective Observational Study

Effects of burosumab on osteocalcin and bone mineral density in patient with 15-year history of nonremission tumor-induced osteomalacia initially treated with conventional therapy: Case report

Safety and Efficacy of Burosumab in Pediatric Patients With X-Linked Hypophosphatemia: A Phase 3/4 Open-Label Trial

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