Dataset Information

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia.

ABSTRACT:

Purpose

In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 weeks from an open-label, multicenter, randomized, dose-finding trial of burosumab for 5- to 12-year-old children with XLH.

Methods

After 1 week of conventional therapy washout, patients were randomized 1:1 to burosumab every 2 weeks (Q2W) or every 4 weeks (Q4W) for 64 weeks, with dosing titrated based on fasting serum phosphorus levels between baseline and week 16. From week 66 to week 160, all patients received Q2W burosumab.

Results

Twenty-six children were randomized initially into each Q2W and Q4W group and all completed treatment to week 160. In 41 children with open distal femoral and proximal tibial growth plates (from both treatment groups), total Rickets Severity Score significantly decreased by 0.9 ± 0.1 (least squares mean ± SE; P < 0.0001) from baseline to week 160. Fasting serum phosphorus increases were sustained by burosumab therapy throughout the study, with an overall population mean (SD) of 3.35 (0.39) mg/dL, within the pediatric normal range (3.2-6.1 mg/dL) at week 160 (mean change from baseline P < 0.0001). Most adverse events were mild to moderate in severity.

Main conclusions

In children with XLH, burosumab administration for 160 weeks improved phosphate homeostasis and rickets and was well-tolerated. Long-term safety was consistent with the reported safety profile of burosumab.

Clinicaltrials.gov

NCT02163577.

SUBMITTER: Linglart A

PROVIDER: S-EPMC8851952 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia.

Linglart Agnès A Imel Erik A EA Whyte Michael P MP Portale Anthony A AA Högler Wolfgang W Boot Annemieke M AM Padidela Raja R Van't Hoff William W Gottesman Gary S GS Chen Angel A Skrinar Alison A Scott Roberts Mary M Carpenter Thomas O TO

The Journal of clinical endocrinology and metabolism 20220201 3

<h4>Purpose</h4>In X-linked hypophosphatemia (XLH), excess fibroblast growth factor-23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We have previously reported outcomes up to 64 weeks, and here we report safety and efficacy follow-up results up to 160 week ...[more]

PMID: 34636899

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Project description:X-linked hypophosphatemia (XLH) is a disease caused by abnormally elevated FGF23 levels, which cause persistent hypophosphatemia accompanied by subsequent reduction in bone mineralization that presents as rickets or osteomalacia. Burosumab is a fully human monoclonal antibody targeting FGF23 that is under development for the treatment of FGF23-related hypophosphatemia including XLH. The safety, tolerability, and proof of concept of burosumab have been evaluated in patients with XLH in previous studies conducted in countries outside of Asia. The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and expression of anti-drug antibodies in Japanese and Korean adults with XLH. This was a multicenter, sequential dose-escalation, open-label, single-dose study. This study began with cohort 1 (s.c. dose of burosumab 0.3?mg/kg), after which the dose was escalated sequentially in cohort 2 (s.c. dose of burosumab 0.6?mg/kg) and cohort 3 (s.c. dose of burosumab 1.0?mg/kg). The PK of burosumab were linear within the dose range of 0.3 to 1.0?mg/kg. The PD effects such as serum phosphorus concentration, serum 1,25[OH]2D3 concentration, and ratio of tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) were elevated after a single s.c. administration. The area under the receiver-operating characteristic curve from 0 to t (AUC0-t) values calculated using the change from baseline values of serum phosphorus, serum 1,25(OH)2D3, and TmP/GFR were correlated with the AUC0-t of burosumab. Furthermore, no serious adverse events (AEs), deaths, remarkable increase or decrease in the corrected calcium or intact PTH levels, or signs of nephrocalcinosis or its worsening were observed after treatment. Some AEs and drug-related AEs were observed; however, there were no clinically meaningful tendencies. The positive effects and acceptable safety profile seen in this study are encouraging for Japanese and Korean patients with XLH.

Project description:Abstract XLH is characterized by excess FGF23, hypophosphatemia, skeletal deformities, and growth impairment. For the last 40 years, XLH has been treated with multiple daily doses of oral phosphate and active vitamin D (Pi/D). Burosumab, a fully human monoclonal antibody to FGF23, has been approved by the FDA for the treatment of XLH in patients ≥1 year-old. In this Phase 3 trial (NCT02915705), 61 children with XLH (1-12 years old) were randomized (1:1) to receive subcutaneous burosumab starting at 0.8 mg/kg every 2 weeks or continue Pi/D titrated and individualized for each subject by investigators. Eligibility criteria included a Total Rickets Severity Score (RSS) ≥2.0 despite prior treatment with Pi/D (>7-day washout before baseline). The primary endpoint was healing of rickets at Week 40 assessed by radiologists blinded to treatment using the Radiographic Global Impression of Change (RGI-C). The mean ± SE daily oral phosphate dose from baseline to Week 40 was 37.8 ± 3.2 mg/kg, with >99% compliance reported based on days of dosing. Compared with Pi/D, 40 weeks of burosumab resulted in a greater LS mean ± SE increase in serum phosphorus (0.92 ± 0.08 vs 0.20 ± 0.06 mg/dL), TmP/GFR (1.19 ± 0.11 vs -0.16 ± 0.05 mg/dL), and 1,25(OH)2D (30 ± 4 vs 19 ± 4 pg/mL). At Week 40, rickets improved in both groups; RGI-C global score was significantly higher in burosumab subjects than in Pi/D subjects (LS mean ± SE: +1.9 ± 0.1 vs +0.8 ± 0.1; p<0.0001). More burosumab subjects had substantial healing (RGI-C ≥+2.0), compared with Pi/D subjects (21/29, 72% vs 2/32, 6%; odds ratio of 39.1, p<0.0001). Improvement in the RGI-C lower limb deformity score was greater with burosumab than with Pi/D (+0.62 ± 0.12 vs +0.21 ± 0.12; p=0.02). Alkaline phosphatase decreased more with burosumab compared with Pi/D (-131 ± 13 vs 35 ± 19; p<0.0001). Consistent with decreases in rickets severity, burosumab improved growth and mobility. Standing height Z-score increased by a LS mean change (95% CI) of +0.15 (0.05, 0.25) for burosumab and +0.08 (-0.02, 0.19) for Pi/D. The 6 Minute Walk Test percent predicted distance increased with burosumab (Baseline to Week 40: 62% to 72%) and was unchanged with Pi/D (76% to 75%). Nephrocalcinosis score (range 0-4) shifted 0 in 20 Pi/D and 24 burosumab subjects; +1 in 3 Pi/D and 0 burosumab subjects; and -1 in 3 Pi/D and 2 burosumab subjects. Pre-defined adverse events (AEs) of interest, including hypersensitivity and injection site reactions, were higher in the burosumab group and were mild to moderate in severity overall. There were 4 serious AEs (3 burosumab, 1 Pi/D); none were treatment-related and all resolved. No subject discontinued study drug in either group. Data after 64 weeks of treatment will be available at the time of presentation. In this randomized Phase 3 trial, burosumab resulted in increases in growth and mobility, and significantly greater improvements in rickets than Pi/D in 1-12 year-old children with XLH.

Dataset Information

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia.

Purpose

Methods

Results

Main conclusions

Clinicaltrials.gov

Publications

Sustained Efficacy and Safety of Burosumab, a Monoclonal Antibody to FGF23, in Children With X-Linked Hypophosphatemia.

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