Post-authorisation safety study of burosumab use in paediatric, adolescent and adult patients with X-linked hypophosphataemia: rationale and description

Abstract

Background: X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year.

Methods: The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab.

Results: Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports.

Conclusion: This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab.

Registry identification: The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://ichgcp.net/clinical-trials-registry/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191).

Keywords: X-linked hypophosphataemia (XLH); burosumab; patient registry; phosphate; post-authorisation safety study (PASS); rare bone disease; real-world evidence.

Conflict of interest statement

Competing interests: AB has received research grants and received honoraria as a consultant and speaker, paid to her institution, from Kyowa Kirin and Ultragenyx. CLC has received honoraria as a consultant for Kyowa Kirin. MCZ reports that her institution has received a research grant from Kyowa Kirin. DH has received a research grant or honoraria as a consultant and speaker from Amgen, Chiesi and Kyowa Kirin. DS has received honoraria as a consultant from BioMarin, Kyowa Kirin, Novo Nordisk and Sandoz. EL has received honoraria as a consultant from Advicenne, Chiesi, Kyowa Kirin, Novartis and Recordati. FE declares competing interests with Avrobio, Chiesi, Kyowa Kirin, Otsuka and Recordati Rare Diseases. GA has received personal fees and non-financial support from Advicenne, Alexion, Kyowa Kirin, Recordati Rare Diseases and received personal fees from Alnylam and Dicerna, and received personal fees and other from Chiesi. KB has received honoraria as a consultant from Amgen, Kyowa Kirin, Theramex and UCB. LTS has received honoraria as a consultant from Amgen and Kyowa Kirin. MB has received research grants or honoraria as a consultant or speaker from Abiogen, Alexion, Amgen, Bruno Farmaceutici, Calilytix, Echolight, Eli Lilly, Kyowa Kirin, SPA, Theramex and UCB. ON has received honoraria as a consultant from BioMarin and Kyowa Kirin. OM has received honoraria as a consultant from BridgeBio, Kyowa Kirin and Ultragenyx. RK has received honoraria as a consultant or for advisory boards from Kyowa Kirin. SBN and ZM have received honoraria as a consultant or speaker from Inozyme Pharma and Kyowa Kirin. JL and AT are employees of Kyowa Kirin International plc. SG declares no conflict of interests.

© The Author(s), 2022.

Figures

Figure 1.

Flow chart of patient inclusion/selection. *Total number of patients to be enrolled in the International XLH Registry during the 10-year lifespan of the registry is projected to be approximately 1200. Based on the assumption that 50% of these patients in the International XLH Registry are children and adolescents 1–17 years of age or adults who may be considered suitable for burosumab treatment, the number of burosumab-eligible patients within this group of 1200 patients is projected to be approximately 600. Assuming then that two-thirds of these 600 patients receive burosumab, based on numerous factors, such as in-country reimbursement decisions, individual patients’ factors/choice, and personal consent to their inclusion for participation in the PASS, the number of burosumab-treated patients included in the PASS for the primary objectives is estimated to be approximately 400. Assuming the other patients not exposed to burosumab receive alternative treatments (i.e. other than burosumab), this cohort will amount to approximately 800 patients and will act as the comparator group for the secondary objective in the PASS. 1,25(OH)2D, active vitamin D; PASS, post-authorisation safety study; XLH, X-linked hypophosphataemia.