Abstract
The anti-fibroblast growth factor 23 monoclonal antibody burosumab corrects hypophosphatemia in adults with X-linked hypophosphatemia (XLH) and improves pain, stiffness, physical function, and fatigue. This post hoc subgroup analysis used data from the 24-week placebo-controlled period of a phase 3 study in 134 adults with XLH (ClinicalTrials.gov NCT02526160), to assess whether the benefits of burosumab are evident in 14 clinically relevant subgroups defined by baseline demographic and functional criteria, including sex, Brief Pain Inventory-short form (BPI-SF) Average And Worst Pain, region, race, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC®) Stiffness, Physical Function and Pain domains and total score, use of opioid/other pain medication, active fractures/pseudo-fractures, and 6-min walk test distance. There were no statistically significant interactions between any of the subgroups and treatment arm for any endpoint. Higher proportions of subjects achieved mean serum phosphate concentration above the lower limit of normal (the primary endpoint) with burosumab than with placebo in all subgroups. For the key secondary endpoints (WOMAC Stiffness and Physical Function; BPI-SF Worst Pain) individual subgroup categories showed improvements with burosumab relative to placebo. For additional efficacy endpoints, burosumab was favored in some subgroups but differences were not significant and confidence intervals were wide. For some endpoints the treatment effect is small at 24 weeks in all subjects. This subgroup analysis shows that burosumab was largely superior to placebo across endpoints in the 14 clinically relevant subgroup variables at 24 weeks and is likely to benefit all symptomatic adults with active XLH.
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The corresponding author had full access to all the data in the study.
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Acknowledgements
The authors thank the participants, caregivers, investigators, and healthcare professionals who participated in this study. The authors would like to thank Mark Nixon PhD and Jennifer Liu PhD for support with quality checking and interpretation of the statistical analyses, Helen Barham PhD (thetextdoctor) for writing and editing support, and Jenna Zan of Zed for creating the figures.
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This study was funded by Ultragenyx Pharmaceutical Inc. and Kyowa Kirin International.
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Study design: KI, EAI, AP, and TC; data collection: MLB, SJB, KB, TC, HIC, MC-S, RKC, RE, YI, EAI, KI, SWI, NI, KJ, PK, RK, TK, RHL, FP, PP, AP, SHR, HT, TW, H-WY, and YT; data analysis: WS, data interpretation: all authors, drafting of the manuscript: MLB, AN, AW, and WS; revising manuscript content: all authors.
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The following authors served as clinical investigators for one or more studies, including this trial, sponsored by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc: MLB, SJdB, KB, TOC, HIC, MC-S, RKC, RE, YI, EAI, KI, SI, NI, MKJ, PK, RK, TK, RHL, FP, PP, AAP, SHR, HT, TJW, H-WY, YT. SJdB, TOC, EAI, RHL, FP, AAP, and TJW have also received honoraria from Ultragenyx Pharmaceutical Inc. for serving as an advisory board member or for delivering lectures and AAP and TJW have received travel reimbursement. TOC, YI, MJK, RK, TK, and YT have received honoraria for serving as an advisory board member or for speaker fees from Kyowa Kirin International plc. During the past 3 years, the following authors have received grants outside of the submitted work: RE from Alexion Pharmaceuticals, Amgen, Immunodiagnostic Systems Holdings plc, Nittobo Medical Co., Ltd., and Roche; SI from Alexion Pharmaceuticals, Radius Health, and Takeda Pharmaceutical Company; NI, MJK, and RHL from Kyowa Kirin International plc; TK from Teijin Pharma; PP from Ultragenyx Pharmaceutical Inc.; and SHR from Amgen, UCB, and AstraZeneca. PP is currently an employee of Ascendis Pharma Inc. AW is an employee of Kyowa Kirin International plc and WS is an employee of Kyowa Kirin Pharmaceutical Development, Inc. AN and MN are employees of Chilli Consultancy and have received consultancy fees from Kyowa Kirin International plc to support the development of this manuscript and for projects outside this submitted work.
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As stated in the abstract, this study is a post hoc subgroup analysis from an approved phase 3 Clinical Trial (ClinicalTrials.gov NCT02526160) for which informed consent was obtained from all participants in the study.
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Brandi, M.L., Jan de Beur, S., Briot, K. et al. Efficacy of Burosumab in Adults with X-linked Hypophosphatemia (XLH): A Post Hoc Subgroup Analysis of a Randomized Double-Blind Placebo-Controlled Phase 3 Study. Calcif Tissue Int 111, 409–418 (2022). https://doi.org/10.1007/s00223-022-01006-7
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DOI: https://doi.org/10.1007/s00223-022-01006-7