Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia

Abstract

Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.Trial registration: ClinicalTrials.gov NCT02915705.

Keywords: Burosumab; Patient-reported outcomes; Patient-reported outcomes measurement information system; X-linked hypophosphatemia.

Conflict of interest statement

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: RP, MPW, FHG, CFM, LMW, ON, AAP, JHS, NN, HIC, PP, ES, WH, KM, HT, GSG, AB, FP, and EAI. AAP, NN, FP, and EAI have also received honoraria for serving as advisory board members or for lectures from Ultragenyx Pharmaceutical Inc. RP has received personal fees from Ultragenyx Pharmaceutical Inc. and Kyowa Kirin International plc, a research grant, consultation fees, honoraria, and travel grants from Kyowa Kirin International plc and Alexion UK, and non-financial support from Kyowa Kirin International plc. MPW has received research grant support, honoraria, and travel from Alexion Pharmaceutical Inc. FHG has received personal fees from Kyowa Kirin International plc and research funding from Amgen and Mereo BioPharma. LMW has served as a consultant to Ultragenyx, with funds to LMW’s institution. NN has received personal fees and non-financial support from Kyowa Kirin International plc and Ultragenyx Pharmaceutical Inc. during the conduct of the study, and personal fees and non-financial support (honoraria, consulting fees, and travel support) from Alexion UK outside the submitted work. PP has received research funding from Ultragenyx Pharmaceutical Inc. and is currently an employee of Ascendis Pharma Inc. WH has received honoraria, consulting fees, and travel support from Ultragenyx Pharmaceutical Inc. and research funding, honoraria, and travel support from Kyowa Kirin. GSG has received consulting fees from Ultragenyx Pharmaceutical Inc. AW and WS are employees of Kyowa Kirin International plc. AN is an employee of Chilli Consultancy and has received consultancy fees from Kyowa Kirin International plc to support the development of this manuscript. AC and AS are employees and stockholders of Ultragenyx Pharmaceutical Inc.

Figures

Fig. 1

Baseline PROMIS (a) pain interference, (b) physical function mobility, and (c) fatigue scores for patients aged ≥ 5 years (n = 35). Data show standardized PROMIS T-scores; higher T-scores indicate more pain interference, better function mobility, and worse fatigue. Reference lines at ± 1 SD of the mean are based on a population mean of 50 and SD of 10. PROMIS Patient-Reported Outcomes Measurement Information System, SD standard deviation

Fig. 2

Change from baseline in PROMIS (a) pain interference, (b) physical function mobility, and (c) fatigue scores for patients aged ≥ 5 years (n = 35). Data are expressed as LS mean (standard error). *p < 0.05 for LS mean change at week 40 (burosumab–conventional therapy). †Indicates the mean change is ≥ 3-point MID from baseline. LS least-squares, MID minimally important difference, PROMIS Patient-Reported Outcomes Measurement Information System

Fig. 3

Baseline SF-10 Health Survey for Children (a) PHS-10 and (b) PSS-10 for patients aged ≥ 5 years (n = 35). P.25, P.50, and P.75 are the 25th, 50th, and 75th percentiles from the general population. Higher global scores indicate better HRQoL. HRQoL health-related quality of life, PHS-10 physical health score, PSS-10 psychosocial health score, SF-10 Short Form-10

Fig. 4

Changes from baseline to weeks 40 and 64 for SF-10 Health Survey for Children (a) PHS-10 and (b) PSS-10 for all patients aged ≥ 5 years (n = 35). Data are expressed as LS mean ± standard error. *p < 0.01 for change from baseline to week 64; **p < 0.001 for change from baseline to week 40. LS least-squares, PHS-10 physical health score, PSS-10 psychosocial health score, SF-10 Short Form-10