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

Etienne Sochett,Noriyuki Namba,Hiroyuki Tanaka,Andrew Biggin,Wei Sun,Gary S. Gottesman,Erik A. Imel,Hae Il Cheong,Annabel Nixon,Raja Padidela,Ola Nilsson,Alison Skrinar,Jill H. Simmons,Anthony A. Portale,Michael P. Whyte,Leanne M. Ward,Craig F Munns ,Angel Chen,Koji Muroya,Francis H. Glorieux,Farzana Perwad,Angela Williams,Pisit Pitukcheewanont,Wolfgang Högler

doi:10.1007/s00223-020-00797-x

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

Highlights

X-linked hypophosphatemia (XLH) is a rare, heritable, lifelong phosphate-wasting disease
Baseline characteristics were similar between the two age cohorts; serum 1,25(OH)2D concentration was lower in the cohort aged ≥ 5 years than in the total patient group, in the burosumab group (96 ± 38 vs 110 ± 48 pmol/L) (Table 1)
Our phase 3 CL301 trial demonstrated that burosumab results in greater improvement in phosphorus homeostasis, growth, lower-extremity deformities, and healing of rickets in children with XLH compared with continuing conventional therapy [9]

Summary

Introduction

X-linked hypophosphatemia (XLH) is a rare, heritable, lifelong phosphate-wasting disease. Loss-of-function mutations in the PHEX (phosphate-regulating endopeptidase homologue, X-linked) gene result in characteristic elevation of circulating fibroblast growth factor 23 (FGF23) levels, leading to reduced renal phosphate reabsorption and decreased production of active vitamin D (1,25[OH]2D) manifesting as chronic hypophosphatemia and impaired mineralization of bones and teeth, as well as muscle weakness [1, 2]. XLH typically manifests in early childhood as rickets, skeletal deformities, short stature, and in some children with dental abscesses [1,2,3,4]. Elevated circulating FGF23 and hypophosphatemia persist into adulthood; adults often develop pseudofractures, fractures, enthesopathies, hyperparathyroidism, and early-onset osteoarthritis, and suffer increasing pain, stiffness, and loss of physical function [3]

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Conclusion