Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial

Abstract

In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, -54%, osteoid thickness, -32%, osteoid surface/bone surface, -26%, [median] mineralization lag time, -83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment-emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure-related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Keywords: BIOCHEMICAL MARKERS OF BONE TURNOVER; BONE HISTOMORPHOMETRY; CLINICAL TRIALS; OSTEOMALACIA AND RICKETS; THERAPEUTICS > OTHER.

Figure 1

Histomorphometric indices. Data are presented as median, interquartile, range, mean (+), and individual data points (○). Gray line indicates upper limit of normal reference ranges: osteoid volume/bone volume 3.05%, osteoid thickness 8.9 μm, osteoid surface/bone surface 23.9%, mineralization lag time 28.6 days. Data are from Glorieux and colleagues.14

Figure 2

Undecalcified Goldner‐stained iliac bone samples in a 24‐year‐old female before and after treatment with burosumab. Mineralized bone is shown in green, unmineralized osteoid is shown in orange or red. After treatment, the layer of unmineralized osteoid (arrows) is thinner and covers a smaller percentage of mineralized bone surface. Magnification ×100.

Figure 3

Biochemical markers of bone formation and resorption including (A) Serum Procollagen Type 1N‐Propetide, (B) Serum C‐terminal Telopeptode, and (C) Serum Bone‐specific Alkaline Phosphatase. Data is presented as mean ± standard error.

Figure 4

(A) Serum phosphorus, (B) TmP/GFR, and (C) serum 1,25(OH)₂D. Data is presented as mean ± standard error. Assessments made at the mid‐point of the dose interval are shown in blue, and assessments made at the end‐point of the dose interval are shown in green. TmP/GFR = renal tubular maximum reabsorption of phosphate per glomerular filtration rate.