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J Bone Miner Res. 2018 Aug;33(8):1383-1393. doi: 10.1002/jbmr.3475. Epub 2018 Jun 26.

A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis.

Author information

1
Yale School of Medicine, New Haven, CT, USA.
2
Centre d'Evaluation des Maladies Osseuses, Hôpital Cochin, Paris, France.
3
Indiana University School of Medicine, Indianapolis, IN, USA.
4
Université Paris-Sud, Le Kremlin Bicêtre, France.
5
Houston Methodist Hospital, Houston, TX, USA.
6
University of California, San Francisco, CA, USA.
7
Duke University Medical Center, Durham, NC, USA.
8
Children's Hospital Los Angeles, University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
9
Seoul National University Children's Hospital, Seoul, South Korea.
10
Johns Hopkins University School of Medicine, Baltimore, MD, USA.
11
Osaka City University Graduate School of Medicine, Osaka, Japan.
12
University of Tokyo Hospital, Tokyo, Japan.
13
University College London Hospitals, London, UK.
14
Okayama Saiseikai General Hospital, Okayama, Japan.
15
Ultragenyx Pharmaceutical Inc., Novato, CA, USA.

Abstract

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.

KEYWORDS:

BUROSUMAB; FGF23; OSTEOMALACIA; VITAMIN D; X-LINKED HYPOPHOSPHATEMIA (XLH)

PMID:
29947083
DOI:
10.1002/jbmr.3475

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