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

被引:236
作者
Insogna, Karl L. [1 ]
Briot, Karine [2 ]
Imel, Erik A. [3 ]
Kamenicky, Peter [4 ]
Ruppe, Mary D. [5 ]
Portale, Anthony A. [6 ]
Weber, Thomas [7 ]
Pitukcheewanont, Pisit [8 ]
Cheong, Hae Il [9 ]
de Beur, Suzanne Jan [10 ]
Imanishi, Yasuo [11 ]
Ito, Nobuaki [12 ]
Lachmann, Robin H. [13 ]
Tanaka, Hiroyuki [14 ]
Perwad, Farzana [6 ]
Zhang, Lin [15 ]
Chen, Chao-Yin [15 ]
Theodore-Oklota, Christina [15 ]
Mealiffe, Matt [15 ]
Martin, Javier San [15 ]
Carpenter, Thomas O. [1 ]
机构
[1] Yale Sch Med, New Haven, CT USA
[2] Hop Cochin, Ctr Evaluat Malad Osseuses, Paris, France
[3] Indiana Univ Sch Med, Indianapolis, IN 46202 USA
[4] Univ Paris Sud, Le Kremlin Bicetre, France
[5] Houston Methodist Hosp, Houston, TX USA
[6] Univ Calif San Francisco, San Francisco, CA 94143 USA
[7] Duke Univ, Med Ctr, Durham, NC USA
[8] Univ So Calif, Keck Sch Med, Childrens Hosp Los Angeles, Los Angeles, CA 90033 USA
[9] Seoul Natl Univ, Childrens Hosp, Seoul, South Korea
[10] Johns Hopkins Univ, Sch Med, Baltimore, MD USA
[11] Osaka City Univ, Grad Sch Med, Osaka, Japan
[12] Univ Tokyo Hosp, Tokyo, Japan
[13] Univ Coll London Hosp, London, England
[14] Okayama Saiseikai Gen Hosp, Okayama, Japan
[15] Ultragenyx Pharmaceut Inc, Novato, CA USA
关键词
BUROSUMAB; FGF23; X-LINKED HYPOPHOSPHATEMIA (XLH); OSTEOMALACIA; VITAMIN D; RICKETS; PHOSPHATE; THERAPY; FIBROBLAST-GROWTH-FACTOR-23; KRN23; FGF23;
D O I
10.1002/jbmr.3475
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 burosumabis a novel therapeutic addressing an important medical need in adults with XLH. (C) 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
引用
收藏
页码:1383 / 1393
页数:11
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