TY - JOUR
T1 - A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia
T2 - Week 24 Primary Analysis
AU - on behalf of the AXLES 1 Investigators
AU - Insogna, Karl L.
AU - Briot, Karine
AU - Imel, Erik A.
AU - Kamenický, Peter
AU - Ruppe, Mary D.
AU - Portale, Anthony A.
AU - Weber, Thomas
AU - Pitukcheewanont, Pisit
AU - Cheong, Hae Il
AU - Jan de Beur, Suzanne
AU - Imanishi, Yasuo
AU - Ito, Nobuaki
AU - Lachmann, Robin H.
AU - Tanaka, Hiroyuki
AU - Perwad, Farzana
AU - Zhang, Lin
AU - Chen, Chao Yin
AU - Theodore-Oklota, Christina
AU - Mealiffe, Matt
AU - San Martin, Javier
AU - Carpenter, Thomas O.
N1 - Funding Information:
The authors thank the subjects, caregivers, investigators (see Supplemental Materials), and health care professionals who participated in this study. The authors also acknowledge Jonathan Latham of PharmaScribe, LLC (on behalf of Ultragenyx Pharmaceutical Inc.) for medical writing assistance. This work was supported by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Hakko Kirin Co., Ltd.
Funding Information:
The authors thank the subjects, caregivers, investigators (see Supplemental Materials), and health care professionals who participated in this study. The authors also acknowledge Jonathan Latham of PharmaScribe, LLC (on behalf of Ultragenyx Pharmaceutical Inc.) for medical writing assistance. This work was supported by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Hakko Kirin Co., Ltd. Authors’ roles: Study design: KLI, EAI, MDR, AAP, CYC, CTO, MM, JSM, and TOC. Study conduct: all authors. Data analysis: LZ, CYC, CTO, MM, and JSM. Data collection: KLI, KB, EAI, PK, MDR, AAP, TW, PP, HIC, SJdB, YI, NI, RHL, HT, FP, and TOC. Data interpretation: all authors. Drafting manuscript: KLI, MM, and JSM. Revising manuscript content: all authors. Approving final version of manuscript: all authors.
Publisher Copyright:
© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.
PY - 2018/8
Y1 - 2018/8
N2 - 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.
AB - 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.
KW - BUROSUMAB
KW - FGF23
KW - OSTEOMALACIA
KW - VITAMIN D
KW - X-LINKED HYPOPHOSPHATEMIA (XLH)
UR - http://www.scopus.com/inward/record.url?scp=85051290171&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85051290171&partnerID=8YFLogxK
U2 - 10.1002/jbmr.3475
DO - 10.1002/jbmr.3475
M3 - Article
C2 - 29947083
AN - SCOPUS:85051290171
SN - 0884-0431
VL - 33
SP - 1383
EP - 1393
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 8
ER -