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

on behalf of the AXLES 1 Investigators

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1383-1393
Number of pages11
JournalJournal of Bone and Mineral Research
Volume33
Issue number8
DOIs
StatePublished - Aug 1 2018

Fingerprint

Familial Hypophosphatemic Rickets
Placebos
Antibodies
Hypophosphatemia
Pain
Osteoarthritis
Phosphates
Nephrocalcinosis
Social Adjustment
Musculoskeletal Pain
Osteomalacia
fibroblast growth factor 23
Ontario
Bone Resorption
Least-Squares Analysis
Parathyroid Hormone
Serum
Osteogenesis
Chronic Pain
Abscess

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

@article{93361d70fa2c406a8168cc8d5ffd00b0,
title = "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",
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.",
keywords = "BUROSUMAB, FGF23, OSTEOMALACIA, VITAMIN D, X-LINKED HYPOPHOSPHATEMIA (XLH)",
author = "{on behalf of the AXLES 1 Investigators} and Insogna, {Karl L.} and Karine Briot and Erik Imel and Peter Kamenick{\'y} and Ruppe, {Mary D.} and Portale, {Anthony A.} and Thomas Weber and Pisit Pitukcheewanont and Cheong, {Hae Il} and {Jan de Beur}, Suzanne and Yasuo Imanishi and Nobuaki Ito and Lachmann, {Robin H.} and Hiroyuki Tanaka and Farzana Perwad and Lin Zhang and Chen, {Chao Yin} and Christina Theodore-Oklota and Matt Mealiffe and {San Martin}, Javier and Carpenter, {Thomas O.}",
year = "2018",
month = "8",
day = "1",
doi = "10.1002/jbmr.3475",
language = "English (US)",
volume = "33",
pages = "1383--1393",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "8",

}

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

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.

PY - 2018/8/1

Y1 - 2018/8/1

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)

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DO - 10.1002/jbmr.3475

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