Prolonged Correction of Serum Phosphorus in Adults With X-Linked Hypophosphatemia Using Monthly Doses of KRN23

J Clin Endocrinol Metab. 2015 Jul;100(7):2565-73. doi: 10.1210/jc.2015-1551. Epub 2015 Apr 28.

Abstract

Context: In X-linked hypophosphatemia (XLH), elevated fibroblast growth factor 23 (FGF23) decreases the renal tubular maximum reabsorption rate of phosphate/glomerular filtration rate (TmP/GFR) and serum inorganic phosphorus (Pi), resulting in rickets and/or osteomalacia.

Objective: The objective was to test the hypothesis that monthly KRN23 (anti-FGF23 antibody) would safely improve serum Pi in adults with XLH.

Design: Two sequential open-label phase 1/2 studies were done.

Setting: Six academic medical centers were used.

Participants: Twenty-eight adults with XLH participated in a 4-month dose-escalation study (0.05-0.6 mg/kg); 22 entered a 12-month extension study (0.1-1 mg/kg).

Intervention: KRN23 was injected sc every 28 days.

Main outcome measure: The main outcome measure was the proportion of subjects attaining normal serum Pi and safety.

Results: At baseline, mean TmP/GFR, serum Pi, and 1,25-dihydroxyvitamin D [1,25(OH)2D] were 1.6 ± 0.4 mg/dL, 1.9 ± 0.3 mg/dL, and 36.6 ± 14.3 pg/mL, respectively. During dose escalation, TmP/GFR, Pi, and 1,25(OH)2D increased, peaking at 7 days for TmP/GFR and Pi and at 3-7 days for 1,25(OH)2D, remaining above (TmP/GFR, Pi) or near [1,25(OH)2D] pre-dose levels at trough. After each of the four escalating doses, peak Pi was between 2.5 and 4.5 mg/dL in 14.8, 37.0, 74.1, and 88.5% of subjects, respectively. During the 12-month extension, peak Pi was in the normal range for 57.9-85.0% of subjects, and ≥25% maintained trough Pi levels within the normal range. Serum Pi did not exceed 4.5 mg/dL in any subject. Although 1,25(OH)2D levels increased transiently, mean serum and urinary calcium remained normal. KRN23 treatment increased biomarkers of skeletal turnover and had a favorable safety profile.

Conclusions: Monthly KRN23 significantly increased serum Pi, TmP/GFR, and 1,25(OH)2D in all subjects. KRN23 has potential for effectively treating XLH.

Trial registration: ClinicalTrials.gov NCT01340482 NCT01571596.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal / administration & dosage*
  • Antibodies, Monoclonal / adverse effects
  • Antibodies, Monoclonal, Humanized
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Familial Hypophosphatemic Rickets / blood*
  • Familial Hypophosphatemic Rickets / drug therapy*
  • Female
  • Fibroblast Growth Factor-23
  • Fibroblast Growth Factors / immunology*
  • Glomerular Filtration Rate / drug effects
  • Humans
  • Immunoglobulin G / administration & dosage*
  • Immunoglobulin G / adverse effects
  • Male
  • Middle Aged
  • Phosphorus / blood*
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / adverse effects
  • Treatment Outcome
  • Young Adult

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • FGF23 protein, human
  • Immunoglobulin G
  • Recombinant Proteins
  • Phosphorus
  • Fibroblast Growth Factors
  • Fibroblast Growth Factor-23
  • burosumab

Associated data

  • ClinicalTrials.gov/NCT01340482
  • ClinicalTrials.gov/NCT01571596