title: Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia.
abstract: BACKGROUND
  X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH.
  
  
  METHODS
  Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days.
  
  
  RESULTS
  KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P<0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine.
  
  
  CONCLUSIONS
  KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.
authors.forename: Thomas O
authors.initials: TO
authors.lastname: Carpenter
authors.forename: Erik A
authors.initials: EA
authors.lastname: Imel
authors.forename: Mary D
authors.initials: MD
authors.lastname: Ruppe
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Weber
authors.forename: Mark A
authors.initials: MA
authors.lastname: Klausner
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Wooddell
authors.forename: Tetsuyoshi
authors.initials: T
authors.lastname: Kawakami
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ito
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Humphrey
authors.forename: Karl L
authors.initials: KL
authors.lastname: Insogna
authors.forename: Munro
authors.initials: M
authors.lastname: Peacock
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D002118:Calcium / Q000097:blood / Q000652:urine; D053098:Familial Hypophosphatemic Rickets / Q000097:blood / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005919:Glomerular Filtration Rate; D006207:Half-Life; D006801:Humans; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007684:Kidney Tubules / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D010710:Phosphates / Q000097:blood; D014807:Vitamin D / Q000031:analogs & derivatives / Q000097:blood; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C000717427:FGF23 protein, human; D010710:Phosphates; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; C000601956:burosumab; D002118:Calcium