title: Enzyme-replacement therapy in life-threatening hypophosphatasia.
abstract: BACKGROUND
  Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice.
  
  
  METHODS
  We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040.
  
  
  RESULTS
  Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment.
  
  
  CONCLUSIONS
  ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, MO 63131, USA. mwhyte@shrinenet.org
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.forename: Cheryl R
authors.initials: CR
authors.lastname: Greenberg
authors.forename: Nada J
authors.initials: NJ
authors.lastname: Salman
authors.forename: Michael B
authors.initials: MB
authors.lastname: Bober
authors.forename: William H
authors.initials: WH
authors.lastname: McAlister
authors.forename: Deborah
authors.initials: D
authors.lastname: Wenkert
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Van Sickle
authors.forename: Jill H
authors.initials: JH
authors.lastname: Simmons
authors.forename: Terence S
authors.initials: TS
authors.lastname: Edgar
authors.forename: Martin L
authors.initials: ML
authors.lastname: Bauer
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Hamdan
authors.forename: Nick
authors.initials: N
authors.lastname: Bishop
authors.forename: Richard E
authors.initials: RE
authors.lastname: Lutz
authors.forename: Mairead
authors.initials: M
authors.lastname: McGinn
authors.forename: Stanley
authors.initials: S
authors.lastname: Craig
authors.forename: Jean N
authors.initials: JN
authors.lastname: Moore
authors.forename: John W
authors.initials: JW
authors.lastname: Taylor
authors.forename: Robert H
authors.initials: RH
authors.lastname: Cleveland
authors.forename: William R
authors.initials: WR
authors.lastname: Cranley
authors.forename: Ruth
authors.initials: R
authors.lastname: Lim
authors.forename: Tom D
authors.initials: TD
authors.lastname: Thacher
authors.forename: Jill E
authors.initials: JE
authors.lastname: Mayhew
authors.forename: Matthew
authors.initials: M
authors.lastname: Downs
authors.forename: José Luis
authors.initials: JL
authors.lastname: Millán
authors.forename: Alison M
authors.initials: AM
authors.lastname: Skrinar
authors.forename: Philippe
authors.initials: P
authors.lastname: Crine
authors.forename: Hal
authors.initials: H
authors.lastname: Landy
mesh_terms: D000469:Alkaline Phosphatase / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001682:Biological Availability; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy / Q000009:adverse effects; D005260:Female; D006801:Humans; D007014:Hypophosphatasia / Q000150:complications / Q000188:drug therapy*; D007074:Immunoglobulin G / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007223:Infant; D007231:Infant, Newborn; D007262:Infusions, Intravenous; D007279:Injections, Subcutaneous / Q000009:adverse effects; D008297:Male; D011859:Radiography; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012279:Rickets / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D016896:Treatment Outcome
chemical_list: D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D000469:Alkaline Phosphatase; C570710:asfotase alfa