title: Asfotase alfa therapy for children with hypophosphatasia.
abstract: Background.Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) of the gene that encodes the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Consequently, cell-surface deficiency of TNSALP phosphohydrolase activity leads to extracellular accumulation of inorganic pyrophosphate, a natural substrate of TNSALP and inhibitor of mineralization. Children with HPP can manifest rickets, skeletal pain, deformity, fracture, muscle weakness, and premature deciduous tooth loss. Asfotase alfa is a recombinant, bone-targeted, human TNSALP injected s.c. to treat HPP. In 2012, we detailed the 1-year efficacy of asfotase alfa therapy for the life-threatening perinatal and infantile forms of HPP.Methods.Here, we evaluated the efficacy and safety of asfotase alfa treatment administered to children 6-12 years of age at baseline who were substantially impaired by HPP. Two radiographic scales quantitated HPP skeletal disease, including comparisons to serial radiographs from similarly affected historical control patients.Results.Twelve children receiving treatment were studied for 5 years. The 6-month primary endpoint was met, showing significant radiographic improvement. Additional significant improvements included patient growth, strength, motor function, agility, and quality of life, which for most patients meant achieving normal values for age- and sex-matched peers that were sustained at 5 years of treatment. For most, pain and disability resolved. Mild to moderate injection-site reactions were common and were sometimes associated with lipohypertrophy. Low anti-asfotase alfa antibody titers were noted in all patients. No evidence emerged for clinically important ectopic calcification or treatment resistance.Conclusions.Asfotase alfa enzyme replacement therapy has substantial and sustained efficacy with a good safety profile for children suffering from HPP.Trial Registration.ClinicalTrials.gov NCT00952484 (https://clinicaltrials.gov/ct2/show/NCT00952484) and NCT01203826 (https://clinicaltrials.gov/ct2/show/NCT01203826).Funding.Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children.
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, USA.|Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine at Barnes-Jewish Hospital, St. Louis, Missouri, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Whyte
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Madson
authors.affiliation: University of North Carolina, Division of Physical Therapy, Department of Allied Health Sciences, Chapel Hill, North Carolina, USA.
authors.forename: Dawn
authors.initials: D
authors.lastname: Phillips
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, USA.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Reeves
authors.affiliation: Department of Pediatric Radiology, Mallinckrodt Institute of Radiology at St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, Missouri, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: McAlister
authors.affiliation: The University of Manitoba, Faculty of Health Sciences, Department of Pediatrics and Child Health, Winnipeg, Manitoba, Canada.
authors.forename: Amy
authors.initials: A
authors.lastname: Yakimoski
authors.affiliation: Center for Metabolic Bone Disease and Molecular Research, Shriners Hospital for Children, St. Louis, Missouri, USA.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Mack
authors.affiliation: Children's Hospital, Winnipeg, Manitoba, Canada.
authors.forename: Kim
authors.initials: K
authors.lastname: Hamilton
authors.affiliation: Children's Hospital, Winnipeg, Manitoba, Canada.
authors.forename: Kori
authors.initials: K
authors.lastname: Kagan
authors.affiliation: Alexion Pharmaceuticals Inc., Cheshire, Connecticut, USA.
authors.forename: Kenji P
authors.initials: KP
authors.lastname: Fujita
authors.affiliation: Alexion Pharmaceuticals Inc., Cheshire, Connecticut, USA.
authors.forename: David D
authors.initials: DD
authors.lastname: Thompson
authors.affiliation: Alexion Pharmaceuticals Inc., Cheshire, Connecticut, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Moseley
authors.affiliation: Alexion Pharmaceuticals Inc., Cambridge, Massachusetts, USA.
authors.forename: Tatjana
authors.initials: T
authors.lastname: Odrljin
authors.affiliation: The University of Manitoba, Faculty of Health Sciences, Department of Pediatrics and Child Health, Winnipeg, Manitoba, Canada.|Children's Hospital, Winnipeg, Manitoba, Canada.
authors.forename: Cheryl
authors.initials: C
authors.lastname: Rockman-Greenberg
mesh_terms: D000469:Alkaline Phosphatase / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use*; D002648:Child; D005260:Female; D006801:Humans; D007014:Hypophosphatasia / Q000188:drug therapy*; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008297:Male; D011788:Quality of Life; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
chemical_list: D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D000469:Alkaline Phosphatase; C570710:asfotase alfa