TY - JOUR
T1 - Asfotase alfa therapy for children with hypophosphatasia
AU - Whyte, Michael P.
AU - Madson, Katherine L.
AU - Phillips, Dawn
AU - Reeves, Amy L.
AU - McAlister, William H.
AU - Yakimoski, Amy
AU - Mack, Karen E.
AU - Hamilton, Kim
AU - Kagan, Kori
AU - Fujita, Kenji P.
AU - Thompson, David D.
AU - Moseley, Scott
AU - Odrljin, Tatjana
AU - Rockman-Greenberg, Cheryl
N1 - Funding Information:
We thank the parents and patients for making this study possible. Identifiable patients in Videos 1 and 2 have provided a signed statement of informed consent to publish their image (in print and online). We are grateful to Thomas E. Herman, Rebecca Hulett, Geetika Khanna, and Thomas Thacher for radiographic evaluations; Jill Mayhew for performing the physical therapy assessments; Beth Leiro for central scoring of source documents; and Catherine Siener and Elizabeth Malkus for performing the assessments for the Shri-ners Hospital for Children site. Ian Clark, (Winnipeg), James Hoekel, and Mark Rallo (St. Louis) provided the ophthalmologic assessments. Deborah Wenkert, Hal Landy, and Alison Skrinar helped design and initiate the study. Agustin Melian helped analyze and interpret the data and provided critical comments for the draft manuscript. These data were presented in part at the following meetings: 92nd Annual Meeting of the Endocrine Society 2010, San Diego, California, USA; 33rd Annual Meeting of the American Society for Bone and Mineral Research 2011, San Diego, California, USA; 53rd Annual Meeting of the European Society for Paediatric Endocrinology 2014, Dublin, Ireland; 35th Annual Meeting of the American Society for Bone and Mineral Research 2014, Houston, Texas, USA; and 97th Annual Meeting of the Endocrine Society 2015, San Diego, California, USA. Eileen Sawyer, and Stephanie Rock of Alexion Pharmaceuticals Inc. helped create, edit, and finalize the manuscript. SVS Writing Group (Chicago, Illinois, USA) and PharmaWrite LLC (Princeton, New Jersey, USA), funded by Alexion Pharmaceuticals Inc., worked to prepare the report.
Funding Information:
We thank the parents and patients for making this study possible. Identifiable patients in Videos 1 and 2 have provided a signed statement of informed consent to publish their image (in print and online). We are grateful to Thomas E. Herman, Rebecca Hulett, Geetika Khanna, and Thomas Thacher for radiographic evaluations; Jill Mayhew for performing the physical therapy assessments; Beth Leiro for central scoring of source documents; and Catherine Siener and Elizabeth Malkus for performing the assessments for the Shriners Hospital for Children site. Ian Clark, (Winnipeg), James Hoekel, and Mark Rallo (St. Louis) provided the ophthalmologic assessments. Deborah Wenkert, Hal Landy, and Alison Skrinar helped design and initiate the study. Agustin Melian helped analyze and interpret the data and provided critical comments for the draft manuscript. These data were presented in part at the following meetings: 92nd Annual Meeting of the Endocrine Society 2010, San Diego, California, USA; 33rd Annual Meeting of the American Society for Bone and Mineral Research 2011, San Diego, California, USA; 53rd Annual Meeting of the European Society for Paediatric Endocrinology 2014, Dublin, Ireland; 35th Annual Meeting of the American Society for Bone and Mineral Research 2014, Houston, Texas, USA; and 97th Annual Meeting of the Endocrine Society 2015, San Diego, California, USA. Eileen Sawyer, and Stephanie Rock of Alexion Pharmaceuticals Inc. helped create, edit, and finalize the manuscript. SVS Writing Group (Chicago, Illinois, USA) and PharmaWrite LLC (Princeton, New Jersey, USA), funded by Alexion Pharmaceuticals Inc., worked to prepare the report.
Funding Information:
Pharmaceuticals Inc. was involved in the trial design and data interpretation and funded the data collection and analyses. Editorial and writing support was funded by Alexion Pharmaceuticals Inc. and Shriners Hospitals for Children, which also funded the acquisition of the historical control radiographs.
Publisher Copyright:
© 2016 American Society for Clinical Investigation. All rights reserved.
PY - 2016/6/16
Y1 - 2016/6/16
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85055604876&partnerID=8YFLogxK
U2 - 10.1172/jci.insight.85971
DO - 10.1172/jci.insight.85971
M3 - Article
C2 - 27699270
AN - SCOPUS:85055604876
SN - 2379-3708
VL - 1
JO - JCI Insight
JF - JCI Insight
IS - 9
M1 - e85971
ER -