TY - JOUR
T1 - Asfotase alfa treatment improves survival for perinatal and infantile hypophosphatasia
AU - Whyte, Michael P.
AU - Rockman-Greenberg, Cheryl
AU - Ozono, Keiichi
AU - Riese, Richard
AU - Moseley, Scott
AU - Melian, Agustin
AU - Thompson, David D.
AU - Bishop, Nicholas
AU - Hofmann, Christine
N1 - Funding Information:
The authors thank the parents and patients for making this study possible. The following investigators were collaborators and could comment on the draft paper. ENB-002-08/ENB-003-08: Richard E. Lutz, University of Nebraska Medical Center, Omaha, NE; Mairead McGinn, Royal Belfast Hospital for Sick Children, Belfast, Northern Ireland, UK; Nada J. Salman, Tawam ospital, Al Ain, United Arab Emirates; Jill H. Simmons, Vanderbilt University, Nashville, TN; John W. Taylor, Prevea Health Clinic and St Vincent''s Hospital, Green Bay, WI. ENB-011-10: Linda DiMeglio, Indiana University School of Medicine, Indianapolis, IN; Wuh-Liang Hwu, National Taiwan University Hospital, Taipei, Taiwan; Edward Leung and Aizeddin Mhanni, University of Manitoba, Winnipeg, Manitoba, Canada; Gabriel Á. Martos-Moreno and Jesús Argente, Department of Endocrinology, Hospital Infantil Universitario Niño Jesús. Department of Pediatrics, Universidad Autónoma de Madrid. CIBEROBN, ISCIII. Madrid, Spain; Peter Simm, The Royal Children''s Hospital Melbourne and Murdoch Children''s Research Institute, Melbourne, Australia; Robert Steiner, University of Wisconsin School of Medicine and Public Health, Madison, WI; Andreas Superti-Furga, Universitätsklinikum Würzburg Kinderklinik, Pädiatrische Infektiologie und Immunologie, Würzburg, Germany; William Wilcox, Cedars-Sinai Medical Center, Los Angeles, CA. ENB-010-10: Paul Harmatz, University of California San Francisco Benioff Children''s Hospital Oakland, Oakland, CA; Seiki Horita, Ishikawa Prefectural Central Hospital, Japan; Wuh-Liang Hwu, National Taiwan University Hospital, Taiwan; Hirashi Kawashima, Tokyo Medical University Hospital, Japan; Hiroshi Masaki, St Marianna University School of Medicine, Japan; Hideki Nakayama, National Hospital Organization Fukuoka Higashi Medical Center, Japan; Halil Saglam, Uludag University Faculty of Medicine, Turkey; Seiji Sato, Saitama Municipal Hospital, Japan; and Gerald Vockley, Children''s Hospital of Pittsburgh, PA. Eileen Sawyer of Alexion Pharmaceuticals helped create, edit, and finalize the manuscript. Johannes Liese of Würzburg, Germany, and Katherine L. Madson of St Louis, MO, gave critical review and helpful comments. Amy Reeves of St Louis, MO, assisted in chart reviews. Sarah Thornburg of Fishawack Communications GmbH and Sharon McKenzie of St Louis, MO, helped prepare the report. This study was funded by Alexion Pharmaceuticals, Inc. Partial funding for this study was provided by a grant (FD-R-003745-03) from the Office of Orphan Products Development (OOPD). Funding for the University of California San Francisco Benioff Children''s Hospital Oakland''s ENB-010-10 segment was derived in part through University of California San Francisco-Clinical & Translational Science Institute Grant UL1 TR000004. Work done by Fishawack Communications GmbH, Basel, Switzerland, in preparing the report was funded by Alexion Pharmaceuticals, Inc. Presented in part at the Pediatric Academic Societies 2014 Annual Meeting, Vancouver, BC, Canada, May 3-6, 2014 (Whyte et al, available at: http://www.abstracts2view.com/ pasall/view.php?nu=PAS14L1_3808.200); the 28th Annual Meeting, American Society for Bone and Mineral Research, Houston, TX, September 12-15, 2014 (Whyte et al, J Bone Miner Res 29 (Suppl 1); and the American College of Medical Genetics and Genomics 2015 Annual Clinical Genetics Meeting, Salt Lake City, UT, March 24-28, 2015 (Leung et al, available at: https://ww4.aievolution.com/acm1501/index.cfm?do=abs.viewAbs&abs=1389). Clinical Trial Registration Numbers: NCT00744042, NCT01205152, NCT01176266, and NCT01419028. Contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health. M.P.W., C.R.-G., N.B., and C.H. are study investigators with Alexion Pharmaceuticals, Inc. M.P.W. and C.H. received research grants; M.P.W., C.R.-G., N.B., and C.H. received honoraria and travel support; and K.O. and C.H. received consultancy fees from Alexion Pharmaceuticals, Inc. R.R., S.M., A.M., and D.D.T. are employees of Alexion Pharmaceuticals, Inc.
PY - 2016/1
Y1 - 2016/1
N2 - Context: Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50â€"100% mortality, typically from respiratory complications. Objectives: Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. Design/Setting: Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. Patients: Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. Interventions: Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly. Main Outcome Measures: Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study. Results: Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95%vs42%at age 1 yearand84%vs27%at age 5 years, respectively (P=.0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. Conclusions: Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP. (.
AB - Context: Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50â€"100% mortality, typically from respiratory complications. Objectives: Our objective was to better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. Design/Setting: Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. Patients: Thirty-seven treated patients (median treatment duration, 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. Interventions: Treated patients received asfotase alfa as sc injections either 1 mg/kg six times per week or 2 mg/kg thrice weekly. Main Outcome Measures: Survival, skeletal health quantified radiographically on treatment, and ventilatory status were the main outcome measures for this study. Results: Asfotase alfa was associated with improved survival in treated patients vs historical controls: 95%vs42%at age 1 yearand84%vs27%at age 5 years, respectively (P=.0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) were weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. Conclusions: Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP. (.
UR - http://www.scopus.com/inward/record.url?scp=84954547947&partnerID=8YFLogxK
U2 - 10.1210/jc.2015-3462
DO - 10.1210/jc.2015-3462
M3 - Article
C2 - 26529632
AN - SCOPUS:84954547947
SN - 0021-972X
VL - 101
SP - 334
EP - 342
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 1
ER -