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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Enzyme-replacement therapy in life-threatening hypophosphatasia
New England Journal of Medicine, Volume 366, No. 10, Year 2012
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Description
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.). Copyright © 2012 Massachusetts Medical Society.
Authors & Co-Authors
Whyte, Michael P.
United States, St. Louis
Washington University School of Medicine in St. Louis
United States, St. Louis
Barnes-jewish Hospital
Greenberg, Cheryl R.
Canada, Winnipeg
University of Manitoba
Salman, Nada J.
United Arab Emirates, Al Ain
Tawam Hospital
Bober, Michael B.
United States, Wilmington
Alfred I. Dupont Hospital for Children
McAlister, William H.
United States, St. Louis
St. Louis Children's Hospital
Wenkert, Deborah
United States, St. Louis
Washington University School of Medicine in St. Louis
Van Sickle, Bradley J.
United States, Nashville
Monroe Carell Jr. Children's Hospital at Vanderbilt
Simmons, Jill H.
United States, Nashville
Monroe Carell Jr. Children's Hospital at Vanderbilt
Edgar, Terence S.
United States, Green Bay
Prevea Health Clinic
Bauer, Martin L.
United States, Little Rock
University of Arkansas for Medical Sciences
Hamdan, Mohamed A.
United Arab Emirates, Al Ain
Tawam Hospital
Bishop, Nick J.
United Kingdom, Sheffield
Sheffield Children's Hospital
Lutz, Richard E.
United States, Omaha
University of Nebraska Medical Center
McGinn, Mairead
United Kingdom, Belfast
Royal Belfast Hospital for Sick Children
Craig, Stanley
United Kingdom, Belfast
Royal Belfast Hospital for Sick Children
Moore, Jean N.
United States, Springfield
St. John's Hospital
Taylor, John W.
United States, Green Bay
Prevea Health Clinic
United States, Green Bay
St. Vincent Hospital Green Bay
Cleveland, Robert H.
United States, Boston
Boston Children's Hospital
Cranley, William R.
United States, Boston
Boston Medical Center
Lim, Ruth
United States, Boston
Massachusetts General Hospital
Thacher, Tom D.
United States, Rochester
Mayo Clinic
Mayhew, Jill E.
Canada, Montreal
Enobia Pharma
Downs, Matthew
United States, Washington, D.c.
Statistics Collaborative
Millán, José Luis San
United States, San Diego
Sanford Burnham Prebys Medical Discovery Institute
Skrinar, Alison M.
Canada, Montreal
Enobia Pharma
Crine, Philippe
Canada, Montreal
Enobia Pharma
Landy, Hal
Canada, Montreal
Enobia Pharma
Statistics
Citations: 443
Authors: 27
Affiliations: 21
Identifiers
Doi:
10.1056/NEJMoa1106173
ISSN:
00284793
e-ISSN:
15334406
Research Areas
Genetics And Genomics
Maternal And Child Health