Enzyme-replacement therapy in life-threatening hypophosphatasia

Michael P. Whyte, Cheryl R. Greenberg, Nada J. Salman, Michael B. Bober, William H. McAlister, Deborah Wenkert, Bradley J. Van Sickle, Jill H. Simmons, Terence S. Edgar, Martin L. Bauer, Mohamed A. Hamdan, Nick Bishop, Richard E Lutz, Mairead McGinn, Stanley Craig, Jean N. Moore, John W. Taylor, Robert H. Cleveland, William R. Cranley, Ruth LimTom D. Thacher, Jill E. Mayhew, Matthew Downs, José Luis Millán, Alison M. Skrinar, Philippe Crine, Hal Landy

Research output: Contribution to journalArticle

251 Citations (Scopus)

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.).

Original languageEnglish (US)
Pages (from-to)904-913
Number of pages10
JournalNew England Journal of Medicine
Volume366
Issue number10
DOIs
StatePublished - Mar 8 2012

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Hypophosphatasia
Enzyme Replacement Therapy
Rickets
Isoenzymes
Alkaline Phosphatase
Dietary Calcium
Osteomalacia
Lung
Pyridoxal Phosphate
Hypocalcemia
Bone Diseases
Therapeutics
Dietary Supplements
Parathyroid Hormone
Knockout Mice
Respiratory Insufficiency
Thorax
Pharmacokinetics
asfotase alfa
Safety

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Whyte, M. P., Greenberg, C. R., Salman, N. J., Bober, M. B., McAlister, W. H., Wenkert, D., ... Landy, H. (2012). Enzyme-replacement therapy in life-threatening hypophosphatasia. New England Journal of Medicine, 366(10), 904-913. https://doi.org/10.1056/NEJMoa1106173

Enzyme-replacement therapy in life-threatening hypophosphatasia. / Whyte, Michael P.; Greenberg, Cheryl R.; Salman, Nada J.; Bober, Michael B.; McAlister, William H.; Wenkert, Deborah; Van Sickle, Bradley J.; Simmons, Jill H.; Edgar, Terence S.; Bauer, Martin L.; Hamdan, Mohamed A.; Bishop, Nick; Lutz, Richard E; McGinn, Mairead; Craig, Stanley; Moore, Jean N.; Taylor, John W.; Cleveland, Robert H.; Cranley, William R.; Lim, Ruth; Thacher, Tom D.; Mayhew, Jill E.; Downs, Matthew; Millán, José Luis; Skrinar, Alison M.; Crine, Philippe; Landy, Hal.

In: New England Journal of Medicine, Vol. 366, No. 10, 08.03.2012, p. 904-913.

Research output: Contribution to journalArticle

Whyte, MP, Greenberg, CR, Salman, NJ, Bober, MB, McAlister, WH, Wenkert, D, Van Sickle, BJ, Simmons, JH, Edgar, TS, Bauer, ML, Hamdan, MA, Bishop, N, Lutz, RE, McGinn, M, Craig, S, Moore, JN, Taylor, JW, Cleveland, RH, Cranley, WR, Lim, R, Thacher, TD, Mayhew, JE, Downs, M, Millán, JL, Skrinar, AM, Crine, P & Landy, H 2012, 'Enzyme-replacement therapy in life-threatening hypophosphatasia', New England Journal of Medicine, vol. 366, no. 10, pp. 904-913. https://doi.org/10.1056/NEJMoa1106173
Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D et al. Enzyme-replacement therapy in life-threatening hypophosphatasia. New England Journal of Medicine. 2012 Mar 8;366(10):904-913. https://doi.org/10.1056/NEJMoa1106173
Whyte, Michael P. ; Greenberg, Cheryl R. ; Salman, Nada J. ; Bober, Michael B. ; McAlister, William H. ; Wenkert, Deborah ; Van Sickle, Bradley J. ; Simmons, Jill H. ; Edgar, Terence S. ; Bauer, Martin L. ; Hamdan, Mohamed A. ; Bishop, Nick ; Lutz, Richard E ; McGinn, Mairead ; Craig, Stanley ; Moore, Jean N. ; Taylor, John W. ; Cleveland, Robert H. ; Cranley, William R. ; Lim, Ruth ; Thacher, Tom D. ; Mayhew, Jill E. ; Downs, Matthew ; Millán, José Luis ; Skrinar, Alison M. ; Crine, Philippe ; Landy, Hal. / Enzyme-replacement therapy in life-threatening hypophosphatasia. In: New England Journal of Medicine. 2012 ; Vol. 366, No. 10. pp. 904-913.
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T1 - Enzyme-replacement therapy in life-threatening hypophosphatasia

AU - Whyte, Michael P.

AU - Greenberg, Cheryl R.

AU - Salman, Nada J.

AU - Bober, Michael B.

AU - McAlister, William H.

AU - Wenkert, Deborah

AU - Van Sickle, Bradley J.

AU - Simmons, Jill H.

AU - Edgar, Terence S.

AU - Bauer, Martin L.

AU - Hamdan, Mohamed A.

AU - Bishop, Nick

AU - Lutz, Richard E

AU - McGinn, Mairead

AU - Craig, Stanley

AU - Moore, Jean N.

AU - Taylor, John W.

AU - Cleveland, Robert H.

AU - Cranley, William R.

AU - Lim, Ruth

AU - Thacher, Tom D.

AU - Mayhew, Jill E.

AU - Downs, Matthew

AU - Millán, José Luis

AU - Skrinar, Alison M.

AU - Crine, Philippe

AU - Landy, Hal

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N2 - 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.).

AB - 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.).

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