Enzyme-replacement therapy in life-threatening hypophosphatasia.

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.).

• Authors: 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 Lim, Tom D Thacher, Jill E Mayhew, Matthew Downs, José Luis Millán, Alison M Skrinar, Philippe Crine, Hal Landy
• Journal: The New England journal of medicine (N Engl J Med) Vol. 366 Issue 10 Pg. 904-13 (Mar 08 2012) ISSN: 1533-4406 [Electronic] United States
• PMID: 22397652 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't)

Chemical References

• Immunoglobulin G
• Recombinant Fusion Proteins
• Alkaline Phosphatase
• asfotase alfa

Topics

• Alkaline Phosphatase (administration & dosage, pharmacology, therapeutic use)
• Biological Availability
• Bone and Bones (diagnostic imaging, drug effects)
• Child, Preschool
• Enzyme Replacement Therapy (adverse effects)
• Female
• Humans
• Hypophosphatasia (complications, drug therapy)
• Immunoglobulin G (administration & dosage, pharmacology, therapeutic use)
• Infant
• Infant, Newborn
• Infusions, Intravenous
• Injections, Subcutaneous (adverse effects)
• Male
• Radiography
• Recombinant Fusion Proteins (administration & dosage, pharmacology, therapeutic use)
• Rickets (diagnostic imaging, drug therapy, etiology)
• Treatment Outcome