Safety Study of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)
This Clinical Trial is being conducted to study Hypophosphatasia (HPP), a bone disorder caused by gene mutations or changes. These gene mutations cause low levels of an enzyme needed to harden bone. The purpose of this study is to test the safety of Asfotase Alfa and see what effects it has on humans and HPP. The study will also look at differences in injecting the drug into a vein with a needle (intravenously) and injecting it under the surface of the skin (subcutaneously).
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Multicenter, Open-Label, Dose Escalating Study of the Safety, Tolerability and Pharmacology of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)|
- To determine the safety and tolerability of Asfotase Alfa given intravenously and given subcutaneously. [ Time Frame: Within the first 2 months (8 weeks). ] [ Designated as safety issue: Yes ]
- To assess the pharmacokinetics (PK) of Asfotase Alfa given intravenously and subcutaneously [ Time Frame: Within the first 2 months (8 weeks) ] [ Designated as safety issue: No ]
- To assess the bioavailability of the subcutaneous Asfotase Alfa [ Time Frame: Within the first 2 months (8 weeks) ] [ Designated as safety issue: No ]
|Study Start Date:||August 2008|
|Study Completion Date:||February 2009|
|Primary Completion Date:||January 2009 (Final data collection date for primary outcome measure)|
Experimental: Cohort 1
3 HPP patients are to be enrolled in Cohort 1 and receive a single IV dose and three weekly SC doses of Asfotase Alfa . End of Study for patients in Cohort 1 is at 8 weeks.
Biological: Asfotase Alfa
The initial IV dose to be administered to patients was set at one-tenth the no adverse effect level (NOAEL) as determined by one month toxicology studies in animals in which Asfotase Alfa was administered as a single weekly IV dose. The SC doses to be administered are lower than the IV doses and are thought to be near or at the anticipated daily efficacious dose. Dosing will be as follows:
Cohort 1: In Week 1, patients will receive an IV infusion of Asfotase Alfa at a dose of 3 mg/kg. In Weeks 2, 3 and 4, patients will receive weekly SC injections of Asfotase Alfa at a dose of 1 mg/kg SC.
Experimental: Cohort 2
Cohort 2 will begin when the safety and PK data for Cohort 1 weeks 1-4 has been reviewed by the DSMB. Cohort 2 will enroll 3 HPP patients and will receive a higher dose level than Cohort 1. Cohort 2 patients will have a single IV dose and three weekly SC doses of Asfotase Alfa . End of Study for patients in Cohort 2 is at 8 weeks.
Biological: Asfotase Alfa
Cohort 2: In Week 1, patients will receive an IV infusion of Asfotase Alfa at a dose of 7 mg/kg. In Weeks 2, 3 and 4, patients will receive weekly SC injections of Asfotase Alfa at a dose of 1.5 mg/kg SC.
Asfotase Alfa was formerly referred to as ENB-0040
Hypophosphatasia (HPP) is a rare inherited form of rickets and osteomalacia caused by inactivating mutations in the gene encoding the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). The prevalence of the disease is thought to be about 1:100,000 although it is markedly higher in a small Canadian Mennonite population (Fraser 1957, Chodirker 1990). Inheritance can be autosomal recessive or dominant, and penetrance is variable resulting in a wide range of clinical expressivity. HPP differs from other forms of rickets and osteomalacia in that serum levels of calcium and phosphorus are generally normal or even elevated (Whyte 2002). Low circulating levels of alkaline phosphatase with elevated serum or urine levels of the TNSALP substrates inorganic pyrophosphate (PPi), pyridoxal 5'-phosphate (PLP) and phosphoethanolamine (PEA) are the biochemical hallmarks of this inborn error of metabolism.
Disease severity in HPP is inversely related to the age at symptom presentation. The most severe cases occur in utero and almost invariably result in death, generally due to pulmonary compromise. Infants who present in the first six months of life have about 50% mortality. Children and adults have less severe disease but can have frequent fractures, bone pain, bowing of the long bones and muscle weakness, and morbidity is generally cumulative. Some patients cannot ambulate independently and end up wheelchair-bound.
|United States, Missouri|
|Barnes Jewish Hospital- Washington University School of Medicine|
|St. Louis, Missouri, United States, 63110|
|United States, North Carolina|
|Duke University Medical Center|
|Durham, North Carolina, United States, 27710|
|Department of Pediatrics & Child Health, Health Sciences Centre Winnipeg, University of Manitoba|
|Winnipeg, Manitoba, Canada, R3A 1S1|
|Principal Investigator:||Cheryl Rockman-Greenberg, MD||Department of Pediatrics, University of Manitoba, 840 Sherbrooke Street, Winnipeg, Canada R3A 1S1|