Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)

• Effect of Asfotase Alfa on reduction in plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5' phosphate (PLP) [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
  Blood samples will be collected to evaluate the effect of Asfotase Alfa on reduction in plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5' phosphate (PLP)
  
  
• Safety and Tolerability of Asfotase Alfa [ Time Frame: Month 6 ] [ Designated as safety issue: Yes ]
  The safety and tolerability of daily subcutaneous (SC) injections of Asfotase Alfa will be assessed by routine monitoring of patients for adverse events (AEs) and injection-associated reactions (IARs) and monitoring changes from Baseline in physical examination findings, vital signs, clinical laboratory evaluations, renal ultrasound findings, funduscopic examinations, antibody evaluations, and results of pregnancy testing (in women of childbearing potential only). Monitoring for changes in concomitant medications and therapies will also occur.
  
  

• Change in bone mineral content and density as measured by dual-energy X-ray absorptiometry (DXA) [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
  A DXA scan will be performed to evaluate bone mineral content and density of the spine, hip, and whole body.
  
  
• Change in walking ability as measured by the Six-Minute Walk Test (6MWT) [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
  The effect of Asfotase Alfa on gross motor function as measured by a modified version of the Bruininks-Oseretsky Test of Motor Proficiency - Second Edition (BOT-2)
  
  
• Change in HPP-related osteomalacia as measured by trans-iliac crest bone biopsy [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
  A trans-iliac crest bone biopsy will be performed to quantify osteomalacia severity.
  
  
• Change in biomarkers of Asfotase Alfa activity [ Time Frame: Month 6 ] [ Designated as safety issue: No ]
  Change in biomarkers of Asfotase Alfa activity as measured by plasma inorganic pyrophosphate (PPi), plasma pyridoxal-5'-phosphate (PLP) and serum parathyroid hormone (PTH)
  
  

Asfotase Alfa was formerly referred to as ENB-0040

Hypophosphatasia is 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. 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. Low circulating levels of alkaline phosphatase with elevated serum or urine levels of the TNSALP substrates, inorganic pyrophosphate (PPi), pyroxidal 5'-phosphate (PLP) and phosphoethanolamine (PEA), are the biochemical hallmarks of this inborn error of metabolism.

Disease severity 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 a mortality rate of approximately 50%. Children and adults have less severe disease but can have frequent fractures, bone pain, bowing of the long bones and muscle weakness. Morbidity is generally cumulative; some patients cannot ambulate independently and end up wheelchair-bound.