• Effect of ENB-0040 treatment on skeletal manifestations of HPP [ Time Frame: Baseline, every 6 months through End of Study ] [ Designated as safety issue: No ]
  The effect of ENB-0040 on the skeletal manifestations of HPP after 6 months of ENB-0040 treatment will be measured by comparing Baseline, Months 6, 12, and End of Study radiographs of the lateral skull and spine, chest, upper and lower extremities using a qualitative Radiographic Global Impression of Change (RGI-C) scale
  
  
• Safety and tolerability of repeated subcutaneous (SC) injections of ENB-0040 [ Time Frame: Baseline through End of Study ] [ Designated as safety issue: Yes ]
  The safety and tolerability of ENB-0040 will be assessed by monitoring adverse events and injection-associated reactions, as well as changes in physical examination findings, vital signs, clinical laboratory evaluations (including routine chemistry, hematology and urinalysis, 25(OH) vitamin D and urinary calcium:creatinine ratio), renal ultrasound and funduscopy findings and antibody evaluations. Changes in concomitant medications and therapies, calcium intake and caloric input will also be monitored.
  
  

• Effect of ENB-0040 treatment on ventilator-free survival [ Time Frame: Baseline through End of Study ] [ Designated as safety issue: No ]
  For patients who are not mechanically ventilated at the time of enrollment, the percentage who are alive and ventilator free after receiving ENB-0040 as compared to an age-matched historical control group
  
  
• Effect of ENB-0040 treatment on respiratory function [ Time Frame: Screening, Baseline, through End of Study ] [ Designated as safety issue: No ]
  Effect of ENB-0040 treatment on respiratory function will be measured by monitoring ventilator status and settings (where applicable).
  
  
• Effect of ENB-0040 treatment on physical growth [ Time Frame: Screening, Baseline, through End of Study ] [ Designated as safety issue: No ]
  Effect of ENB-0040 treatment on physical growth will be measured by body weight, length, arm span, head circumference, and chest circumference
  
  
• Effect of ENB-0040 treatment on tooth loss [ Time Frame: Baseline through End of Study ] [ Designated as safety issue: No ]
  Tooth loss will be evaluated by counting the number of teeth present at Baseline and the number of teeth gained and lost during the study
  
  
• Pharmacokinetic (PK) properties of ENB-0040 [ Time Frame: Baseline through End of Study ] [ Designated as safety issue: No ]
  The PK properties of ENB-0040 will be evaluated by monitoring ENB-0040 activity in serum
  
  
• Effect of ENB-0040 on biomarkers [ Time Frame: Screening, Baseline, through End of Study ] [ Designated as safety issue: No ]
  Effect of ENB-0040 on plasma inorganic pyrophosphate (PPi) and plasma pyridoxal-5' phosphate (PLP).
  
  
• Effect of ENB-0040 on serum parathyroid hormone (PTH) [ Time Frame: Baseline through End of Study ] [ Designated as safety issue: No ]
  Effect of ENB-0040 on serum parathyroid hormone (PTH)
  
  

Biological: ENB-0040
Patients will receive a total of 6 mg/kg/week of ENB-0040 administered by SC injection. Patients may receive either 1 mg/kg ENB-0040 6 times per week or 2 mg/kg ENB-0040 3 times per week at the discretion of the Investigator and Sponsor. The maximum dose of ENB-0040 per injection will be 40 mg.

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 may have less severe disease but can have frequent fractures, bone pain, bowing of the long bones and muscle weakness. Morbidity is generally cumulative.