Safety and Efficacy Study of Asfotase Alfa in Severely Affected Infants With Hypophosphatasia (HPP)

Hypophosphatasia (HPP) is a life-threatening, genetic, and ultra-rare metabolic disease
characterized by defective bone mineralization and impaired phosphate and calcium regulation
that can lead to progressive damage to multiple vital organs, including destruction and
deformity of bones, profound muscle weakness, seizures, impaired renal function, and
respiratory failure. There are no approved disease-modifying treatments for patients with
this disease. There is also limited data available on the natural course of this disease over
time, particularly in patients with the juvenile-onset form.

Inclusion Criteria:

- Legal guardian(s) must provide informed consent prior to any study procedures

- Documented diagnosis of severe HPP as indicated by:

- Total serum alkaline phosphatase at least 3 standard deviations (SD) below the
mean for age

- Plasma pyridoxal 5'-phosphate (PLP) at least 4 times the upper limit of normal

- Radiographic evidence of HPP (hypophosphatasia), characterized by:

- Flared and frayed metaphyses

- Severe, generalized osteopenia

- Widened growth plates

- One or more HPP-related findings:

- History or presence of:

- Non-traumatic post-natal fracture

- Delayed fracture healing

- History of elevated serum calcium

- Functional craniosynostosis with decreased head circumference growth

- Nephrocalcinosis

- Respiratory compromise

- Rachitic chest deformity and/or vitamin B6 dependent seizures

- Failure to thrive

- Onset of symptoms prior to 6 months of age

- Age ≤ 36 months

- Otherwise medically stable (patient may be on ventilatory support)

- Legal guardian(s) must be willing to comply with the study

Exclusion Criteria:

- History of sensitivity to any of the constituents of the study drug

- Current or prior clinically significant cardiovascular, endocrinologic, hematologic,
hepatic, immunologic, metabolic, infectious, urologic, pulmonary, neurologic,
dermatologic, renal condition and/or other major disease which, in the opinion of the
investigator, precludes study participation

- Treatment with an investigational drug within 1 month prior to the start of study drug
administration

- Current enrollment in any other study involving an investigational new drug, device or
treatment for HPP (e.g., bone marrow transplantation)

- Low serum calcium, phosphate or 25(OH) vitamin D

- Current evidence of a treatable form of rickets

- Prior treatment with bisphosphonate