Open-Label Study of Asfotase Alfa in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)

An Open-Label, Multicenter, Multinational Study of the Safety, Efficacy and Pharmacokinetics of Asfotase Alfa (Human Recombinant Tissue-nonspecific Alkaline Phosphatase Fusion Protein) in Infants and Children ≤ 5 Years of Age With Hypophosphatasia (HPP)

This clinical trial was 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 was to test the safety and efficacy of a study drug called asfotase alfa (human recombinant tissue non-specific alkaline phosphate fusion protein) to see what effects it has on patients 5 years of age or less with HPP.

Asfotase alfa was formerly referred to as ENB-0040

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 limited data available on the natural course of this disease over time, particularly in patients with the juvenile-onset form.

Inclusion Criteria:

Patients must meet all of the following criteria for enrollment in this study:

1. Parent or legal guardian(s) must provide written informed consent prior to any study procedures being performed and must be willing to comply with all study-required procedures. Where appropriate and required by local regulations, patient assent should also be provided prior to any study procedures being performed.

2. Documented diagnosis of HPP as indicated by:

   1. Total serum alkaline phosphatase (ALP) below the lower limit of normal for age NOTE: Historical values for ALP may be used to determine patient eligibility.

   2. Plasma pyridoxal-5'-phosphate (PLP) above the upper limit of normal (unless patient is receiving pyridoxine for seizures) NOTE: Historical values for PLP may be used to determine patient eligibility.

   3. Radiographic evidence of HPP at screening, characterized by:

      • Flared and frayed metaphyses, and
      • Severe, generalized osteopenia, and
      • Widened growth plates, and
      • Areas of radiolucency or sclerosis

   4. Two or more of the following HPP-related findings:

      • History or presence of: i) Nontraumatic post-natal fracture or ii) Delayed fracture healing
      • Nephrocalcinosis or history of elevated serum calcium
      • Functional craniosynostosis
      • Respiratory compromise or rachitic chest deformity
      • Vitamin B6-responsive seizures
      • Failure to thrive

3. Onset of symptoms prior to 6 months of age

4. Chronological age or adjusted age for premature infants born ≤ 37 weeks gestation of ≤ 5 years

5. Otherwise medically stable in the opinion of the Investigator and/or Sponsor

Exclusion criteria:

Patients will be excluded from enrollment in this study if they meet any of the following exclusion criteria:

1. Clinically significant disease that precludes study participation, in the opinion of the Investigator and/or Sponsor
2. Serum calcium or phosphate levels below the normal range
3. Current evidence of treatable form of rickets
4. Prior treatment with bisphosphonates
5. Treatment with an investigational drug within 1 month prior to the start of asfotase alfa treatment
6. Current enrollment in any other study involving an investigational new drug, device or treatment for HPP (e.g., bone marrow transplantation)
7. Intolerance to the investigational product (IP) or any of its excipients
8. Previous participation in the same study
9. Family relative of the Investigator