Safety Study of Human Recombinant Tissue Non-Specific Alkaline Phosphatase Fusion Protein Asfotase Alfa in Adults With Hypophosphatasia (HPP)

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)

This clinical trial studies the safety, tolerability, and pharmacology of asfotase alfa when given to adults with HPP.

Study Overview

• Status: Completed
• Conditions: Hypophosphatasia (HPP)
• Intervention / Treatment: Biological: Asfotase Alfa; Biological: Asfotase Alfa

Detailed Description

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 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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1S1
      • Department of Pediatrics & Child Health, Health Sciences Centre Winnipeg, University of Manitoba
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Barnes Jewish Hospital- Washington University School of Medicine
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

In order to qualify for participation, patients must meet all of the following criteria:

• Patients must provide written informed consent, including privacy authorization, prior to participation.
• Women of childbearing potential must sign the Women of Childbearing Potential Addendum and must be using an acceptable method of birth control. Women considered not of childbearing potential must be surgically sterile (total hysterectomy, bilateral salpingo-oophorectomy, or tubal ligation) or post-menopausal, which is defined as a complete cessation of menstruation for at least one year after the age of 45 years. All women must have a serum pregnancy test conducted at Screening prior to enrollment and the results must be negative.
• Be between 18 and 80 years of age at the time of consent
• Patients must be medically stable in the opinion of the Investigator.
• Patients must be willing to comply with study procedures and the visit schedule.

• Pre-established clinical diagnosis of HPP as indicated by:

  • a. Serum alkaline phosphatase at least 3 SD below the mean for age
  • b. Radiologic evidence of osteopenia or osteomalacia

  • c. Two or more HPP-related findings:

    • i. Plasma pyridoxal 5'-phosphate at least 2.5 SD above the mean (no vitamin B6 administered for at least 1 week prior to determination
    • ii. History of rickets
    • iii. History of premature loss of deciduous teeth
    • iv. Bone deformity consistent with osteomalacia or past history of rickets

    • v. History of any one of the following:

      • 1. Non-traumatic fracture
      • 2. Pseudofracture
      • 3. Non-healing fracture

Exclusion Criteria:

In order to qualify for participation, patients must not meet any of the following criteria:

• Women who are pregnant or lactating.
• History of sensitivity to any of the constituents of the study drug.
• Low levels of serum calcium, magnesium or phosphate.
• Serum 25(OH) vitamin D level below 9.2 ng/mL.
• Elevated serum creatinine or parathyroid hormone level.
• Known cause of hypophosphatasemia other than HPP.
• Current or prior clinically significant cardiac, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal condition and/or other major disease which, in the opinion of the investigator, precludes study participation.
• Treatment with a bisphosphonate or parathyroid hormone (PTH) within 6 months prior to the start of Asfotase Alfa administration.
• Participation in an interventional or investigational drug study within 30 days prior to study participation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.; 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.
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; 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.; 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the safety and tolerability of Asfotase Alfa given intravenously and given subcutaneously.	Within the first 2 months (8 weeks).

Secondary Outcome Measures

Outcome Measure	Time Frame
To assess the pharmacokinetics (PK) of Asfotase Alfa given intravenously and subcutaneously	Within the first 2 months (8 weeks)
To assess the bioavailability of the subcutaneous Asfotase Alfa	Within the first 2 months (8 weeks)

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals

Publications and helpful links

General Publications

• Millan JL, Narisawa S, Lemire I, Loisel TP, Boileau G, Leonard P, Gramatikova S, Terkeltaub R, Camacho NP, McKee MD, Crine P, Whyte MP. Enzyme replacement therapy for murine hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):777-87. doi: 10.1359/jbmr.071213.
• Drake MT, Khosla S. Bone-targeted replacement therapy for hypophosphatasia. J Bone Miner Res. 2008 Jun;23(6):775-6. doi: 10.1359/jbmr.080305. No abstract available.

Helpful Links

• Hypophosphatasia Website
• Hypophosphatasia Website for Healthcare Providers
• HPP support group
• US Hypophosphatasia Group (Soft Bones)

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (Actual): January 1, 2009
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: August 19, 2008
• First Submitted That Met QC Criteria: August 20, 2008
• First Posted (Estimate): August 21, 2008

Study Record Updates

• Last Update Posted (Actual): March 29, 2019
• Last Update Submitted That Met QC Criteria: March 28, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: Hypophosphatasia; Bone Disease; Soft Bones; Low Alkaline Phosphatase; genetic metabolic disorder; alkaline phosphatase; tissue non-specific alkaline phosphatase; rickets; osteomalacia
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Metal Metabolism, Inborn Errors; Hypophosphatasia; Physiological Effects of Drugs; Immunologic Factors; Immunoglobulin G
• Other Study ID Numbers: ENB-001-08