Safety and Efficacy of Asfotase Alfa in Juvenile Patients With Hypophosphatasia (HPP)

A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Historical Control Study of the Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Children With Hypophosphatasia (HPP)

This clinical trial studied the safety and efficacy of asfotase alfa in children with HPP compared to a historical control group.

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.

Efficacy analyses were prospectively defined in the protocol with a comparison to historical controls. The historical control group came from patients whose characteristics matched as closely as possible the entry criteria for the trial. The control group included all patients who had x-rays within the age range defined by the inclusion criteria of this study (5 to 12 years of age, inclusive, with open growth plates).

The pre-specified plan for analysis was to combine the two asfotase alfa treated groups (asfotase alfa 2 mg/kg subcutaneous (SC) injection three times per week or 3 mg/kg subcutaneous (SC) injection three times per week) and compare them to historical controls.

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1S1
      • The University of Manitoba Health Services Centre
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63131
      • Shriners Hospital for Children

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 10 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Written informed consent from parent or legal guardian prior to participation
2. Patients > 5 and < 12 years of age with open growth plates at time of enrollment
3. Tanner stage of 2 or less indicating pre-pubescence

4. Documented history of HPP, as evidenced by:

   • Presence of HPP-related rickets on skeletal radiographs of the wrist and knee
   • Serum alkaline phosphatase (ALP) below age-adjusted normal range
   • Plasma PLP at least twice the upper limit of normal
5. 25(OH) vitamin D level > 20 ng/mL
6. Ability of patient and parent/guardian to comply with study requirements

Exclusion Criteria:

1. Serum calcium or phosphorus below age-adjusted normal range
2. History of sensitivity to any study drug constituent
3. Medical condition, serious intercurrent illness, or other extenuating circumstance that, in the opinion of the Investigator, may significantly interfere with study compliance, including all prescribed evaluations and follow-up activities
4. Treatment with an investigational drug within 1 month before start of study drug
5. Current enrollment in any other study involving an investigational new drug, device, or treatment for HPP (e.g., bone marrow transplantation)
6. Current evidence of a treatable form of rickets
7. Prior treatment with bisphosphonates
8. Bone fracture or orthopedic surgery within the past 12 months that, in the opinion of the Investigator would interfere with the ability of study patient to comply with study protocol
9. Major congenital abnormality other than those associated with HPP

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 2 mg/kg; 2 mg/kg subcutaneous injection three times per week.	Biological: asfotase alfa; 2 mg/kg subcutaneous injection three times per week for 6 months.; Other Names: Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein; sALP-Fc-D10; Biological: asfotase alfa; 3 mg/kg subcutaneous injection three times per week for 6 months.; Other Names: Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein; sALP-Fc-D10
Active Comparator: 3 mg/kg; 3 mg/kg subcutaneous injection three times per week.	Biological: asfotase alfa; 2 mg/kg subcutaneous injection three times per week for 6 months.; Other Names: Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein; sALP-Fc-D10; Biological: asfotase alfa; 3 mg/kg subcutaneous injection three times per week for 6 months.; Other Names: Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein; sALP-Fc-D10

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Rickets Severity on Skeletal Radiographs From Baseline to Week 24 as Measured by the Radiographic Global Impression of Change (RGI-C) Scale	A 7-point RGI-C (radiographic global impression of change) score was used to rate change in rickets severity. Only those patients with a minimum score of +2 indicating substantial healing of rickets) were considered responders. Three pediatric radiologists not affiliated with the conduct of the study performed the ratings.	Baseline and Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Osteomalacia - Osteoid Thickness (as Measured by Trans-iliac Crest Bone Biopsy)	Change from Baseline to Week 24 in osteoid thickness.	Baseline and Week 24
Change in Osteomalacia - Osteoid Volume/Bone Volume (as Measured by Trans-iliac Crest Bone Biopsy)	Change from Baseline to Week 24 in osteoid volume/bone volume (%), calculated as the absolute difference of the Baseline and Week 24 percentages.	Baseline and Week 24
Change in Osteomalacia - Mineralization Lag Time (as Measured by Trans-iliac Crest Bone Biopsy)	Change from Baseline to Week 24 in mineralization lag time.	Baseline and Week 24
Change in Height (Z-scores)	Change from Baseline to Week 24 in Height Z-Score. Height Z-Scores assigned based on Centers for Disease Control (CDC) growth charts and methodology.	Baseline and Week 24
Change in Biomarkers of Asfotase Alfa Activity as Measured by Plasma Inorganic Pyrophosphate (PPi)	Change from Baseline to Week 24 in Plasma PPi	Baseline and Week 24
Change in Biomarkers of Asfotase Alfa Activity as Measured by Pyridoxal-5'-Phosphate (PLP)	Change from Baseline to Week 24 in Plasma PLP	Baseline and Week 24
Maximum Serum Concentration of Asfotase Alfa (Cmax).	Maximum serum concentration observed following single dose of asfotase alfa.	Study Week 1 (0 to 48 hours post-dose)
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax)	Maximum serum concentration observed following single dose of asfotase alfa.	Study Week 1 (0 to 48 hours post-dose)
Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)	Area under serum concentration-time curve to last measurable concentration following single dose of asfotase alfa.	Study Week 1 (0 to 48 hours post-dose)
Maximum Serum Concentration of Asfotase Alfa (Cmax).	Maximum serum concentration observed following multiple doses of asfotase alfa.	Study Week 6 (0 to 48 hours post-dose)
Time at Maximum Serum Concentration of Asfotase Alfa (Tmax).	Time at maximum serum concentration observed following multiple doses of asfotase alfa.	Study Week 6 (0 to 48 hours post-dose)
Area Under Serum Concentration-time Curve to Last Measurable Concentration of Asfotase Alfa (AUCt)	Area under serum concentration-time curve to last measurable concentration following multiple doses of asfotase alfa.	Study Week 6 (0 to 48 hours post-dose).

Collaborators and Investigators

• Sponsor: Alexion Pharmaceuticals

Publications and helpful links

General Publications

• Simmons JH, Rush ET, Petryk A, Zhou S, Martos-Moreno GA. Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data. Bone. 2020 Aug;137:115413. doi: 10.1016/j.bone.2020.115413. Epub 2020 May 14.
• Whyte MP, Madson KL, Phillips D, Reeves AL, McAlister WH, Yakimoski A, Mack KE, Hamilton K, Kagan K, Fujita KP, Thompson DD, Moseley S, Odrljin T, Rockman-Greenberg C. Asfotase alfa therapy for children with hypophosphatasia. JCI Insight. 2016 Jun 16;1(9):e85971. doi: 10.1172/jci.insight.85971.
• 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.

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: September 1, 2009
• Primary Completion (Actual): July 1, 2010
• Study Completion (Actual): July 1, 2010

Study Registration Dates

• First Submitted: August 3, 2009
• First Submitted That Met QC Criteria: August 5, 2009
• First Posted (Estimate): August 6, 2009

Study Record Updates

• Last Update Posted (Actual): April 1, 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; HPP; 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-006-09