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

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

Detailed Description
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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.

Official Title
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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)

Conditions
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Hypophosphatasia (HPP)

Intervention / Treatment
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* Biological: asfotase alfa
* Biological: asfotase alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent from parent or legal guardian prior to participation Patients > 5 and < 12 years of age with open growth plates at time of enrollment Tanner stage of 2 or less indicating pre-pubescence 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 25(OH) vitamin D level > 20 ng/mL Ability of patient and parent/guardian to comply with study requirements Exclusion Criteria: Serum calcium or phosphorus below age-adjusted normal range History of sensitivity to any study drug constituent 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 Treatment with an investigational drug within 1 month before start of study drug Current enrollment in any other study involving an investigational new drug, device, or treatment for HPP (e.g., bone marrow transplantation) Current evidence of a treatable form of rickets Prior treatment with bisphosphonates 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 Major congenital abnormality other than those associated with HPP

Ages Eligible for Study
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Minimum Age: 5 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 2 mg/kg<br>2 mg/kg subcutaneous injection three times per week. | Biological: asfotase alfa<br>* 2 mg/kg subcutaneous injection three times per week for 6 months.<br>* Other names: sALP-Fc-D10;|
| Active Comparator: 3 mg/kg<br>3 mg/kg subcutaneous injection three times per week. | Biological: asfotase alfa<br>* 3 mg/kg subcutaneous injection three times per week for 6 months.<br>* Other names: sALP-Fc-D10;|

What is the study measuring?
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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). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rickets, Hypophosphatasia, HPP, Bone Disease, Soft Bones, Low Alkaline Phosphatase, genetic metabolic disorder, alkaline phosphatase, tissue non-specific alkaline phosphatase, osteomalacia