Safety and Efficacy Study of Asfotase Alfa in Adolescents and Adults With Hypophosphatasia (HPP)

Study Overview
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Brief Summary
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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 two doses of the study drug called asfotase alfa as compared to a control group to see effects on adolescents and adults with HPP.

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

Official Title
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A Randomized, Open-Label, Multicenter, Multinational, Dose-Ranging, Concurrent Control Study of the Safety, Efficacy, Pharmacokinetic of ENB-0040 (Human Recombinant Tissue Nonspecific Alkaline Phosphatase Fusion Protein) in Adolescents and Adults With Hypophosphatasia (HPP)

Conditions
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Hypophosphatasia

Intervention / Treatment
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* Drug: asfotase alfa
* Drug: asfotase alfa


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Patients must meet all of the following inclusion criteria to be eligible for participation in this study: Patients or their legal representative(s) must provide written informed consent prior to undergoing any study-related procedures Patients must be ≥ 13 and ≤ 65 years of age at the time of study enrollment Female patients of childbearing potential and sexually mature males must agree to use a medically acceptable form of birth control; for the purposes of this study, females are considered of non-childbearing potential if they are surgically sterile (i.e., have undergone a total hysterectomy, bilateral salpingo-oophorectomy or tubal ligation) or are post-menopausal, defined as having complete cessation of menstruation for at least 1 year after 45 years of age Patients must have a pre-established clinical diagnosis of HPP as indicated by: Serum alkaline phosphatase (ALP) below the age-adjusted normal range Plasma PLP at least twice the upper limit of normal (no vitamin B6 administered for at least 1 week prior to determination) Evidence of osteopenia or osteomalacia on skeletal radiographs Patients must have osteomalacia on bone biopsy, characterized by an MLT z-score of +2 or more (results from ENB-001-08 may be used) Patients must be willing to comply with study procedures and the visit schedule Exclusion criteria: Patients will be excluded from participation in this study if they meet any of the following exclusion criteria: Women who are pregnant or lactating History of sensitivity to tetracycline Serum calcium or phosphate levels below the normal range Serum 25(OH) vitamin D below 20 ng/mL Serum creatinine or parathyroid hormone (PTH) levels above the upper limit of normal 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 Orthopedic surgery within 12 months prior to study entry that may interfere with the ability to perform functional assessments for the study Prior treatment with bisphosphonates within 2 years of study entry for any length of time or for more than 2 years at any time point; for patients with prior bisphosphonate use that is allowed, the bone resorption markers serum C-telopeptide and urine N-telopeptide or urine deoxypyridinoline must also be within the normal range or elevated to be eligible for study participation Treatment with 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

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 65 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 |
| --- | --- |
| Experimental: Cohort 1<br>Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (2.1 mg/kg/week total) | Drug: asfotase alfa<br>* Cohort 1: Daily SC injections of 0.3 mg/kg asfotase alfa (total of 2.1 mg/kg/week)<br>|
| Experimental: Cohort 2<br>Cohort 2: Daily SC injections of 0.5 mg/kg asfotase alfa (3.5 mg/kg/week total) | Drug: asfotase alfa<br>* Cohort 2: Daily SC injections of 0.5 mg/kg Asfotase Alfa (3.5 mg/kg/week total)<br>|
| No Intervention: Concurrent Control<br>Following completion of the Week 24 visit, all patients (including those randomized to the concurrent control cohort) may be eligible to participate in an open-label extension treatment period. In this extension period, all patients will be treated with daily SC injections of 0.5 mg/kg/day asfotase alfa (a total of 3.5 mg/kg/week) for approximately 24 weeks, then subjects will receive 1 mg/kg/day 6 days/week for an additional 48 weeks or until regulatory approval of the drug. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline to Week 24 for Plasma Pyridoxal-5' Phosphate (PLP) | Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma pyridoxal-5' phosphate (PLP) | Baseline, Week 24 | 
| Change From Baseline to Week 24 for Plasma Inorganic Pyrophosphate (PPi) | Blood samples were collected to evaluate the effect of asfotase alfa on reduction in plasma inorganic pyrophosphate (PPi) | Baseline, Week 24 | 
| Safety and Tolerability of Asfotase Alfa | The safety and tolerability of daily subcutaneous (SC) injections of asfotase alfa was assessed by routine monitoring of patients for treatment-emergent adverse events (TEAEs) and injection-associated reactions (IARs). | Up to 288 weeks exposure to asfotase alfa | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Bone Mineral Content (BMC) as Measured by Dual-energy X-ray Absorptiometry (DXA) | A DXA scan was performed to evaluate bone mineral content (BMC) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks). | Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288. | 
| Change From Baseline in Bone Mineral Density (BMD) as Measured by Dual-energy X-ray Absorptiometry (DXA) | A DXA scan was performed to evaluate bone bone mineral density (BMD) of the spine, hip, and whole body during the primary (first 24 weeks) and extension treatment periods (up to 288 weeks). | Baseline, every 24 weeks through Week 96, then every 48 weeks until Week 288. | 
| Change in Walking Ability as Measured by the Six-Minute Walk Test (6MWT) | The patient was instructed to walk the length of a pre-measured hallway for 6 minutes. The primary measurement was distance walked (in meters). | Baseline, Week 24 (primary treatment period) and up to 288 weeks of asfotase alfa exposure | 
| Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Volume/Bone Volume | A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Volume/Bone Volume (%). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit. | Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). | 
| Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Osteoid Thickness | A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Osteoid Thickness (um). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit. | Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). | 
| Change From Baseline in HPP-related Osteomalacia as Measured by Trans-iliac Crest Bone Biopsy: Mineralization Lag Time | A trans-iliac crest bone biopsy was performed to quantify changes from Baseline in histomorphometric parameters relevant for evaluation of osteomalacia severity, including Mineralization Lag Time (days). The difference in time under observation between asfotase alfa groups (Week 48) and control group (Week 24) resulted from study design, ie, control subjects transitioned to active treatment after the Week 24 visit. | Baseline, Week 24 (Control group), and Week 48 (Asfotase alfa groups). | 

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