Pharmacokinetic and Dose Response Study of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia (HPP)

Study Overview
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Brief Summary
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The purpose of this study was to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of asfotase alfa in adult participants with pediatric-onset HPP.

Official Title
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A Phase 2a, Randomized, Multicenter, Open-Label, Pharmacokinetic, and Dose Response Study of Asfotase Alfa in Adult Patients With Pediatric-Onset Hypophosphatasia

Conditions
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Hypophosphatasia

Intervention / Treatment
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* Drug: Asfotase alfa


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants or their legal representative(s) provided written informed consent prior to undergoing any study-related procedures. Participants were ≥18 years of age at Screening. Participant had pediatric-onset hypophosphatasia (HPP), defined as onset of first sign(s)/symptom (s) of HPP prior to 18 years of age. Participants had a documented diagnosis of HPP as indicated by a documented history of HPP-related skeletal abnormalities and 1 or more of the following: Documented tissue-nonspecific alkaline phosphatase (TNSALP) gene mutation(s) from a certified laboratory. Serum alkaline phosphatase (ALP) level below the age-adjusted normal range AND plasma pyridoxal-5'-phosphate (PLP) above the upper limit of normal at Screening. Participants had a plasma inorganic pyrophosphate (PPi) level of ≥3.9 micromolar (µM) at Screening. Female participants of childbearing potential had a negative pregnancy test at the time of enrollment. Sexually active male and female participants of childbearing potential agreed to use a highly effective method of birth control during the study. Female participants not of child-bearing potential due to sterilization (at least 6 weeks after surgical bilateral oophorectomy with or without hysterectomy or at least 6 weeks after tubal ligation) confirmed by medical history, or menopause. Participants were willing to comply with study procedures and the visit schedule. Exclusion Criteria: Investigational site personnel directly affiliated with this study and/or their immediate families. Immediate family was defined as a spouse, parent, child, or sibling, whether biological or legally adopted. Employees of Alexion Pharmaceuticals. Currently enrolled in a clinical study involving another study drug or non-approved use of a drug or device. Participated, within the last 30 days, in a clinical study involving a study drug (other than the study drug used in this study). Completed or withdrawn from this study or any other study investigating asfotase alfa in the previous 3 years. Women who were pregnant, planning to become pregnant, or breastfeeding. Serum 25-hydroxy Vitamin D levels below 20 nanogram (ng) per milliliter (mL) at Screening. Screening serum creatinine or parathyroid hormone (PTH) levels ≥1.5 times the upper limit of normal. Any medical condition, serious concurrent illness and/or injury, recent orthopedic surgery, or other extenuating circumstance that, in the opinion of the Investigator, may have significantly interfered with study compliance or study endpoints. Prior treatment with bisphosphonates within 2 years of study entry for any length of time or for more than 2 consecutive years at any prior timepoint. Treatment with PTH, strontium, or sclerostin inhibitors within 6 months prior to the first dose of study drug. Unwilling or unable to comply with the use of a data collection device on which study participants directly recorded data.

Ages Eligible for Study
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Minimum Age: 18 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: Asfotase Alfa 0.5 mg/kg Dose<br>Participants received 0.5 milligrams (mg) per kilogram (kg) of asfotase alfa administered subcutaneously (SC) 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1. | Drug: Asfotase alfa<br> <br> * Other names: Strensiq;|
| Experimental: Asfotase Alfa 2.0 mg/kg Dose<br>Participants received 2.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1. | Drug: Asfotase alfa<br> <br> * Other names: Strensiq;|
| Experimental: Asfotase Alfa 3.0 mg/kg Dose<br>Participants received 3.0 mg/kg of asfotase alfa administered SC 3 times a week from Weeks 3 through 9 following the initial single dose on Day 1 in Week 1. | Drug: Asfotase alfa<br> <br> * Other names: Strensiq;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9 | Plasma PPi concentrations were determined using a specific enzyme-catalyzed reaction with a radiolabelled marker in a 3-step process. Baseline plasma PPi values were calculated by averaging pre-dose values from samples collected during the Run-in Period at -168, -156, -24, -12, and 0 hours before Baseline. Week 9 plasma PPi values were calculated using blood samples collected before administration of the 3rd dose. The analysis was a restricted maximum likelihood (REML)-based repeated measures mixed model with treatment, visit, sex, Baseline PPi, Baseline weight group (≥ median versus < median), and study drug lot assignment as factors, and an unstructured covariance structure for within-participant correlation. Per inclusion criteria, participants had to have had a Screening PPi concentration of ≥3.9 micromolar (μM). Three participants (1 in each group) had Screening PPi concentrations of ≥3.9 μM, but Baseline PPi values ranged between 3.5 to 3.8 μM. | Baseline to Week 9 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9 | Plasma PLP was quantified using liquid chromatography/mass spectrometry. Baseline plasma PLP values were calculated by averaging the pre-dose PLP values from blood samples collected during the Run-in Period at -168, -156, -24, -12, and 0 hours before Baseline. Week 9 PLP values were calculated using blood samples collected before the administration of the 3rd dose. The analysis was a REML-based repeated measures mixed model with treatment, visit, sex, Baseline PPi, Baseline weight group (≥ median versus < median) and study drug lot assignment as factors, and an unstructured covariance structure for within-participant correlation. | Baseline to Week 9 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPP, asfotase alfa