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

Phase 2

Completed

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

Recruitment & Eligibility

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Completed or withdrawn from this study or any other study investigating asfotase alfa in the previous 3 years.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.

Arm && Interventions

Group	Intervention	Description
Asfotase Alfa 2.0 mg/kg Dose	Asfotase alfa	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.
Asfotase Alfa 0.5 mg/kg Dose	Asfotase alfa	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.
Asfotase Alfa 3.0 mg/kg Dose	Asfotase alfa	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.

Primary Outcome Measures

Name	Time	Method
Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9	Baseline to 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.

Secondary Outcome Measures

Name	Time	Method
Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9	Baseline to 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.

Locations (4): University of Würzburg
🇩🇪
Würzburg, Germany
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
Vanderbilt Medical Center Endocrinology
🇺🇸
Nashville, Tennessee, United States
Shriners Hospitals for Children
🇺🇸
Saint Louis, Missouri, United States