Hypophosphatasia
Conditions
Keywords
HPP, asfotase alfa
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.
Interventions
DRUGAsfotase alfa
Sponsors
Alexion Pharmaceuticals, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Participants or their legal representative(s) provided written informed consent prior to undergoing any study-related procedures. 2. Participants were ≥18 years of age at Screening. 3. Participant had pediatric-onset hypophosphatasia (HPP), defined as onset of first sign(s)/symptom (s) of HPP prior to 18 years of age. 4. 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. 5. Participants had a plasma inorganic pyrophosphate (PPi) level of ≥3.9 micromolar (µM) at Screening. 6. Female participants of childbearing potential had a negative pregnancy test at the time of enrollment. 7. Sexually active male and female participants of childbearing potential agreed to use a highly effective method of birth control during the study. 8. 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. 9. Participants were willing to comply with study procedures and the visit schedule.
Exclusion criteria
1. 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. 2. Employees of Alexion Pharmaceuticals. 3. Currently enrolled in a clinical study involving another study drug or non-approved use of a drug or device. 4. Participated, within the last 30 days, in a clinical study involving a study drug (other than the study drug used in this study). 5. Completed or withdrawn from this study or any other study investigating asfotase alfa in the previous 3 years. 6. Women who were pregnant, planning to become pregnant, or breastfeeding. 7. Serum 25-hydroxy Vitamin D levels below 20 nanogram (ng) per milliliter (mL) at Screening. 8. Screening serum creatinine or parathyroid hormone (PTH) levels ≥1.5 times the upper limit of normal. 9. 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. 10. 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. 11. Treatment with PTH, strontium, or sclerostin inhibitors within 6 months prior to the first dose of study drug. 12. Unwilling or unable to comply with the use of a data collection device on which study participants directly recorded data.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Germany, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Asfotase Alfa 0.5 mg/kg Dose Participants received 0.5 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. | 8 |
| Asfotase Alfa 2.0 mg/kg Dose 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. | 10 |
| Asfotase Alfa 3.0 mg/kg Dose 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. | 9 |
| Total | 27 |
Baseline characteristics
| Characteristic | Asfotase Alfa 2.0 mg/kg Dose | Asfotase Alfa 3.0 mg/kg Dose | Asfotase Alfa 0.5 mg/kg Dose | Total |
|---|---|---|---|---|
| Age, Continuous | 42.7 years STANDARD_DEVIATION 16.77 | 50 years STANDARD_DEVIATION 17.01 | 41.5 years STANDARD_DEVIATION 17.9 | 44.8 years STANDARD_DEVIATION 16.94 |
| Baseline Inorganic Pyrophosphate (PPi) | 5.3 μM (micromolar) STANDARD_DEVIATION 1.22 | 5 μM (micromolar) STANDARD_DEVIATION 0.86 | 5.4 μM (micromolar) STANDARD_DEVIATION 1.64 | 5.2 μM (micromolar) STANDARD_DEVIATION 1.23 |
| Baseline Pyridoxal 5'-Phosphate (PLP) | 382.1 nanogram (ng)/milliliter (mL) STANDARD_DEVIATION 385.89 | 229.5 nanogram (ng)/milliliter (mL) STANDARD_DEVIATION 321.43 | 309.5 nanogram (ng)/milliliter (mL) STANDARD_DEVIATION 349.16 | 309.7 nanogram (ng)/milliliter (mL) STANDARD_DEVIATION 346.99 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 9 Participants | 8 Participants | 27 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 9 Participants | 7 Participants | 26 Participants |
| Sex: Female, Male Female | 6 Participants | 5 Participants | 5 Participants | 16 Participants |
| Sex: Female, Male Male | 4 Participants | 4 Participants | 3 Participants | 11 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 8 | 0 / 10 | 0 / 9 |
| other Total, other adverse events | 8 / 8 | 10 / 10 | 9 / 9 |
| serious Total, serious adverse events | 0 / 8 | 0 / 10 | 0 / 9 |
Outcome results
Primary
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.
Time frame: Baseline to Week 9
Population: FAS: randomized participants who received ≥1 dose of study drug and had ≥1 pretreatment and ≥1 on-treatment PPi result.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Asfotase Alfa 0.5 mg/kg Dose | Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9 | -2.604 μM | Standard Error 0.2399 |
| Asfotase Alfa 2.0 mg/kg Dose | Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9 | -3.797 μM | Standard Error 0.1949 |
| Asfotase Alfa 3.0 mg/kg Dose | Change In Plasma PPi From Baseline To Pre-3rd Dose At Week 9 | -4.484 μM | Standard Error 0.212 |
Comparison: A fixed sequence testing procedure was performed to compare the 3.0 mg/kg cohort with the 0.5 mg/kg cohort first. The hypothesis testing for the second comparison of the 2.0 mg/kg cohort compared with the 0.5 mg/kg cohort was only performed if the null hypothesis was rejected for the previous comparison at a significance level of 0.05 (p-value \<0.05). The primary endpoint was met if the null hypothesis was rejected for both comparisons at a significance level of 0.05 (both p-values \<0.05).p-value: <0.000195% CI: [-2.544, -1.216]REML
Comparison: A fixed sequence testing procedure was performed to compare the 3.0 mg/kg cohort with the 0.5 mg/kg cohort first. The hypothesis testing for the second comparison of the 2.0 mg/kg cohort compared with the 0.5 mg/kg cohort was only performed if the null hypothesis was rejected for the first comparison at a significance level of 0.05 (p-value \<0.05). The primary endpoint was met if the null hypothesis was rejected for both comparisons at a significance level of 0.05 (both p-values \<0.05).p-value: 0.000895% CI: [-1.805, -0.581]REML
Secondary
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.
Time frame: Baseline to Week 9
Population: FAS: randomized participants who received ≥1 dose of study drug and had ≥1 pretreatment and ≥1 on-treatment PPi result.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Asfotase Alfa 0.5 mg/kg Dose | Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9 | -303.955 ng/mL | Standard Error 9.4075 |
| Asfotase Alfa 2.0 mg/kg Dose | Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9 | -333.447 ng/mL | Standard Error 8.1486 |
| Asfotase Alfa 3.0 mg/kg Dose | Change In Plasma PLP From Baseline To Pre-3rd Dose At Week 9 | -338.002 ng/mL | Standard Error 85145 |
p-value: 0.012895% CI: [-60.171, -7.922]Restricted maximum likelihood-based
p-value: 0.023995% CI: [-54.723, -4.261]Restricted maximum likelihood-based