Fabry Disease
Conditions
Keywords
Amicus Therapeutics, AT1001, Galafold, Migalastat, Pharmacokinetics
Brief summary
The objective was to determine the effects of a single dose of migalastat hydrochloride (HCl) (migalastat) 150 and 450 milligrams (mg) on the safety and plasma pharmacokinetics (PK) of agalsidase and the effects of agalsidase on the safety and PK of migalastat 150 mg.
Detailed description
This open-label study was conducted in 2 stages (Stage 1, Stage 2). Stage 1 included migalastat 150 mg; Stage 2 included migalastat 450 mg. Each dose of migalastat was selected to evaluate interaction with each of 3 doses of recombinant agalsidase: 0.5 mg/kilogram (kg) agalsidase beta; 1.0 mg/kg agalsidase beta; 0.2 mg/kg agalsidase alfa. Migalastat was administered orally. Agalsidase alfa was administered as a 40-minute intravenous (IV) infusion and agalsidase beta was administered as a 2-hour (hr) IV infusion. Stage 1 consisted of 3 treatment periods with 14 days intervening between each period. Period 1, Day 1: agalsidase was administered alone. Period 2, Day 1: migalastat was administered, followed 2 hrs later by agalsidase. Period 3, Day 7: migalastat was administered alone. Stage 2 consisted of two 14-day treatment periods in which the plasma exposure of migalastat was characterized when migalastat was administered with agalsidase solely to confirm the attainment of adequate migalastat plasma concentrations. Period 1, Day 1: agalsidase was administered as an IV infusion using a calibrated infusion pump. Period 2, Day 1: migalastat was administered, followed 2 hrs later by agalsidase.
Interventions
DRUGMigalastat HCl
Oral capsules, single dose
BIOLOGICALAgalsidase Beta
IV infusion, single dose
BIOLOGICALAgalsidase Alfa
IV infusion, single dose
Sponsors
Amicus Therapeutics
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
A 2-stage design was used to study the effects of 2 dose levels of migalastat, while a 2- or 3-period design within each stage enabled study of the effects of one drug on the PK, pharmacodynamics, and safety of the other drug.
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Male diagnosed with Fabry disease and between 18 and 65 years of age, inclusive * Body mass index between 18-35 kg per meter squared * Had initiated treatment with agalsidase at least 1 month prior to screening, and had received at least 2 infusions before screening * Had stable dose level, dosing regimen, and form of agalsidase for at least 1 month before screening * Had an estimated creatinine clearance greater than or equal to 50 milliliters (mL)/minute at screening * Agreed to use medically accepted methods of contraception during the study and for 30 days after study completion * Were willing and able to provide written informed consent
Exclusion criteria
* Had a documented transient ischemic attack, ischemic stroke, unstable angina, or myocardial infarction within the 3 months before screening * Had clinically significant unstable cardiac disease (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association class III or IV congestive heart failure) * History of allergy or sensitivity to study drug (including excipients) or other iminosugars (such as miglustat, miglitol) * Required a concomitant medication prohibited by the protocol: Glyset® (miglitol), or Zavesca® (miglustat) * Any investigational/experimental drug or device within 30 days of screening, except for use of investigational enzyme replacement therapy for Fabry disease * Had any intercurrent illness or condition that might have precluded the participant from fulfilling the protocol requirements or suggested to the investigator that the potential participant might have had an unacceptable risk by participating in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | 0 hr, 1 day post dose | This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated LC-MS assay. The migalastat plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat. |
| Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter values for AUC extrapolated from time 0 to infinity (AUCinfinity) and AUC to the last time point at which concentration is quantified (AUC0-t) are reported in hr\*\[nanomoles/hr/milliliter\] (hr\*\[nmol/hr/mL\]). In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14. |
| Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter value for Cmax is reported in nmol/hr/mL. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14. |
| Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14. |
| Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter value for AUC0-t is reported in hr\*\[nanogram (ng)/hr/mL\]. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14. |
| Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for AUCextrapolated % are reported. AUCextrapolated % is reported instead of AUCinfinity because small but quantifiable concentrations of α-Gal A protein past 24 hr post-dose extrapolated to infinity comprised \>50% of total AUC in most participants and were unevaluable. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hour after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14. |
| Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for Cmax is reported in nmol/hr/mL. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14. |
| Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the total α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14. |
| Change In AUC For Migalastat After Administration Of Agalsidase | 0 hr, 1 day post dose | This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated liquid chromatography-tandem mass spectrometry (LC-MS) assay. The migalastat plasma PK parameter values for AUCinfinity and AUC0-t are reported in hr\*\[ng/hr/mL\]. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat. |
| Change In Cmax For Migalastat After Administration Of Agalsidase | 0 hr, 1 day post dose | This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated liquid LC-MS assay. The migalastat plasma PK parameter values for Cmax are reported in nmol/hr/mL. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Baseline, Day 7 | This measure characterized the effects of agalsidase and migalastat on α-Gal A activity in the skin using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. Baseline was defined as Day 1/Period 1 pre-infusion level. α-Gal A activity is reported in picomoles/mg/hr (pmol/mg/hr). Biopsy samples were obtained: on Day -1/Period 1; 24 hr after initiation of the infusion during Period 1 and Period 2; on Day 7 of Period 1 and Period 2. |
Countries
Australia, Belgium, Canada, Netherlands, United States
Participant flow
Pre-assignment details
The total number of unique participants in this study was 20: 3 from Stage 1 were re-enrolled and newly identified in Stage 2. Of those, 1 initially received 0.5 milligrams (mg)/kilogram (kg) agalsidase beta; after resolution of an agalsidase beta shortage, their dose was increased to 1.0 mg/kg; all remaining visits were completed at this dose.
Participants by arm
| Arm | Count |
|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) Stage 1: This arm consisted of 3 sequential treatment periods (Period 1 - Period 3). A single 150-mg oral dose (1 capsule) of migalastat HCl 2 hr before initiation of an IV infusion of 0.5 mg/kg agalsidase beta. | 5 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) Stage 1: This arm consisted of 3 sequential treatment periods (Period 1 - Period 3). A single 150-mg oral dose (1 capsule) of migalastat HCl 2 hr before initiation of an IV infusion of 1.0 mg/kg agalsidase beta. | 3 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) Stage 1: This arm consisted of 3 sequential treatment periods (Period 1 - Period 3). A single 150-mg oral dose (1 capsule) of migalastat HCl 2 hr before initiation of an IV infusion of 0.2 mg/kg agalsidase alfa. | 4 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) Stage 2: This arm consisted of 2 sequential treatment periods (Period 1, Period 2). A single 450-mg oral dose (3 × 150-mg capsules) of migalastat HCl 2 hr before initiation of an IV infusion of 0.5 mg/kg agalsidase beta. | 2 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) Stage 2: This arm consisted of 2 sequential treatment periods (Period 1, Period 2). A single 450-mg oral dose (3 × 150-mg capsules) of migalastat HCl 2 hr before initiation of an IV infusion of 1.0 mg/kg agalsidase beta. | 6 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) Stage 2: This arm consisted of 2 sequential treatment periods (Period 1, Period 2). A single 450-mg oral dose (3 x 150-mg capsules) of migalastat HCl 2 hr before initiation of an IV infusion of 0.2 mg/kg agalsidase alfa. | 4 |
| Total | 24 |
Baseline characteristics
| Characteristic | Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Total | Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) |
|---|---|---|---|---|---|---|---|
| Age, Continuous Stage 1 | 50.6 years STANDARD_DEVIATION 6.88 | 45.7 years STANDARD_DEVIATION 8.02 | 43.5 years STANDARD_DEVIATION 5.07 | 47.0 years STANDARD_DEVIATION 6.84 | — | — | — |
| Age, Continuous Stage 2 | — | — | — | 40.1 years STANDARD_DEVIATION 11.11 | 53.5 years STANDARD_DEVIATION 2.12 | 38.7 years STANDARD_DEVIATION 12.16 | 38.5 years STANDARD_DEVIATION 9.15 |
| Sex: Female, Male Stage 1 Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | — | — | — |
| Sex: Female, Male Stage 1 Male | 5 Participants | 3 Participants | 4 Participants | 12 Participants | — | — | — |
| Sex: Female, Male Stage 2 Female | — | — | — | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Stage 2 Male | — | — | — | 12 Participants | 2 Participants | 6 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk | EG010 affected / at risk | EG011 affected / at risk | EG012 affected / at risk | EG013 affected / at risk | EG014 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 5 | 0 / 5 | 3 / 5 | 3 / 3 | 2 / 3 | 0 / 3 | 1 / 4 | 0 / 4 | 2 / 4 | 1 / 2 | 0 / 1 | 1 / 6 | 1 / 6 | 3 / 4 | 4 / 4 |
| serious Total, serious adverse events | 0 / 5 | 0 / 5 | 0 / 5 | 0 / 3 | 0 / 3 | 0 / 3 | 0 / 4 | 0 / 4 | 0 / 4 | 1 / 2 | 0 / 1 | 0 / 6 | 0 / 6 | 0 / 4 | 0 / 4 |
Outcome results
Primary
Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat
This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter values for AUC extrapolated from time 0 to infinity (AUCinfinity) and AUC to the last time point at which concentration is quantified (AUC0-t) are reported in hr\*\[nanomoles/hr/milliliter\] (hr\*\[nmol/hr/mL\]). In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.
Time frame: 0 hr, 2 hr, 2 days, 7 days, 14 days post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUC0-t | 1132.72 hr*[nmol/hr/mL] | Standard Deviation 223.215 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUC0-t | 3255.09 hr*[nmol/hr/mL] | Standard Deviation 904.716 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUCinfinity | 1145.73 hr*[nmol/hr/mL] | Standard Deviation 217.894 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUCinfinity | 3287.09 hr*[nmol/hr/mL] | Standard Deviation 907.073 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUCinfinity | 4871.66 hr*[nmol/hr/mL] | Standard Deviation 1242.965 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUC0-t | 9541.21 hr*[nmol/hr/mL] | Standard Deviation 2813.139 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUC0-t | 4730.47 hr*[nmol/hr/mL] | Standard Deviation 1045.068 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUCinfinity | 9765.04 hr*[nmol/hr/mL] | Standard Deviation 3118.875 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUCinfinity | 1626.67 hr*[nmol/hr/mL] | Standard Deviation 407.595 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUCinfinity | 388.10 hr*[nmol/hr/mL] | Standard Deviation 83.77 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUC0-t | 1602.58 hr*[nmol/hr/mL] | Standard Deviation 425.798 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUC0-t | 384.20 hr*[nmol/hr/mL] | Standard Deviation 86.904 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUC0-t | 2409.02 hr*[nmol/hr/mL] | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUCinfinity | 6197.71 hr*[nmol/hr/mL] | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUC0-t | 6127.75 hr*[nmol/hr/mL] | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUCinfinity | 2523.87 hr*[nmol/hr/mL] | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUCinfinity | 5851.62 hr*[nmol/hr/mL] | Standard Deviation 4345.407 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUCinfinity | 10280.79 hr*[nmol/hr/mL] | Standard Deviation 3399.342 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUC0-t | 9908.56 hr*[nmol/hr/mL] | Standard Deviation 3097.746 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUC0-t | 5670.76 hr*[nmol/hr/mL] | Standard Deviation 3926.295 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUC0-t | 2199.98 hr*[nmol/hr/mL] | Standard Deviation 875.14 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUCinfinity | 800.38 hr*[nmol/hr/mL] | Standard Deviation 509.308 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 2: AUCinfinity | 2253.95 hr*[nmol/hr/mL] | Standard Deviation 859.586 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Area Under The Plasma Concentration Versus Time Curve (AUC) For Active α-Galactosidase A (α-Gal A) Levels After Administration Of Migalastat | Period 1: AUC0-t | 787.23 hr*[nmol/hr/mL] | Standard Deviation 509.967 |
Comparison: Statistical Analysis of Stage 1 AUC0-t Data: Point estimates for the geometric means and their 90% confidence interval (CI) are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [2.439, 3.548]
Comparison: Statistical Analysis of Stage 1 AUCinfinity Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [2.431, 3.56]
Comparison: Statistical Analysis of Stage 2 AUC0-t Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [1.826, 3.035]
Comparison: Statistical Analysis of Stage 2 AUCinfinity Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [1.839, 3.068]
Primary
Change In AUC For Migalastat After Administration Of Agalsidase
This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated liquid chromatography-tandem mass spectrometry (LC-MS) assay. The migalastat plasma PK parameter values for AUCinfinity and AUC0-t are reported in hr\*\[ng/hr/mL\]. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat.
Time frame: 0 hr, 1 day post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUC0-t | 15717.87 hr*[ng/hr/mL] | Standard Deviation 7140.484 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUC0-t | 13009.11 hr*[ng/hr/mL] | Standard Deviation 3747.086 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUCinfinity | 15889.34 hr*[ng/hr/mL] | Standard Deviation 7841.968 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUCinfinity | 13708.03 hr*[ng/hr/mL] | Standard Deviation 4278.951 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUCinfinity | 9653.09 hr*[ng/hr/mL] | Standard Deviation 2185.031 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUC0-t | 9285.71 hr*[ng/hr/mL] | Standard Deviation 2270.875 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUC0-t | 9413.79 hr*[ng/hr/mL] | Standard Deviation 2153.161 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUCinfinity | 9597.10 hr*[ng/hr/mL] | Standard Deviation 2253.444 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUCinfinity | 16586.14 hr*[ng/hr/mL] | Standard Deviation 5818.395 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUCinfinity | 16523.94 hr*[ng/hr/mL] | Standard Deviation 3804.018 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUC0-t | 16011.88 hr*[ng/hr/mL] | Standard Deviation 5361.097 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUC0-t | 16051.81 hr*[ng/hr/mL] | Standard Deviation 3441.663 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUC0-t | 49483.00 hr*[ng/hr/mL] | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUCinfinity | NA hr*[ng/hr/mL] | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUC0-t | NA hr*[ng/hr/mL] | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUCinfinity | 53034.59 hr*[ng/hr/mL] | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUCinfinity | 31856.37 hr*[ng/hr/mL] | Standard Deviation 11283.94 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUCinfinity | NA hr*[ng/hr/mL] | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUC0-t | NA hr*[ng/hr/mL] | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUC0-t | 30450.61 hr*[ng/hr/mL] | Standard Deviation 10750.31 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUC0-t | NA hr*[ng/hr/mL] | — |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUCinfinity | 34700.89 hr*[ng/hr/mL] | Standard Deviation 8429.954 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 3: AUCinfinity | NA hr*[ng/hr/mL] | — |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In AUC For Migalastat After Administration Of Agalsidase | Period 2: AUC0-t | 33920.71 hr*[ng/hr/mL] | Standard Deviation 8559.677 |
Comparison: Statistical Analysis of Stage 1 AUC0-t Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [0.818, 1.371]
Comparison: Statistical Analysis of Stage 1 AUCinfinity Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [0.807, 1.371]
Primary
Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat
This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter value for AUC0-t is reported in hr\*\[nanogram (ng)/hr/mL\]. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.
Time frame: 0 hr, 2 hr, 2 days, 7 days, 14 days post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: AUC0-t | 57187.48 hr*[ng/hr/mL] | Standard Deviation 47381.96 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: AUC0-t | 56895.40 hr*[ng/hr/mL] | Standard Deviation 45753.77 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: AUC0-t | 29905.87 hr*[ng/hr/mL] | Standard Deviation 20470.28 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: AUC0-t | 34298.23 hr*[ng/hr/mL] | Standard Deviation 17022.13 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: AUC0-t | 42256.74 hr*[ng/hr/mL] | Standard Deviation 13868 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: AUC0-t | 42528.55 hr*[ng/hr/mL] | Standard Deviation 14652.93 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: AUC0-t | 16229.13 hr*[ng/hr/mL] | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: AUC0-t | 16272.03 hr*[ng/hr/mL] | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: AUC0-t | 17200.63 hr*[ng/hr/mL] | Standard Deviation 16906.97 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: AUC0-t | 22031.50 hr*[ng/hr/mL] | Standard Deviation 16754.04 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: AUC0-t | 28770.37 hr*[ng/hr/mL] | Standard Deviation 10941.44 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In AUC For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: AUC0-t | 29816.41 hr*[ng/hr/mL] | Standard Deviation 8956.789 |
Comparison: Statistical Analysis of Stage 1 AUC0-t Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [0.921, 1.14]
Comparison: Statistical Analysis of Stage 2 AUC0-t Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [1.026, 1.538]
Primary
Change In Cmax For Migalastat After Administration Of Agalsidase
This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated liquid LC-MS assay. The migalastat plasma PK parameter values for Cmax are reported in nmol/hr/mL. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat.
Time frame: 0 hr, 1 day post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 2: Cmax | 1690.00 nmol/hr/mL | Standard Deviation 606.548 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 3: Cmax | 1634.00 nmol/hr/mL | Standard Deviation 396.081 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 2: Cmax | 1295.67 nmol/hr/mL | Standard Deviation 501.654 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 3: Cmax | 1374.00 nmol/hr/mL | Standard Deviation 574.132 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 2: Cmax | 2047.50 nmol/hr/mL | Standard Deviation 192.592 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 3: Cmax | 2035.00 nmol/hr/mL | Standard Deviation 512.803 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 2: Cmax | 4750.00 nmol/hr/mL | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 3: Cmax | NA nmol/hr/mL | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 2: Cmax | 3763.33 nmol/hr/mL | Standard Deviation 984.574 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 3: Cmax | NA nmol/hr/mL | — |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 2: Cmax | 4455.00 nmol/hr/mL | Standard Deviation 1840.697 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Cmax For Migalastat After Administration Of Agalsidase | Period 3: Cmax | NA nmol/hr/mL | — |
Comparison: Statistical Analysis of Stage 1 Cmax Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [0.791, 1.259]
Primary
Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat
This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for Cmax is reported in nmol/hr/mL. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.
Time frame: 0 hr, 2 hr, 2 days, 7 days, 14 days post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: Cmax | 7159.13 nmol/hr/mL | Standard Deviation 4599.113 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: Cmax | 7060.29 nmol/hr/mL | Standard Deviation 5016.147 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: Cmax | 5156.74 nmol/hr/mL | Standard Deviation 2411.601 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: Cmax | 5572.63 nmol/hr/mL | Standard Deviation 1915.073 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: Cmax | 3813.49 nmol/hr/mL | Standard Deviation 1036.627 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: Cmax | 4196.18 nmol/hr/mL | Standard Deviation 1264.763 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: Cmax | 3141.84 nmol/hr/mL | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: Cmax | 2715.38 nmol/hr/mL | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: Cmax | 3983.05 nmol/hr/mL | Standard Deviation 1422.734 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: Cmax | 4170.15 nmol/hr/mL | Standard Deviation 935.512 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: Cmax | 3587.46 nmol/hr/mL | Standard Deviation 1181.299 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Cmax For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: Cmax | 3773.21 nmol/hr/mL | Standard Deviation 950.71 |
Comparison: Statistical Analysis of Stage 1 Cmax Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [0.929, 1.152]
Comparison: Statistical Analysis of Stage 2 Cmax Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [0.972, 1.164]
Primary
Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat
This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter value for Cmax is reported in nmol/hr/mL. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.
Time frame: 0 hr, 2 hr, 2 days, 7 days, 14 days post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 1:Cmax | 514.18 nmol/hr/mL | Standard Deviation 87.458 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: Cmax | 899.93 nmol/hr/mL | Standard Deviation 235.701 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 1:Cmax | 1682.13 nmol/hr/mL | Standard Deviation 407.862 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: Cmax | 2400.86 nmol/hr/mL | Standard Deviation 928.257 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 1:Cmax | 309.02 nmol/hr/mL | Standard Deviation 91.568 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: Cmax | 515.34 nmol/hr/mL | Standard Deviation 77.207 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 1:Cmax | 684.36 nmol/hr/mL | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: Cmax | 1351.18 nmol/hr/mL | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 1:Cmax | 1775.12 nmol/hr/mL | Standard Deviation 684.734 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: Cmax | 2413.31 nmol/hr/mL | Standard Deviation 798.09 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 1:Cmax | 370.91 nmol/hr/mL | Standard Deviation 113.362 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Maximum Observed Plasma Concentration (Cmax) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: Cmax | 619.00 nmol/hr/mL | Standard Deviation 141.411 |
Comparison: Statistical Analysis of Stage 1 Cmax Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [1.44, 1.843]
Comparison: Statistical Analysis of Stage 2 Cmax Data: Point estimates for the geometric means and their 90% CI are obtained by exponentiating the least squares mean and the lower and upper bounds of the 90% CI of the natural log-transformed data.90% CI: [1.3, 1.838]
Primary
Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat
This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the α-Gal A protein level by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for AUCextrapolated % are reported. AUCextrapolated % is reported instead of AUCinfinity because small but quantifiable concentrations of α-Gal A protein past 24 hr post-dose extrapolated to infinity comprised \>50% of total AUC in most participants and were unevaluable. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hour after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.
Time frame: 0 hr, 2 hr, 2 days, 7 days, 14 days post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1 | 60.50 percentage of AUC | Standard Deviation 22.241 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2 | 33.97 percentage of AUC | Standard Deviation 31.662 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1 | 27.55 percentage of AUC | Standard Deviation 14.642 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2 | 17.91 percentage of AUC | Standard Deviation 11.091 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1 | 73.26 percentage of AUC | Standard Deviation 13.324 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2 | 54.06 percentage of AUC | Standard Deviation 21.538 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1 | 8.49 percentage of AUC | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2 | 3.25 percentage of AUC | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1 | 12.30 percentage of AUC | Standard Deviation 15.307 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2 | 11.90 percentage of AUC | Standard Deviation 13.029 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1 | 58.37 percentage of AUC | Standard Deviation 11.065 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Percentage Of AUCinfinity Extrapolated From The Last Time Point At Which Concentration Is Quantified To Infinity (AUCextrapolated %) For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2 | 47.47 percentage of AUC | Standard Deviation 18.832 |
Primary
Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat
This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the active α-Gal A enzyme level in plasma using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. The agalsidase plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.
Time frame: 0 hr, 2 hr, 2 days, 7 days, 14 days post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: tmax | 2.07 hr | Standard Deviation 0.149 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: tmax | 2.30 hr | Standard Deviation 0.447 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: t1/2 | 3.91 hr | Standard Deviation 2.054 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: t1/2 | 3.51 hr | Standard Deviation 1.304 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: t1/2 | 5.33 hr | Standard Deviation 4.082 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: tmax | 2.41 hr | Standard Deviation 0.526 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: tmax | 2.16 hr | Standard Deviation 0.778 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: t1/2 | 4.30 hr | Standard Deviation 1.712 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: t1/2 | 4.27 hr | Standard Deviation 1.536 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: t1/2 | 4.48 hr | Standard Deviation 3.132 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: tmax | 0.75 hr | Standard Deviation 0.17 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: tmax | 0.75 hr | Standard Deviation 0.17 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: tmax | 3.00 hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: t1/2 | 3.49 hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: tmax | 3.00 hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: t1/2 | 6.50 hr | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: t1/2 | 3.11 hr | Standard Deviation 1.875 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: t1/2 | 4.96 hr | Standard Deviation 1.532 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: tmax | 2.58 hr | Standard Deviation 0.801 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: tmax | 2.58 hr | Standard Deviation 0.801 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: tmax | 0.75 hr | Standard Deviation 0.17 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: t1/2 | 5.15 hr | Standard Deviation 3.645 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 2: t1/2 | 5.31 hr | Standard Deviation 2.462 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Time To Maximum Observed Plasma Concentration (Tmax) And Terminal Elimination Half-life (T1/2) For Active α-Gal A Levels After Administration Of Migalastat | Period 1: tmax | 0.75 hr | Standard Deviation 0.17 |
Primary
Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase
This measure characterized the effects of agalsidase on the plasma PK of migalastat using a validated LC-MS assay. The migalastat plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 2 of Stages 1 and 2, blood samples were collected: just before dosing with migalastat (2 hr prior to the agalsidase infusion) and at 1 hr after migalastat dosing; immediately before the agalsidase infusion and over a 24-hr period after infusion. In Period 3 (Stage 1 only), blood samples were collected before dosing and over the 24-hr period after administration of migalastat.
Time frame: 0 hr, 1 day post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: tmax | 3.70 hr | Standard Deviation 0.651 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: tmax | 3.03 hr | Standard Deviation 0.71 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: t1/2 | 5.39 hr | Standard Deviation 1.098 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: t1/2 | 5.31 hr | Standard Deviation 1.241 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: t1/2 | 4.95 hr | Standard Deviation 0.335 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: tmax | 3.00 hr | Standard Deviation 0 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: tmax | 3.33 hr | Standard Deviation 0.577 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: t1/2 | 5.05 hr | Standard Deviation 0.558 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: tmax | 3.03 hr | Standard Deviation 0.05 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: t1/2 | 4.86 hr | Standard Deviation 0.831 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: t1/2 | 4.81 hr | Standard Deviation 0.601 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: tmax | 3.02 hr | Standard Deviation 0.818 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: tmax | 4.00 hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: tmax | NA hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: t1/2 | NA hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: t1/2 | 6.36 hr | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: t1/2 | 4.87 hr | Standard Deviation 1.202 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: t1/2 | NA hr | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: tmax | NA hr | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: tmax | 3.33 hr | Standard Deviation 1.102 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: tmax | NA hr | — |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: t1/2 | 4.44 hr | Standard Deviation 1.328 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 2: tmax | 4.50 hr | Standard Deviation 1 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Migalastat After Administration Of Agalsidase | Period 3: t1/2 | NA hr | — |
Primary
Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat
This measure characterized the effects of migalastat on the plasma PK of agalsidase by measurement of the total α-Gal A protein level in plasma by Western blot using anti-human Gal A antibody. The agalsidase plasma PK parameter values for tmax and t1/2 are reported in hr. In Period 1 of Stages 1 and 2, blood samples were collected: immediately before the agalsidase infusion and over a 24-hr period after infusion; on Days 2, 7, and 14. In Period 2 of Stages 1 and 2, blood samples were collected: prior to dosing with migalastat (2 hr prior to the agalsidase infusion) and 1 hr after migalastat dosing; immediately before initiation of the agalsidase infusion and over a 24-hr period after initiation of the agalsidase infusion; on Days 2, 7, and 14.
Time frame: 0 hr, 2 hr, 2 days, 7 days, 14 days post dose
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: t1/2 | 23.10 hr | Standard Deviation 22.338 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: t1/2 | 57.78 hr | Standard Deviation 40.019 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: tmax | 2.07 hr | Standard Deviation 0.149 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: tmax | 2.10 hr | Standard Deviation 0.548 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: t1/2 | 9.15 hr | Standard Deviation 5.621 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: t1/2 | 17.77 hr | Standard Deviation 8.837 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: tmax | 2.24 hr | Standard Deviation 0.75 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: tmax | 2.16 hr | Standard Deviation 0.778 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: t1/2 | 32.95 hr | Standard Deviation 20.282 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: tmax | 0.75 hr | Standard Deviation 0.166 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: tmax | 0.75 hr | Standard Deviation 0.17 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: t1/2 | 86.19 hr | Standard Deviation 92.048 |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: tmax | 3.00 hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: t1/2 | 2.00 hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: t1/2 | 2.96 hr | — |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: tmax | 3.00 hr | — |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: tmax | 2.50 hr | Standard Deviation 0.548 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: tmax | 2.50 hr | Standard Deviation 0.775 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: t1/2 | 5.55 hr | Standard Deviation 5.553 |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: t1/2 | 6.71 hr | Standard Deviation 7.702 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: t1/2 | 28.05 hr | Standard Deviation 18.582 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: tmax | 0.75 hr | Standard Deviation 0.17 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 2: tmax | 0.75 hr | Standard Deviation 0.17 |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change In Tmax And T1/2 For Total α-Gal A Protein Levels After Administration Of Migalastat | Period 1: t1/2 | 30.32 hr | Standard Deviation 5.01 |
Secondary
Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat
This measure characterized the effects of agalsidase and migalastat on α-Gal A activity in the skin using a qualified assay that measured the rate of enzyme activity using an artificial, fluorescent substrate. Baseline was defined as Day 1/Period 1 pre-infusion level. α-Gal A activity is reported in picomoles/mg/hr (pmol/mg/hr). Biopsy samples were obtained: on Day -1/Period 1; 24 hr after initiation of the infusion during Period 1 and Period 2; on Day 7 of Period 1 and Period 2.
Time frame: Baseline, Day 7
Population: PK Population: all participants with evaluable PK parameter data who had successfully completed at least Period 1 and Period 2 in any stage. All PK analyses were performed using the PK population.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 7 | 137 pmol/mg/hr |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 2 | 1508 pmol/mg/hr |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 2 | 334 pmol/mg/hr |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 7 | 574 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 2 | 857 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 7 | 553 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 2 | 2977 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 7 | 855 pmol/mg/hr |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 7 | 228 pmol/mg/hr |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 2 | 121 pmol/mg/hr |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 2 | 437 pmol/mg/hr |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 7 | 139 pmol/mg/hr |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 7 | 235 pmol/mg/hr |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 2 | 89 pmol/mg/hr |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 2 | 647 pmol/mg/hr |
| Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 7 | 72 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 7 | 613 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 2 | 4019 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 2 | 1936 pmol/mg/hr |
| Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 7 | 789 pmol/mg/hr |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 7 | -100 pmol/mg/hr |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 1: Day 2 | 18 pmol/mg/hr |
| Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg) | Change From Baseline To Day 7 In Active α-Gal A In Skin Following Treatment With Agalsidase Alone And Co-administration With Migalastat | Period 2: Day 2 | 160 pmol/mg/hr |