Drug-Drug Interaction Study Between AT1001 (Migalastat Hydrochloride) and Agalsidase in Participants With Fabry Disease

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-label Phase 2A Study to Investigate Drug-Drug Interactions Between AT1001 (Migalastat Hydrochloride) and Agalsidase in Subjects With Fabry Disease

Conditions
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Fabry Disease

Intervention / Treatment
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* Drug: Migalastat HCl
* Biological: Agalsidase Beta
* Biological: Agalsidase Alfa


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Agalsidase Beta (0.5 mg/kg)-Migalastat (150 mg)<br> | Drug: Migalastat HCl<br>* Oral capsules, single dose<br>* Other names: migalastat;Biological: Agalsidase Beta<br>* IV infusion, single dose<br>* Other names: Fabrazyme;|
| Experimental: Agalsidase Beta (1.0 mg/kg)-Migalastat (150 mg)<br> | Drug: Migalastat HCl<br>* Oral capsules, single dose<br>* Other names: migalastat;Biological: Agalsidase Beta<br>* IV infusion, single dose<br>* Other names: Fabrazyme;|
| Experimental: Agalsidase Alfa (0.2 mg/kg)-Migalastat (150 mg)<br> | Drug: Migalastat HCl<br>* Oral capsules, single dose<br>* Other names: migalastat;Biological: Agalsidase Alfa<br>* IV infusion, single dose<br>* Other names: Replagal;|
| Experimental: Agalsidase Beta (0.5 mg/kg)-Migalastat (450 mg)<br> | Drug: Migalastat HCl<br>* Oral capsules, single dose<br>* Other names: migalastat;Biological: Agalsidase Beta<br>* IV infusion, single dose<br>* Other names: Fabrazyme;|
| Experimental: Agalsidase Beta (1.0 mg/kg)-Migalastat (450 mg)<br> | Drug: Migalastat HCl<br>* Oral capsules, single dose<br>* Other names: migalastat;Biological: Agalsidase Beta<br>* IV infusion, single dose<br>* Other names: Fabrazyme;|
| Experimental: Agalsidase Alfa (0.2 mg/kg)-Migalastat (450 mg)<br> | Drug: Migalastat HCl<br>* Oral capsules, single dose<br>* Other names: migalastat;Biological: Agalsidase Alfa<br>* IV infusion, single dose<br>* Other names: Replagal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | 
| 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. | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | 
| 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. | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | 
| 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. | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | 
| 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. | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | 
| 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. | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | 
| 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. | 0 hr, 2 hr, 2 days, 7 days, 14 days post dose | 
| 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. | 0 hr, 1 day post dose | 
| 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. | 0 hr, 1 day post dose | 
| 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. | 0 hr, 1 day post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline, Day 7 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Amicus Therapeutics, AT1001, Galafold, Migalastat, Pharmacokinetics