Fabry Disease
Conditions
Keywords
Amicus Therapeutics, AT1001, Galafold, Migalastat, Substrate
Brief summary
Study to evaluate the safety, tolerability, and pharmacodynamics of migalastat hydrochloride (HCl) (migalastat) and how migalastat works in participants with Fabry disease.
Detailed description
This was a Phase 2, open-label study in male participants with Fabry disease. The study consisted of a 4-week screening period during which participants' genotype was assessed for α-galactosidase A (α-Gal A) activity in response to migalastat via an in vitro assay. Participants were required to have α-Gal A activity responsive to migalastat. The study consisted of a 12-week treatment period, followed by an optional 36-week extension period. Participants received migalastat 150 milligrams (mg) once every other day (QOD) for 12 weeks during the treatment period. Participants could then opt to participate in the extension period.
Interventions
DRUGmigalastat HCl
Sponsors
Amicus Therapeutics
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Males between 18 and 65 years of age (inclusive) * Hemizygous for Fabry disease * Had a confirmed diagnosis of Fabry disease with a documented missense gene mutation (individual or familial) * Had enhanceable enzyme activity based on in vitro tests * Had documented evidence of cardiac and/or renal dysfunction (for example, abnormal electrocardiogram (ECG), left ventricular hypertrophy, renal insufficiency) and/or cerebral tissue dysfunction documented by evidence of stroke and/or peripheral nervous tissue dysfunction (for example, intolerance to heat/cold, decrease of perspiration) * Must have been previously untreated by enzyme replacement therapy (ERT) or substrate depletion for Fabry disease or were able to stop ERT for at least 18 weeks or up to three months, and be willing to undergo two kidney and three skin biopsies * Agreed to be sexually abstinent or use a condom with spermicide when engaging in sexual activity during the course of the study and for a period of 30 days following their completion of the study * Were willing and able to sign an informed consent form
Exclusion criteria
* History of significant disease other than Fabry disease * History of organ transplant * Serum creatinine \>2 mg per deciliter on Day -2 * Screening 12-lead ECG demonstrating corrected QT interval \>450 milliseconds prior to dosing * Pacemaker or other contraindication for magnetic resonance imaging (MRI) scanning * Took any of the following prohibited medications: Fabrazyme® (agalsidase beta), Replagal™ (agalsidase alfa), Glyset® (miglitol), Zavesca® (miglustat), or any experimental therapy for any indication * Participated in a previous clinical trial in the last 30 days * Any other condition, which, in the opinion of the investigator, would jeopardize the safety of the participant or impact the validity of the study results
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | Day 1 (after dosing) through Week 48 (end of extension period) | TEAEs were defined as any adverse event with a start date on or after administration of study drug or pre-existing conditions that worsened on or after the start of the first study drug administration (on Day 1). A severe adverse event was defined as an adverse event that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through Week 48 is presented. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Baseline, Week 12 (end of treatment period), Week 48 (end of extension period) | PBMCs were isolated from whole blood and lysed, and α-Gal A activity was measured by a validated fluorometric assay, with catalysis to fluorescent 4-methylumbelliferone (4-MU) as the activity measure. The activity values obtained were normalized to protein (measured using a colorimetric assay) and reported as enzyme activity (nanomole \[nmol\] 4-MU/hour \[hr\]) per mg of protein. On Day 1 of the first visit and at every visit thereafter, the samples were collected prior to dosing with migalastat. α-Gal A activity in PBMCs are presented by individual participants. Values of 0 presented below represent α-Gal A activity levels that were below the lower limit of quantification. |
Countries
Australia, Brazil
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Migalastat Participants received migalastat 150 mg orally QOD during the 12-week treatment period and the optional 36-week extension period. | 4 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Extension Period | Low Compliance | 1 |
Baseline characteristics
| Characteristic | Migalastat |
|---|---|
| Age, Continuous | 33.3 years STANDARD_DEVIATION 21.5 |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 3 / 4 |
| serious Total, serious adverse events | 1 / 4 |
Outcome results
Primary
Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as any adverse event with a start date on or after administration of study drug or pre-existing conditions that worsened on or after the start of the first study drug administration (on Day 1). A severe adverse event was defined as an adverse event that was incapacitating and required medical intervention. The number of participants who experienced one or more severe TEAEs after dosing on Day 1 through Week 48 is presented. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse Events module.
Time frame: Day 1 (after dosing) through Week 48 (end of extension period)
Population: Safety Population: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Migalastat | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 1 Participants |
Secondary
α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48
PBMCs were isolated from whole blood and lysed, and α-Gal A activity was measured by a validated fluorometric assay, with catalysis to fluorescent 4-methylumbelliferone (4-MU) as the activity measure. The activity values obtained were normalized to protein (measured using a colorimetric assay) and reported as enzyme activity (nanomole \[nmol\] 4-MU/hour \[hr\]) per mg of protein. On Day 1 of the first visit and at every visit thereafter, the samples were collected prior to dosing with migalastat. α-Gal A activity in PBMCs are presented by individual participants. Values of 0 presented below represent α-Gal A activity levels that were below the lower limit of quantification.
Time frame: Baseline, Week 12 (end of treatment period), Week 48 (end of extension period)
Population: PD Population: All participants who received at least 1 dose of study drug and had at least 1 non-missing postbaseline PD parameter recorded. Participants who discontinued prior to the specified time point were not analyzed because no data were available.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 4 Baseline | 0.3 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 4 Week 12 | 7.36 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 1 Baseline | 0.14 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 1 Week 12 | NA nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 1 Week 48 | 0.12 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 2 Baseline | 0.24 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 2 Week 12 | 2.3 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 3 Baseline | 0.21 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 3 Week 12 | 2.43 nmol 4-MU/hr/mg protein |
| Migalastat | α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 12, And Week 48 | Participant 4 Week 48 | 6.06 nmol 4-MU/hr/mg protein |