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) in participants with Fabry disease.
Detailed description
This was a Phase 2, open-label study in female participants with Fabry disease. The study consisted of a 4-week screening period, during which participants' galactosidase (GLA) genotype was assessed for α-galactosidase A (α-Gal A) activity in response to migalastat. 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 once every other day (QOD) for 12 weeks during the treatment period and the optional 36-week extension period for a total treatment duration of up to 48 weeks. Participants were stratified by α-Gal A enzyme activity (high \>40%, and low ≤40%) then randomly assigned to receive migalastat at 1 of 3 specified dose levels (50, 150, or 250 milligrams \[mg\]).
Interventions
DRUGmigalastat HCl
Sponsors
Amicus Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Females between 18 and 65 years of age (inclusive) * Heterozygous 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 * Were naïve to enzyme replacement therapy (ERT) and other therapies, except for palliative therapies for the signs and symptoms of Fabry disease, or stopped ERT for at least 18 weeks * Had end organ dysfunction, even minimal, demonstrated by abnormal electrocardiogram (ECG) or evidence of left ventricular hypertrophy documented by echocardiogram or by cardiac biopsy; or renal insufficiency documented by common clinical assessments such as creatinine and glomerular filtration rate or by renal biopsy; or brain tissue dysfunction as documented by evidence of stroke (clinically or imaging); or peripheral nervous tissue dysfunction documented by complaints of intolerance to heat or cold, decreased vibratory sense and proprioception, decreased ability to perspire, or acroparesthesia. * Were willing to undergo 2 renal and 3 skin biopsies * Agreed to be sexually abstinent or practice an effective method of contraception when engaging in sexual activity during the course of the study and for a period of 30 days following their completion of the study for women of childbearing potential. * Were willing and able to provide written informed consent
Exclusion criteria
* Pregnant or lactating * History of organ transplant * History of significant disease other than Fabry disease (for example, end-stage renal disease; Class III or IV heart disease \[per the New York Heart Association classification\]; current diagnosis of cancer, except for basal cell carcinoma of the skin; diabetes \[unless hemoglobin A1c ≤8\]; or neurological disease that would have impaired the participant's ability to participate in the study) * Serum creatinine \>176 micromoles/liter on Day -2 * Screening 12-lead ECG demonstrating corrected QT interval \>450 milliseconds * Pacemaker or other contraindication for magnetic resonance imaging scanning * Taking a medication prohibited by the protocol: 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 | TEAEs were defined as any adverse event with 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 |
|---|---|---|
| PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, and 10 hours (postdose) | The AUC to the last measurable concentration (AUC0-t) was evaluated in plasma following a single oral dose of migalastat on Day 1 and following multiple oral doses on Day 14 (2 weeks) and Day 84 (12 weeks). All samples were collected on each dosing day. |
| α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Baseline, Week 12 (end of treatment period), Week 48 (end of extension period) | Leukocytes were isolated from whole blood and lysed, and α-Gal A activity was measured using 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/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 leukocytes are presented by individual participants. |
Countries
Australia, Brazil, Canada, France, United Kingdom, United States
Participant flow
Pre-assignment details
Before randomization, participants were stratified into 2 groups (high or low) by their baseline α-galactosidase A (α-Gal A) activity. High was defined as activity greater than 40% of normal; low was defined as activity less than or equal to 40% of normal.
Participants by arm
| Arm | Count |
|---|---|
| Migalastat Low Dose 50 mg Migalastat 50 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period. | 2 |
| Migalastat Middle Dose 150 mg Migalastat 150 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period. | 4 |
| Migalastat High Dose 250 mg Migalastat 250 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period. | 3 |
| Total | 9 |
Baseline characteristics
| Characteristic | Migalastat Low Dose 50 mg | Migalastat Middle Dose 150 mg | Migalastat High Dose 250 mg | Total |
|---|---|---|---|---|
| Age, Continuous | 49.0 years STANDARD_DEVIATION 18.38 | 44.8 years STANDARD_DEVIATION 9.95 | 44.0 years STANDARD_DEVIATION 2.65 | 45.4 years STANDARD_DEVIATION 9.23 |
| Sex: Female, Male Female | 2 Participants | 4 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 2 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 0 / 2 | 1 / 4 | 0 / 3 |
Outcome results
Primary
Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs)
TEAEs were defined as any adverse event with 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
Population: Safety Population: all participants who received at least 1 dose of study drug.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Migalastat Low Dose 50 mg | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
| Migalastat Middle Dose 150 mg | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
| Migalastat High Dose 250 mg | Number Of Participants Who Experienced Severe Treatment-emergent Adverse Events (TEAEs) | 0 Participants |
Secondary
PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat
The AUC to the last measurable concentration (AUC0-t) was evaluated in plasma following a single oral dose of migalastat on Day 1 and following multiple oral doses on Day 14 (2 weeks) and Day 84 (12 weeks). All samples were collected on each dosing day.
Time frame: 0 (predose), 0.5, 1, 2, 3, 4, 5, 6, 8, and 10 hours (postdose)
Population: PK Population: all participants who received study drug and had at least 1 postbaseline PK parameter recorded.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Migalastat Low Dose 50 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Multiple Dose, Day 14 | 3191.6 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 64.9 |
| Migalastat Low Dose 50 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Single Dose, Day 1 | 2628.9 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 100.4 |
| Migalastat Low Dose 50 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Multiple Dose, Day 84 | 2300.3 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 79.6 |
| Migalastat Middle Dose 150 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Multiple Dose, Day 14 | 10637.9 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 35.6 |
| Migalastat Middle Dose 150 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Single Dose, Day 1 | 8941.6 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 32.2 |
| Migalastat Middle Dose 150 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Multiple Dose, Day 84 | 8581.9 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 29.7 |
| Migalastat High Dose 250 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Single Dose, Day 1 | 13217.2 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 30.2 |
| Migalastat High Dose 250 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Multiple Dose, Day 84 | 9970.3 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 37.8 |
| Migalastat High Dose 250 mg | PK: Area Under The Concentration Versus Time Curve (AUC) After Administration Of Migalastat | AUC0-t: Multiple Dose, Day 14 | 14850.6 nanograms*hours/milliliters (ng*hr/mL) | Geometric Coefficient of Variation 9.6 |
Secondary
α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48
Leukocytes were isolated from whole blood and lysed, and α-Gal A activity was measured using 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/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 leukocytes are presented by individual participants.
Time frame: Baseline, Week 12 (end of treatment period), Week 48 (end of extension period)
Population: PD Population: all participants who received study drug and had at least 1 postbaseline PD parameter recorded.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Migalastat Low Dose 50 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 2: Baseline | 24.5 nmol 4-MU/hr/mg protein |
| Migalastat Low Dose 50 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 2: Week 12 | 35.8 nmol 4-MU/hr/mg protein |
| Migalastat Low Dose 50 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 2: Week 48 | 39.6 nmol 4-MU/hr/mg protein |
| Migalastat Low Dose 50 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 1: Baseline | 13.4 nmol 4-MU/hr/mg protein |
| Migalastat Low Dose 50 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 1: Week 12 | 2.46 nmol 4-MU/hr/mg protein |
| Migalastat Low Dose 50 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 1: Week 48 | 26 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 5: Baseline | 17.3 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 5: Week 12 | 5.85 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 5: Week 48 | 22.2 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 6: Baseline | 24.6 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 6: Week 12 | 12.6 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 6: Week 48 | 46.5 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 3: Week 48 | NA nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 4: Baseline | 6.39 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 4: Week 12 | 18.4 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 3: Baseline | 25.1 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 3: Week 12 | 4.15 nmol 4-MU/hr/mg protein |
| Migalastat Middle Dose 150 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 4: Week 48 | 16.1 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 7: Baseline | 3.25 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 7: Week 12 | 6.56 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 7: Week 48 | 4.83 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 8: Baseline | 14.7 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 8: Week 12 | 23.3 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 8: Week 48 | 29.2 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 9: Baseline | 13.1 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 9: Week 12 | 8.86 nmol 4-MU/hr/mg protein |
| Migalastat High Dose 250 mg | α-Gal A Activity In Leukocytes At Baseline, Week 12, And Week 48 | Participant 9: Week 48 | 7.58 nmol 4-MU/hr/mg protein |