Fabry Disease
Conditions
Keywords
Amicus Therapeutics, Galafold, AT1001, Migalastat
Brief summary
Study to compare the efficacy and safety of migalastat and enzyme replacement therapy (ERT) in male and female participants with Fabry disease who are currently receiving ERT and who have an alpha galactosidase-A (α Gal-A) mutation that is amenable to migalastat, based on the clinical trial human embryonic kidney cell (HEK) assay.
Detailed description
This was a Phase 3, randomized, open-label, active-controlled study to evaluate the efficacy and safety of 150 milligrams (mg) of migalastat hydrochloride (migalastat) (equivalent to 123 mg of migalastat) once every other day (QOD) and ERT in male and female participants with Fabry disease who were receiving ERT and who have an α Gal-A mutation that is amenable to migalastat, based on the clinical trial HEK assay. This was a 2-part study. Part 1, the 18-month randomized phase, evaluated participants who received either migalastat 150 mg QOD or ERT per prescribing physicians' instructions for efficacy and safety. Part 2, the optional 12-month open-label extension (OLE) phase in which all participants received migalastat, also explored efficacy and safety. For Part 2, all participants who received ERT in Part 1 were given migalastat. Data presented in this posting include efficacy data from the 18-month randomized period and safety data from the entire study (18-month randomized period and 12-month optional OLE \[total of 30 months\]).
Interventions
150-mg capsule administered orally QOD
BIOLOGICALagalsidase
Agalsidase via intravenous infusion as prescribed by the participant's treating physician and in accordance with the approved prescribing information
Sponsors
Amicus Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
16 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
* Male or female between the ages of 16 and 74 diagnosed with Fabry disease * Confirmed α Gal-A mutation that is amenable to migalastat, based on the clinical trial HEK assay * Participant has been on ERT for at least 12 months before screening/baseline * Dose level and regimen of ERT have been stable for 3 months before screening/baseline and is at least 80% of the currently labeled dose and regimen for this time period * Glomerular filtration rate (GFR) ≥ 30 milliliter (mL)/minute (min) /1.73 m\^2 * Participants taking angiotensin converting enzyme inhibitors or angiotensin receptor blockers must be on a stable dose for at least 4 weeks before screening/baseline * Women who can become pregnant and all men agree to be sexually abstinent or use medically accepted methods of birth control throughout the duration of the study and for up to 30 days after last dose of study medication * Participant is willing and able to provide written informed consent and assent if applicable
Exclusion criteria
* Participant has undergone, or is scheduled to undergo, kidney transplantation or any other solid organ transplantation * Participant is on regular dialysis that is specifically for the treatment of chronic kidney disease * Participant has had a documented transient ischemic attack, stroke, unstable angina, or myocardial infarction within the 3 months before screening/baseline * Participant has clinically significant unstable cardiac disease in the opinion of the investigator (for example, cardiac disease requiring active management, such as symptomatic arrhythmia, unstable angina, or New York Heart Association (NYHA) class III or IV congestive heart failure) * Pregnant or breast-feeding * History of allergy or sensitivity to study medication (including excipients) or other iminosugars (for example, miglustat, miglitol) * Participant has absolute contraindication to iohexol and/or inability to undergo iohexol GFR testing * Participant requires treatment with Glyset® (miglitol), or Zavesca® (miglustat) * Participant received any investigational/experimental drug, biologic or device within 30 days of screening/baseline * Any intercurrent illness or condition that may preclude the participant from fulfilling the study requirements or suggests to the investigator that the participant may have an unacceptable risk by participating in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate | Baseline to Month 18 | To assess renal function, measured glomerular filtration rate (GFR) was measured by the plasma clearance of unlabeled iohexol (mGFR-iohexol), a non-ionic contrast agent. The annualized rate of change in mGFR-iohexol from Baseline to Month 18 was analyzed using an analysis of covariance (ANCOVA) model with the following factors as covariates: treatment group, sex, age, Baseline GFR (mGFR-iohexol), and Baseline 24-hour (hr) urine protein. A threshold of \<2.2 milliliter (mL)/minute (min)/1.73 meter squared (m\^2)/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in estimated glomerular filtration rate (eGFR) for participants treated with agalsidase alfa for 18 months. |
| Annualized Rate Of Change From Baseline To Month 18 In eGFR | Baseline to Month 18 | The eGFR assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was calculated using the following: eGFR-CKD-EPI = 141 x min (Serum Creatinine/κ,1)\^(α) x max(Serum Creatinine/κ,1)\^(-1.209) x 0.993\^(Age) x 1.1018 (if female) x 1.159 (if African American or black) where: κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Serum Creatinine/κ or 1; max indicates the maximum of Serum Creatinine/κ or 1. The annualized rate of change in eGFR-CKD-EPI from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein. A threshold of \<2.2 mL/min/1.73m\^2/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in eGFR for participants treated with agalsidase alfa for 18 months. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation | Baseline to Month 18 | The GFR estimated by the Modification Of Diet In Renal Disease equation (eGFR-MDRD) was calculated using the following equation: eGFR-MDRD = 175 x (Serum Creatinine)\^(-1.154) x (Age)\^(-0.203) x 1.212 (if participant's race is black or African American) x 0.742 (if participant is female). The eGFR-MDRD from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein. |
Countries
Australia, Austria, Belgium, Brazil, Denmark, France, Italy, Japan, United Kingdom, United States
Participant flow
Pre-assignment details
The All Migalastat group was comprised of participants who received migalastat during the randomized treatment period (0-18 mo.) and who received enzyme replacement therapy (ERT) during the randomized treatment period (0-18 mo.) and switched to migalastat during the 12-mo. open-label extension (OLE). 8 participants enrolled but did not randomize.
Participants by arm
| Arm | Count |
|---|---|
| Migalastat (0-18 Months) Participants received 150 mg migalastat orally QOD during the 18-month randomized treatment period. Participants received an inactive reminder capsule on alternate days during both treatment periods. | 36 |
| ERT (0-18 Months) Participants received ERT (either agalsidase alfa or agalsidase beta) as prescribed by the participant's treating physician and administered in accordance with the approved prescribing information during the 18-month randomized treatment period. Participants were required to be given \>80% of the currently labeled dose and regimen during the 18-month randomized treatment period. Participants received an inactive reminder capsule on alternate days during the OLE. | 21 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| 12-Month OLE | Declined to participate in the OLE | 0 | 0 | 4 |
| 12-Month OLE | Lack of Efficacy | 0 | 0 | 1 |
| 12-Month OLE | Lost to Follow-up | 0 | 0 | 1 |
| 12-Month OLE | Physician Decision | 0 | 0 | 1 |
| 12-Month OLE | Pregnancy | 0 | 0 | 1 |
| 12-Month OLE | Withdrawal by Subject | 0 | 0 | 2 |
| 18-Month Randomized Period | Did not receive study drug | 0 | 3 | 0 |
| 18-Month Randomized Period | Withdrawal by Subject | 2 | 3 | 0 |
Baseline characteristics
| Characteristic | Migalastat (0-18 Months) | ERT (0-18 Months) | Total |
|---|---|---|---|
| Age, Continuous | 50.5 years STANDARD_DEVIATION 13.76 | 46.3 years STANDARD_DEVIATION 14.91 | 48.9 years STANDARD_DEVIATION 14.21 |
| Sex: Female, Male Female | 20 Participants | 12 Participants | 32 Participants |
| Sex: Female, Male Male | 16 Participants | 9 Participants | 25 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 | 34 / 36 | 20 / 21 | 50 / 51 |
| serious Total, serious adverse events | 7 / 36 | 7 / 21 | 16 / 51 |
Outcome results
Primary
Annualized Rate Of Change From Baseline To Month 18 In eGFR
The eGFR assessed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation was calculated using the following: eGFR-CKD-EPI = 141 x min (Serum Creatinine/κ,1)\^(α) x max(Serum Creatinine/κ,1)\^(-1.209) x 0.993\^(Age) x 1.1018 (if female) x 1.159 (if African American or black) where: κ is 0.7 for females and 0.9 for males; α is -0.329 for females and -0.411 for males; min indicates the minimum of Serum Creatinine/κ or 1; max indicates the maximum of Serum Creatinine/κ or 1. The annualized rate of change in eGFR-CKD-EPI from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein. A threshold of \<2.2 mL/min/1.73m\^2/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in eGFR for participants treated with agalsidase alfa for 18 months.
Time frame: Baseline to Month 18
Population: mITT Population: All randomized participants with an α Gal-A mutation that is amenable to migalastat, based on the GLP HEK assay, who received at least 1 dose of study drug, had Baseline and postbaseline mGFR-iohexol values, and postbaseline measure of the estimated GFR using the CKD-EPI equation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Migalastat (0-18 Months) | Annualized Rate Of Change From Baseline To Month 18 In eGFR | -0.40 mL/min/1.73 m^2/year |
| ERT (0-18 Months) | Annualized Rate Of Change From Baseline To Month 18 In eGFR | -1.03 mL/min/1.73 m^2/year |
Primary
Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate
To assess renal function, measured glomerular filtration rate (GFR) was measured by the plasma clearance of unlabeled iohexol (mGFR-iohexol), a non-ionic contrast agent. The annualized rate of change in mGFR-iohexol from Baseline to Month 18 was analyzed using an analysis of covariance (ANCOVA) model with the following factors as covariates: treatment group, sex, age, Baseline GFR (mGFR-iohexol), and Baseline 24-hour (hr) urine protein. A threshold of \<2.2 milliliter (mL)/minute (min)/1.73 meter squared (m\^2)/year was established to compare migalastat to ERT. This difference of 2.2 mL/min/1.73 m2/year is based on the smallest expected rate of decline in estimated glomerular filtration rate (eGFR) for participants treated with agalsidase alfa for 18 months.
Time frame: Baseline to Month 18
Population: mITT Population: All randomized participants with an α Gal-A mutation that is amenable to migalastat, based on the GLP HEK assay, who received at least 1 dose of study drug, had Baseline and postbaseline mGFR-iohexol values, and postbaseline measure of the estimated GFR using the CKD-EPI equation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Migalastat (0-18 Months) | Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate | -4.35 mL/min/1.73 m^2/year |
| ERT (0-18 Months) | Annualized Rate Of Change From Baseline To Month 18 In Measured Glomerular Filtration Rate | -3.24 mL/min/1.73 m^2/year |
Secondary
Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation
The GFR estimated by the Modification Of Diet In Renal Disease equation (eGFR-MDRD) was calculated using the following equation: eGFR-MDRD = 175 x (Serum Creatinine)\^(-1.154) x (Age)\^(-0.203) x 1.212 (if participant's race is black or African American) x 0.742 (if participant is female). The eGFR-MDRD from Baseline to Month 18 was analyzed using an ANCOVA model with the following factors as covariates: treatment group, sex, age, Baseline GFR (eGFR-CKD-EPI), and Baseline 24-hr urine protein.
Time frame: Baseline to Month 18
Population: mITT Population: All randomized participants with an α Gal-A mutation that is amenable to migalastat, based on the GLP HEK assay, who received at least 1 dose of study drug, had Baseline and postbaseline mGFR-iohexol values, and postbaseline measure of the estimated GFR using the CKD-EPI equation.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Migalastat (0-18 Months) | Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation | -1.51 mL/min/1.73 m^2/year |
| ERT (0-18 Months) | Annualized Rate Of Change From Baseline To Month 18 In eGFR By The Modification Of Diet In Renal Disease Equation | -1.53 mL/min/1.73 m^2/year |