A 12-Week Safety and Pharmacodynamic Study of AT1001 (Migalastat Hydrochloride) in Female Participants With Fabry Disease

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]).

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.