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

Phase 2

Completed

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 \[mg\]).

Recruitment & Eligibility

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.

Arm && Interventions

Group	Intervention	Description
Migalastat Low Dose 50 mg	migalastat HCl	Migalastat 50 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period.
Migalastat Middle Dose 150 mg	migalastat HCl	Migalastat 150 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period.
Migalastat High Dose 250 mg	migalastat HCl	Migalastat 250 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week treatment extension period.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.