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

Phase 2

Completed

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.

Recruitment & Eligibility

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

Arm && Interventions

Group	Intervention	Description
Migalastat	migalastat HCl	Migalastat 150 mg was administered orally QOD during the 12-week treatment period and then during the optional 36-week 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 (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 Outcome Measures

Name	Time	Method
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.