A 24-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) 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' 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 24-week treatment period, followed by an optional 24-week extension period. Participants received migalastat once every other day (QOD) for 24 weeks during the treatment period and the optional 24-week extension for a total treatment duration of up to 48 weeks.

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)
Were previously untreated by enzyme replacement therapy (ERT) or substrate depletion for Fabry disease, or if ERT or other specific treatment for Fabry disease was administered, were able to stop ERT for at least 30 weeks.
Were willing to undergo 2 kidney and 3 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 completion of the study
Were willing and able to sign an informed consent form

Exclusion Criteria

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)
History of organ transplant
Serum creatinine >176 millimole per deciliter on Day -2
Screening 12-lead ECG demonstrating corrected QT interval >450 milliseconds prior to dosing
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	migalastat HCl	Migalastat 150 milligrams (mg) was administered orally QOD during the 24-week treatment period and then during the optional 24-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	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
α-Galactosidase A (α-Gal A) Activity In Peripheral Blood Mononuclear Cells (PBMC) At Baseline, Week 24, And Week 48	Baseline, Week 24 (end of treatment period), Week 48 (end of extension period)	PBMC 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/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 leukocytes are presented by individual participants.