a 12-week safety and pharmacodynamic study of at1001 (migalastat hydrochloride) in female participants with fabry disease

Conditions: Fabry Disease

Summary: study to evaluate the safety, tolerability, and pharmacodynamics of migalastat hydrochloride (hcl) (migalastat) in 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 \[mg\]).

Eligibility criteria:
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.

Keywords: amicus therapeutics at1001 galafold migalastat substrate