A 12-Week Safety and Pharmacodynamic Study of AT1001 in Female Patients With Fabry Disease

• Pharmacodynamic parameters [ Time Frame: Visits 1-8 ] [ Designated as safety issue: No ]
  PD in blood and urine
• Functional parameters (cardiac, renal, CNS) [ Time Frame: Visits 4, 6, 7, 8 ] [ Designated as safety issue: No ]
  24 hour ECG, Cardiac MRI, GFR, kidney ultrasound, transcranial doppler, brain MRI, cognitive testing, QSART

• Pharmacodynamic parameters
• Functional parameters (cardiac, renal, CNS)

The purpose of this study is to determine whether AT1001 (migalastat hydrochloride) is safe and effective in female patients with Fabry disease.

This study will be a phase 2, open-label trial in previously untreated patients with Fabry disease. The trial will consist of a 4 week screening phase, a 12-week treatment phase that may be extended up to an additional 36 weeks, and a 2-week follow-up phase.

Twelve female patients are planned to be enrolled at two sites. The number of visits for the first part of the study is 7 and for the extension treatment part, a further 3. Once patients have completed treatment, they will be required to attend a follow up visit.

After determination of missense genotype, patients will be initially screened on Day -28 by collection of blood for evaluation of enhanceablity of α-Gal A in leukocytes. Patients will come to the treatment facility for Screening assessments on Day -2 and Day -1, and baseline assessments including α-Gal A and GL-3 in plasma (leukocytes), skin tissue, cardiac tissue, and renal tissue, GL-3 in urine, and baseline evaluation of safety, cardiac, renal, and CNS parameters as described in the schedule of assessments. From Day 1, patients will initiate AT1001 once every other day oral dosing for 12 weeks. Patients will be stratified by α-Gal A enzyme activity (high > 40%, and low ≤ 40%) then randomly assigned to receive one of three specified dose levels.

Patients will return to the treatment facility for Visits 1 through 4. Safety measures will be performed at all visits. Pharmacokinetic (PK) measures will be performed predose and up to 10 hours postdose on Days 1, 14 and 84. Pharmacodynamic measurements in the form of blood leukocyte measurements of α-Gal A and plasma and urine measurements of α-Gal A and GL-3 will be performed at each visit. A final set of skin, cardiac, and renal biopsies will be performed at Visit 4. Evaluations of cardiac and renal function parameters as described in the schedule of assessments will be performed at various timepoints: ECG and serum creatinine for Visits 1 through 4; glomerular filtration rate (GFR); and 24-hr Quantitative Holter monitor ECG, ECHO, cardiac MRI, natriuretic factor, treadmill cardiac stress test, renal ultrasound (to be performed at Porto Alegre site only), Brain MRI, QSART (to be performed at Porto Alegre site only) and transcranial Doppler at Screening and Visit 4. Cognitive Testing will be performed at Screening, Baseline, and Visit 4.

Patients will also come to the treatment facility at the end of the treatment period.

If they are not continuing into the 36-week treatment extension, patients will return to the clinic for a follow-up visit 2 weeks after the end of treatment. Patients continuing into the treatment extension will return to the clinic for additional visits at Weeks 24 (Visit 6), 36 (Visit 7) and 48 (Visit 8) for safety assessments and specific pharmacodynamic and functional measurements.

• Experimental: Low dose
  Low dose of AT1001 every other day
  Intervention: Drug: AT1001 (migalastat hydrochloride)
• Experimental: Middle Dose
  Middle dose of AT1001 every other day
  Intervention: Drug: AT1001 (migalastat hydrochloride)
• Experimental: High dose
  High dose of AT1001 every other day
  Intervention: Drug: AT1001 (migalastat hydrochloride)

Inclusion Criteria:

• Patients must be adult females between 18 and 65 years of age (inclusive) and heterozygous for Fabry disease.
• Patients must have a confirmed diagnosis of Fabry disease with a documented missense gene mutation (individual or familial) and enhanceable enzyme activity (in vitro test: presence of residual Gal A activity [greater than or equal to 3% of normal] in lymphocytes and greater than or equal to 20% increase in activity after lymphocytes are incubated with AT1001).
• Patients must be naïve to ERT and other therapies, except for palliative therapies for the signs and symptoms of Fabry disease, or must stop ERT for at least 18 weeks.
• Patients must have end organ dysfunction, even minimal, demonstrated by either evidence of left ventricular hypertrophy documented by abnormal ECG and 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 as documented by evidence of stroke (clinically or imaging), or peripheral nervous tissue documented by complaints of intolerance to heat or cold, decreased vibratory sense and proprioception, decreased ability to perspire, or acroparesthesia.
• Patient agrees 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.
• Patients must be previously untreated by ERT or substrate depletion for Fabry disease, or be willing to temporarily stop treatment during this study, and be willing to undergo two renal, two cardiac, and two skin biopsies.
• Patients must be willing and able to provide written informed consent.

Exclusion Criteria:

The patient will be excluded from the study if:

• She is pregnant or lactating;
• She has a history of organ transplant;
• There is evidence of significant disease other than Fabry disease (e.g., end-stage renal disease;
• Heart disease [per clinical history, documented event, testing or class III/IV according to the New York Heart Association classification];
• Current diagnosis of cancer, except for basal cell carcinoma of the skin;
• Diabetes (unless HbA1c less than or equal to 8);
• Neurological disease that impairs her ability to participate in the study);
• Serum creatinine is greater than 176 umol/L on day -2; QTc interval is > 450 msec;
• Pacemaker or other contraindication for MRI scanning;
• Taking a medication prohibited by the protocol or any experimental therapy for any indication.
• Patients who participated in a clinical trial in the last 30 days.
• Patients who have any other condition which, in the opinion of the investigator would jeopardize the safety of the patient or impact the validity of the study results.