Safety and Efficacy Study of Several Replagal Dosing Regimens on Cardiac Function in Adults With Fabry Disease

Fabry disease is an inherited, metabolic disease caused by mutations in the GALA gene.
Patients with Fabry disease accumulate a complex glycosphingolipid named
globotriaosylceramide (Gb3) in various tissues and organs. All organs are affected in Fabry
disease but the majority of the morbidity and mortality are caused by cardiac, renal and
neurological dysfunction. Accumulation of Gb3 in the heart causes hypertrophic
cardiomyopathy, valvular abnormalities, arrhythmias and infarctions. Replagal has been shown
to reduce Gb3 from key tissues and organs, and stabilize renal function in patients with
Fabry disease. Evidence suggests that Replagal reduces left ventricular mass (LVM) and
improves midwall fractional shortening (MFS) of the heart. Left ventricular hypertrophy is a
major cause of morbidity and mortality in patients with Fabry disease.

This is a study of the safety and effectiveness of 3 dosing regimens of Replagal in adult
patients with left ventricular hypertrophy due to Fabry disease.

The primary objective of the study is to compare the effects of 2 dosing regimens of Replagal
(0.2 mg/kg IV every other week and 0.2 mg/kg IV weekly) on the reduction of left ventricular
mass as measured by echocardiography.

The secondary objectives of this study are to compare the effects of 2 dosing regimens of
Replagal (0.2 mg/kg IV every other week and 0.2 mg/kg IV weekly) on each of the following:
exercise tolerance; improvement in disease-specific quality of life in heart failure
patients; improvement of heart failure symptoms; magnitude of reduction in Gb3; rate of
decline in renal function and improvement in the severity of proteinuria/albuminuria; and
safety.

An alternative treatment regimen of 0.4 mg/kg Replagal IV weekly will also be explored but
without formal comparison to the 0.2 mg/kg regimens. The investigation of the safety and
efficacy of the 0.4 mg/kg IV weekly regimen is a secondary objective of this study.

Inclusion Criteria:

- >18 years-old;

- Male:Fabry disease confirmed by deficiency of alfa galactosidase A activity OR
Female:Fabry disease confirmed by a mutation of the alfa galactosidase A gene;

- ERT-naïve;

- LVM/h > 50g/m2.7 for males and >47 g/m2.7 for females;

- Negative pregnancy test at enrollment and contraception use required throughout study
for female patients;

- Signed informed consent;

Exclusion Criteria:

- Class IV heart failure;

- Clinically significant hypertension;

- Hemodynamically significant valvular stenosis or regurgitation;

- Morbid obesity;

- Known autosomal dominant sarcoplasmic contractile protein gene mutation;

- Treatment with any investigational drug or device within the 30 days;

- Unable to comply with the protocol as determined by the Investigator;

- Positive for hepatitis B, hepatitis C or HIV