Replagal Enzyme Replacement Therapy for Children With Fabry Disease

An Open Label Clinical Trial of Replagal Enzyme Replacement Therapy In Children With Fabry Disease Who Have Completed Study TKT023 or Who Are Naive to Enzyme Replacement Therapy

Primary Objective(s):

• To assess the safety of Replagal at a dose of 0.2 mg/kg administered over 40 (+/-10) minutes in children with Fabry disease
• To assess the effect of Replagal on heart rate variability in patients 7 to 17 years of age

Secondary Objective(s):

• To determine the pharmacokinetics of Replagal at baseline and after the initiation of enzyme replacement therapy (ERT)
• To determine exploratory measurements of efficacy including renal function (ie, estimated glomerular filtration rate [eGFR] and creatinine clearance), clinical outcomes (in Cohorts 1 and 2), and sweating and left ventricular mass index (LVMI) (Cohort 1, Phase 1 only)

TKT029 is an open label multi-center study to assess the safety of enzyme replacement therapy with Replagal (agalsidase alfa) in children with Fabry disease, who have completed 6 months of agalsidase alfa therapy in study TKT023 (Cohort 1) or who are treatment-naïve (Cohort 2) and meet all inclusion/exclusion criteria of this study. The study will consist of every other week treatment with Replagal for 52 weeks, with periodic reassessments by Shire HGT for continuation of the study beyond 52 weeks. A decision on the part of the study sponsor to terminate the study may be made at any time.

In Cohort 1, safety and clinical measurement assessments performed during Week 25 or 26 of Study TKT023 served as the baseline assessments for TKT029. Patients in Cohort 1 began treatment with Replagal manufactured using a roller bottle process (Replagal RB); this portion of treatment is denoted as Cohort 1, Phase 1. Safety evaluation visits for Cohort 1, Phase 1 were to be performed at Weeks 13, 25, 55, and every 26 weeks thereafter until the patient discontinued from the study or transitioned to treatment with Replagal manufactured using a bioreactor process (Replagal AF). The transition to Replagal AF marked the restart of the study clock and was denoted as Cohort 1, Phase 2. Safety evaluation visits for Cohort 1, Phase 2 will be performed at Weeks 1, 13, 25, 55, and every 26 weeks thereafter until the patient discontinues from or the sponsor terminates the study.

Patients in Cohort 2 will receive treatment with Replagal AF only; therefore there is only 1 study phase for these patients. Screening assessments performed at Week -1 will serve as the baseline assessments for this study. Safety evaluation visits for Cohort 2 will be performed at Weeks 13, 25, 37, 55 and every 26 weeks thereafter until the patients discontinues from or the sponsor terminates the study.

The final study visit for both cohorts will follow 30 days after the study study drug infusion, at which time a final safety evaluation will be performed. Patients who complete the study will be interviewed by telephone 30 days after their last study infusion for resolution of any outstanding adverse events (AEs) or concomitant medication changes. Any patient who withdraws early from the study will have a final study visit 30 days after the last study drug infusion, at which time a final safety evaluation will be performed.

Inclusion Criteria:

1a. For Cohort 1 (both phases):

- Patients must have completed all study requirements and assessments for Study TKT023 less than 30 (+/-7) days prior to enrolling in Study TKT029 and must have no safety or medical issues that contraindicate participation.

OR

1b. For Cohort 2:

• The patient is between 7 and 17 years of age at the time of informed consent, inclusive.
• The patient must be ERT-naive.
• The patient is a hemizygous male with Fabry disease as confirmed by a deficiency of alpha-galactosidase A activity measured in serum, leukocytes, or fibroblasts. Male patients who do not already have a documented deficiency of alpha-galactosidase A activity will provide a blood sample during screening for determination of alpha-galactosidase A activity level in their serum.

OR

- The patient is a heterozygous female or hemizygous male with Fabry disease as confirmed by a mutation of the alpha-galactosidase A gene. Patients who do not already have a documented mutation of the alpha-galactosidase A gene will provide a blood sample during screening for genotyping.

2. Adequate general health (as determined by the Investigators) to undergo the specified phlebotomy regimen and protocol-related procedures and no safety or medical contraindications for participation.

3. The minor child must assent to participate in the protocol and the parent(s) or legally authorized guardian(s) must have voluntarily signed an Institutional Review Board/Independent Ethics Committee (IRB/IEC) approved informed concent form after all relevant aspects of the study have been explained and discussed with the child and the child's parent(s) or legal guardian(s).

Exclusion Criteria:

Patients who meet any of the following criteria are not eligible for this study:

• Patient and/or the patient's parent(s) or legal guardian(s) are unable to understand the nature, scope, and possible consequences of the study.
• Patient is unable to comply with the protocol, e.g., uncooperative with protocol schedule, refusal to agree to all of the study procedures, inability to return for safety evaluations, or is otherwise unlikely to complete the study, as determined by the Investigator or the medical monitor.