Protocol AGAL-022-02: A Phase 2, Randomized, Open Label, Dose-Ranging, Multiple Dose Study of Fabrazyme^® In Patients with Fabry Disease and with Severe Renal Disease.

Fabrazyme^® (agalsidase beta)

Drug Name	Generic Name	Studied Indications or Disease	Approved U.S. Drug Label
Fabrazyme®	agalsidase beta	Fabry disease	Prescribing Info

Investigators and Study Center(s)

This was a multicenter study conducted at 9 sites in the US.

Publication (Reference)

None

Studied Period

Patients were to be treated for approximately 36 months. Because the study was terminated early due to inadequacy of design, the study period was only nearly 7 months.

First Patient Enrolled 04 December 2002
Last Patient Completed 25 August 2003

Phase of Development

Phase 2

Objectives

The original objectives were to assess the effectiveness of two different doses of Fabrazyme on the time to clinically significant progression of the composite outcome of cardiac disease, cerebrovascular disease, and/or death among Fabry patients with severe kidney disease.

Methodology

This was a multicenter, open label trial of 2 doses of Fabrazyme (1 mg/kg and 3 mg/kg) among patients with severe renal disease. The trial was terminated early on 30 June 2003 because the study design was not found to be optimal to test the primary endpoint.

Number of Patients (Planned and Analyzed)

Approximately 120 patients were planned; 20 patients were enrolled and analyzed (descriptive assessments only).

Diagnosis and Main Criteria for Inclusion

All patients must have been > 16 years of age, had not previously received enzyme replacement therapy (ERT), and had a current diagnosis of Fabry disease. Patient enrollment was stratified by renal status into three groups with the following characteristics: Group 1: serum creatinine measurement of > 3.0 mg/dL but not undergoing dialysis or kidney transplant; Group 2: undergoing dialysis; and Group 3: had received a kidney transplant > 3 months prior to Baseline.

Test Product, Dose, and Mode of Administration

Patients were randomized to either 1 mg/kg or 3 mg/kg of Fabrazyme, receiving study drug intravenously every 2 weeks according to a ramp infusion scheme.

Duration of Treatment

The duration of the trial varies per patient, as the start of the trial was defined as the first patient randomized and the stopping point for all patients enrolled was 30 June 2003. All patients received at least one infusion of Fabrazyme, and most patients (12) received 6 or more infusions. One patient received 15 infusions over approximately 7 months.

Reference Therapy, Dose and Mode of Administration

None

Criteria for Evaluation
Efficacy

The assessment of efficacy was to be based on comparing treatment group differences in the patients’ times to the composite outcome, defined as clinically significant progression of cardiac disease, cerebrovascular disease, and/or death. This analysis was not performed because the study was terminated early.

Pharmacokinetics:

Pharmacokinetic evaluations were conducted on a subset of patients.

Safety

Adverse events, serious adverse events, infusion-associated reactions (IARs), time to immunoglobulin G (IgG) seroconversion, vital signs, electrocardiogram (ECG) parameters, echocardiograms, physical examinations, concomitant medications, serum tryptase, complement activation testing, and laboratory safety parameters were used to evaluate safety.

Statistical Methods
Efficacy

The trial was ended early as the design was not optimal to test the primary endpoint. Hence the statistical inferences that were initially planned were not conducted. Data were only summarized to show descriptive statistics for all parameters. All analyses were performed on the Intent-to-Treat (ITT) population.

Safety

All adverse events were coded using the World Health Organization Adverse Reaction Thesaurus (WHO ART) dictionary, and a listing of all patients who experienced adverse events and serious adverse events was presented.

Summary – Conclusions
Background Demographic and Medical Data

When the study was terminated on 30 June 2003, 17 male and 3 female patients with Fabry disease and severe renal disease had been randomly enrolled into either the 1 mg/kg or 3 mg/kg dose group. Both dose groups consisted of patients who were classified into one of 3 renal status groups. Most of the patients (13) were in renal status Group 3, (> 3 months status post kidney transplant). Four patients were in Group 2 (undergoing dialysis), and 3 patients were in Group 1 (serum creatinine level > 3.0 mg/dL, but not on dialysis or a post-kidney transplant). Mean patient age at enrollment was 49.2 years. Overall, 17/20 patients (85%) received at least 2 infusions (the Visit 1 and Final visit infusions). All 11 patients in the 1 mg/kg dose group received at least one full infusion in < 2 hours, and all 9 patients in the 3 mg/kg dose group received at least one full infusion in < 5 hours. All patients had a general and Fabry disease specific medical history that was consistent with their renal and Fabry disease status.

Efficacy

During the nearly 7 month long study period, one patient (in Group 3) had a clinical event, a stroke (cerebrovascular accident) that occurred 35 days after his first infusion of 1 mg/kg Fabrazyme.

Pharmacokinetics

Pharmacokinetic parameters were consistent among 5 patients (4 renal transplant patients and 1 dialysis patient) regardless of transplant or dialysis status or dose and infusion time. The Fabrazyme elimination half-life ranged from 1.58 to 3.70 hours.

Safety Results

The results of this brief Phase 2 clinical trial suggest that the administration of a small number of Fabrazyme treatments (from 1 to 15 per patient) was well-tolerated among 20 Fabry patients with severe renal disease (12 patients received at least 6 infusions). Based on this trial, which was terminated early due to inadequate study design, the following safety conclusions were made:

There were no deaths in the study and no new safety concerns were identified during this brief study.

All serious adverse events (5 patients/9 SAEs) were considered unrelated to Fabrazyme.

The most common adverse events without regard to causality were fever, malaise, peripheral edema, headache, abdominal pain, and coughing.

The majority of all reported adverse events were mild in severity.

Four patients experienced 4 non-serious and mild IARs consisting of peripheral edema 2 patients, rigors 1 patient, and flatulence 1 patient.

No direct toxic effects were demonstrated as evidenced by laboratory findings, electrocardiograms and echocardiograms.

Five of the 20 patients (25%) seroconverted. The antibody titers for these patients were not remarkable. The duration of this study was not long enough to assess seroconversion rates and long term antibody formation.

Biweekly infusions of 1 mg/kg and 3 mg/kg were well tolerated using the ramp infusion scheme in this brief study.

No meaningful conclusions can be made about differences in safety between the 1 mg/kg and 3 mg/kg dose groups due to the small numbers of patients in each group and the short duration of the study.

Conclusion

Results of this brief Phase 2 clinical trial demonstrated that enzyme replacement therapy with Fabrazyme was safely administered intravenously using a ramp infusion scheme at doses of 1 mg/kg (the recommended dose) and 3 mg/kg in 20 patients with Fabry disease and severe renal disease. Mean plasma GL-3 levels were normal at the end of the study. No new safety concerns were identified.