Fabrazyme (Page 4 of 6)

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fabry disease is an X-linked genetic disorder of glycosphingolipid metabolism. Deficiency of the lysosomal enzyme α-galactosidase A leads to progressive accumulation of glycosphingolipids, predominantly GL-3, in many body tissues, starting early in life and continuing over decades. Clinical manifestations of Fabry disease include renal failure, cardiomyopathy, and cerebrovascular accidents. Accumulation of GL-3 in renal endothelial cells may play a role in renal failure.

Fabrazyme is intended to provide an exogenous source of α-galactosidase A in Fabry disease patients. Nonclinical and clinical studies evaluating a limited number of cell types indicate that Fabrazyme will catalyze the hydrolysis of glycosphingolipids, including GL-3.

12.2 Pharmacodynamics

In a placebo-controlled study conducted in patients with Fabry disease after intravenous administration of 1 mg/kg of Fabrazyme every two weeks for 20 weeks, a reduction of GL-3 was observed in the capillary endothelium (vasculature) of kidney, heart, and skin as determined by histological assessment, and in plasma as determined by ELISA [see Clinical Studies (14)].

12.3 Pharmacokinetics

Plasma pharmacokinetic profiles of Fabrazyme were characterized at 0.3, 1, and 3 mg/kg in adult patients with Fabry disease. The area under the plasma concentration-time curve (AUC ) and the clearance (CL) did not increase proportionately with increasing doses, demonstrating that the enzyme follows non-linear pharmacokinetics (Table 3). Plasma pharmacokinetic profiles were also characterized in adult patients with Fabry disease given 1 mg/kg Fabrazyme every 14 days for a total of 11 infusions. Refer to Table 3 below for more details.

In 15 pediatric Fabry patients (ranging in age from 8 to 16 years old and weighing between 27.1 to 64.9 kg) who were dosed with 1 mg/kg every 14 days, Fabrazyme pharmacokinetics were not weight-dependent (Table 3). Fabrazyme concentrations were about five times higher after IgG seroconversion, without any detectable impact on GL-3 clearance.

IgG seroconversion in pediatric patients was associated with prolonged half-life and plasma concentrations of Fabrazyme, a phenomenon rarely observed in adult patients. A possible cause for this prolongation likely pertains to the ability of antibodies to potentially act as “carriers” for their antigens [see Adverse Reactions (6.2) and Use in Specific Populations (8.4)].

Table 3: Fabrazyme Pharmacokinetic Summary
Dose Regimen Mean Infusion Length (min) Infusion number(n=patients) AUC(0–∞) µg min/mL Cmax µg/mL Half-lifemin CLmL/min/kg Vss *mL/kg
All data reported as the mean ± standard deviation.
*
Vss = volume of distribution at steady state
Study FB9702-01: Phase 1/2 Study in Adult Patients with Fabry Disease
0.3 mg/kg q14 days × 5 132 1 (n=3) 79 ± 24 0.6 ± 0.2 92 ± 27 4.1 ± 1.2 225 ± 62
128 5 (n=3) 74 ± 30 0.6 ± 0.2 78 ± 67 4.6 ± 2.2 330 ± 231
1 mg/kg q14 days × 5 115 1 (n=3) 496 ± 137 5.0 ± 1.1 67 ± 12 2.1 ± 0.7 112 ± 13
120 5 (n=2) 466 ± 382 4.74 ± 4.3 45 ± 3 3.2 ± 2.6 243 ± 236
3 mg/kg q14 days × 5 129 1 (n=2) 4168 ± 1401 29.7 ± 14.6 102 ± 4 0.8 ± 0.3 81 ± 45
300 5 (n=2) 4327 ± 2074 19.8 ± 5.8 87 ± 21 0.8 ± 0.4 165 ± 80
Study AGAL-1-002-98: Phase 3 Study in Adult Patients with Fabry Disease
1 mg/kg q14 days × 11 280 1–3 (n=11) 649 ± 226 3.5 ± 1.6 89 ± 20 1.8 ± 0.8 120 ± 80
280 7 (n=11) 372 ± 223 2.1 ± 1.14 82 ± 25 4.9 ± 5.6 570 ± 710
300 11 (n=11) 784 ± 521 3.5 ± 2.2 119 ± 49 2.3 ± 2.2 280 ± 230
Study AGAL-016-01: Phase 2 Study in Pediatric Patients with Fabry Disease
1 mg/kg q14 days × 24 208 1 (n=8–9) 344 ± 307 2.2 ± 1.9 86 ± 27 5.8 ± 4.6 1097 ± 912
111 12 (n=15) 1007 ± 688 4.9 ± 2.4 130 ± 41 1.6 ± 1.2 292 ± 185
108 24 (n=9–10) 1238 ± 547 7.1 ± 4.4 151 ± 59 1.1 ± 0.8 247 ± 146

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