Fabrazyme (Page 4 of 6)

8.5 Geriatric Use

Clinical studies of Fabrazyme did not include sufficient numbers of subjects aged 65 years and older to determine whether they respond differently from younger subjects.

11 DESCRIPTION

Agalsidase beta is a recombinant human α-galactosidase A enzyme with the same amino acid sequence as the native enzyme. Purified agalsidase beta is a homodimeric glycoprotein with a molecular weight of approximately 100 kD. The mature protein is comprised of two subunits of 398 amino acids (approximately 51 kD), each of which contains three N-linked glycosylation sites. The enzyme α-galactosidase A catalyzes the hydrolysis of GL-3 and other α-galactyl-terminated neutral glycosphingolipids, such as galabiosylceramide and blood group B substances to ceramide dihexoside and galactose. The specific activity of agalsidase beta is approximately 70 U/mg (one unit is defined as the amount of activity that results in the hydrolysis of 1 µmole of a synthetic substrate, p-nitrophenyl-α-D-galactopyranoside, per minute under the assay conditions).

Agalsidase beta is produced by recombinant DNA technology in a Chinese hamster ovary mammalian cell expression system.

Fabrazyme (agalsidase beta) for injection is intended for intravenous infusion. It is supplied as a sterile, nonpyrogenic, preservative-free, white to off-white, lyophilized cake or powder for reconstitution with Sterile Water for Injection, USP. Each 35 mg vial contains 37 mg of agalsidase beta, as well as 222 mg mannitol, 20.4 mg sodium phosphate monobasic monohydrate, and 59.2 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 35 mg of agalsidase beta (7 mL) may be extracted from each 35 mg vial.

Each 5 mg vial contains 5.5 mg of agalsidase beta, as well as 33.0 mg mannitol, 3.0 mg sodium phosphate monobasic monohydrate, and 8.8 mg sodium phosphate dibasic heptahydrate. Following reconstitution as directed, 5 mg of agalsidase beta (1 mL) may be extracted from each 5 mg vial.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Fabrazyme (agalsidase beta) provides an exogenous source of α-galactosidase A in Fabry disease patients. Agalsidase beta is internalized and transported into lysosomes where it exerts enzymatic activity and reduces accumulated GL-3.

12.2 Pharmacodynamics

In Study 1, baseline mean values for plasma GL-3 were similar in the Fabrazyme (14.4 µg/mL) and the placebo (14.7 µg/mL) treatment groups. In the Fabrazyme treatment group, all 29 patients experienced normalization of plasma GL-3 levels (≤7.03 µg/mL) and they maintained normal plasma GL-3 levels for up to 60 months of treatment. Follow-up heart and kidney biopsies were assessed at month 54 in only 8 of the 44 patients, which showed sustained GL-3 clearance in the capillary endothelium of the kidney in 8 patients, and sustained GL-3 clearance in the capillary endothelium of the heart in 6 patients. The reduction in tissue GL-3 is summarized in the clinical studies section (Table 4) [see Clinical Studies (14)].

In Study 2, patients in the Fabrazyme treatment group had mean plasma GL-3 levels that decreased from 9.0 µg/mL at baseline (N=49) to 4.8 µg/mL at one year (N=37) and 4.8 µg/mL at two years (N=18). In the placebo group, the mean plasma GL-3 was 9.1 µg/mL at baseline (N=31), 8.8 µg/mL at one year (N=21), and 9.4 µg/mL at two years (N=7).

In Study 3, at baseline, all 14 males had elevated plasma GL-3 levels (i.e., >7.03 µg/mL), whereas the two female patients had normal plasma GL-3 levels. At weeks 24 and 48 of treatment, all 14 males had plasma GL-3 within the normal range. The two female patients’ plasma GL-3 levels remained normal through study week 48. Histological evaluation of the capillary endothelium (vasculature), deep vessel endothelium, deep vessel smooth muscle cells, and perineurium of biopsied skin was conducted using histochemistry with light microscopy. Scoring was on a scale of 0 to 3 (0 defined as none; 1 as mild, 2 as moderate, and 3 as severe). At baseline, 12 of the 14 males had GL-3 inclusions present on skin biopsy (scores 1, 2, or 3) and all 12 achieved GL-3 inclusion scores of 0 at weeks 24 and 48 of treatment. The two females had no GL-3 inclusions in skin at baseline.

In Study 5, in an analysis of 24 Fabrazyme-treated pediatric patients with Fabry disease aged 2 to <8 years at Fabrazyme initiation and with elevated plasma GL-3 levels (i.e., >7.03 μg/mL) at baseline, plasma GL-3 levels fell within the normal range (i.e., ≤7.03 μg/mL) in 91% (20/22), 95% (18/19), and 92% (12/13) of patients at 6, 12, and 24 months, respectively.

12.3 Pharmacokinetics

The pharmacokinetics of Fabrazyme in clinical studies with adult and pediatric patients with Fabry disease is summarized in Table 3.

Fabrazyme exhibited nonlinear pharmacokinetics following intravenous infusions at 0.3 (30% of the approved recommended dosage), 1 mg/kg, and 3 mg/kg (3 times the approved recommended dosage) in adult patients. The area under the plasma concentration-time curve (AUCinf ) and the maximum plasma concentration (Cmax ) increased greater than dose proportional with increasing doses. The AUCinf and Cmax following multiple dose administrations were comparable to their values at the first dose.

In pediatric patients 8 to 16 years of age with body weight ranging from 27 to 65 kg, the AUCinf and Cmax following multiple dose administrations were higher compared to their values at the first dose. The increased plasma concentrations following multiple dose administrations in pediatric patients could be due to formation of antidrug antibodies; however, such impact was not observed in adult patients [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) AUCinf 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 1: 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 3: 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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