Fabrazyme (Page 5 of 6)

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

There are no animal or human studies to assess the carcinogenic or mutagenic potential of Fabrazyme. A study to evaluate the effects of agalsidase beta on fertility and general reproduction was performed in male and female rats at doses up to 10 mg/kg/day (23 times the human dose, on a body surface area basis). There were no adverse effects of agalsidase beta on fertility and early embryonic development in rats.

14 CLINICAL STUDIES

The safety and efficacy of Fabrazyme were assessed in four clinical studies in patients with Fabry disease and one matched analysis based on data from observational studies.

Study 1 was a randomized, double-blind, placebo-controlled, multinational, multicenter study of 58 patients with Fabry disease (56 males and 2 females), ages 16 to 61 years, all naive to enzyme replacement therapy [see Clinical Pharmacology (12.2)]. Patients were randomized 1:1 to receive either Fabrazyme 1 mg/kg every 2 weeks or placebo for 20 weeks. Patients had a median age of 24 years in the placebo group and 33 years in the Fabrazyme group at baseline. At baseline, all patients had plasma αGAL activity below the detection limit and 79% had leukocyte αGAL activity below the detection limit. The median plasma GL-3 at baseline was 14.4 ng/uL in the placebo group and 14.7 ng/uL in the Fabrazyme group with the overall range of <1.2 to 36 ng/uL. The median eGFR at baseline was 98.5 mL/hr in the placebo group and 83.0 mL/hr in the Fabrazyme group (overall range 24 to 153 mL/hr). All patients were pretreated with acetaminophen and an antihistamine. Oral steroids were an additional option to the pretreatment regimen for patients who exhibited severe or recurrent infusion-associated reactions. Tissue biopsy specimens (kidney, heart, skin) were evaluated at baseline and at week 20 by light microscopy for the presence and number of GL-3 inclusions using a semi-quantitative methodology. Renal interstitial capillaries were scored based on the number of GL-3 inclusions on a scale of 0 to 3 (0 defined as “nearly none” or “trace,” 1 defined as “mild,” 2 defined as “moderate,” and 3 defined as “severe”). The primary endpoint was the proportion of patients in either group with a renal capillary GL-3 inclusion score of zero at week 20. In the Fabrazyme group, 20 of 29 (69%) patients achieved a score of zero while 0 of 29 placebo-treated patients achieved a score of zero (p<0.001). Similar reductions in GL-3 inclusions were observed in the capillary endothelium of the heart and skin (Table 4). All 58 patients who completed Study 1 were subsequently treated with Fabrazyme 1 mg/kg every two weeks in an open-label extension study. After six months of open-label treatment, most patients with available biopsy data achieved a GL-3 inclusion score of 0 in capillary endothelium (Table 4).

Table 4: Proportion of Patients with Tissue GL-3 Inclusion Score of Zero (study 1 and open-label treatment)
20 weeks of randomized treatment in study 1 6 months of Fabrazyme open-label treatment
Placebo(n=29) Fabrazyme(n=29) Placebo/Fabrazyme(n=29)* Fabrazyme/Fabrazyme(n=29)*
*
Results reported where biopsies were available.
Kidney 0/29 20/29 24/24 23/25
Heart 1/29 21/29 13/18 19/22
Skin 1/29 29/29 25/26 26/27

Study 2 was a randomized (2:1 Fabrazyme to placebo), double-blind, placebo-controlled, multinational, multicenter study of 82 patients (72 males and 10 females) with Fabry disease, all naive to enzyme replacement therapy [see Clinical Pharmacology (12.2)]. Of the 82 enrolled patients, 51 and 31 patients were randomized to the Fabrazyme and placebo groups, respectively. Patients were 20 to 72 years of age with a median age of 45 years at baseline, a median age of 36 years at Fabry disease diagnosis, and at a median of 10 years at symptom onset. The median plasma GL-3 at baseline was 9.3 ug/mL in the placebo group and 8.9 ug/mL in the Fabrazyme group with the overall range of 2.8 to 18.9 ug/mL. At baseline, patients had median plasma αGAL activity 1.5 nmol/hour/mL (range: 0 to 1.5), leukocyte αGAL activity 1.8 nmol/hour/mL (range: 0 to 4.0), eGFR 52 mL/min/1.73 m2 (range: 25 to 113), and protein to creatinine ratio 0.9 mg/mg (range: 0 to 7.3). Patients received either 1 mg/kg Fabrazyme IV or placebo every two weeks for up to 35 months (median follow-up 18.5 months). The primary efficacy endpoint was the time to first occurrence of a clinically significant event (renal, cardiac, or cerebrovascular event, or death). A total of 14 of 51 (28%) Fabrazyme-treated patients and 13 of 31 (42%) placebo-treated patients experienced a clinically significant event (HR 0.57, 95% CI: 0.27, 1.22).

Study 3 (Pediatric Study) was an open-label, single-arm, multinational, multicenter study in 16 pediatric patients with Fabry disease (14 males, 2 females), aged 8 to 16 years (median 12 years) [see Clinical Pharmacology (12.2)]. At baseline, patients had median plasma αGAL activity 0.2 nmol/hour/mL (range: 0.0, 2.0) and median leukocyte αGAL activity 0.5 nmol/hour/mg (range: 0.0, 12.5). All 14 males had elevated plasma GL-3 levels (i.e., >7.03 µg/mL) at baseline, whereas the two females had normal plasma GL-3 levels. Median eGFR was normal (112.1 mL/min/1.73 m2) at baseline and did not change during treatment, and median urinary protein was 151.0 mg/24 hr (range: 70.0, 431.0). All patients received Fabrazyme 1 mg/kg every two weeks for up to 48 weeks.

Study 5 was a long-term, observational study assessing the rate of decline in renal function (eGFR slope) in 122 patients with Fabry disease aged 16 years and older treated with Fabrazyme. Treated patients were matched 1:1 based on age (at Fabrazyme initiation), sex, Fabry disease subtype (classic or non-classic), and baseline eGFR to a historical cohort of untreated patients with Fabry disease. The median follow-up time was 3 years in the untreated group and 4.5 years in the treated group (maximum follow-up time 5 years in both groups). In the matched cohort, the median age (at Fabrazyme initiation) was 35 years, 72% of patients were male, 84% of patients had the classic Fabry disease subtype, and the median baseline eGFR was 93 mL/min/1.73 m2. The estimated mean eGFR slope was -1.5 mL/min/1.73 m2 /year in the Fabrazyme-treated group and -3.2 mL/min/1.73 m2 /year in the untreated group (eGFR slope difference: 1.7 mL/min/1.73 m2 /year; 95% CI: 0.5, 3.0).

16 HOW SUPPLIED/STORAGE AND HANDLING

Fabrazyme (agalsidase beta) for injection is supplied as a sterile, nonpyrogenic, white to off-white lyophilized cake or powder in single-dose vials.

35 mg vial: NDC 58468-0040-1

5 mg vial: NDC 58468-0041-1

Refrigerate vials of Fabrazyme at 2°C to 8°C (36°F to 46°F). Do not use Fabrazyme after the expiration date on the vial.

This product contains no preservatives. Reconstituted and diluted solutions of Fabrazyme should be used immediately. If immediate use is not possible, the reconstituted and diluted solution may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F) [see Dosage and Administration (2.2)].

17 PATIENT COUNSELING INFORMATION

Patient Registry

Inform patients that a Registry has been established in order to better understand the variability and progression of Fabry disease in the population as a whole and in women [see Use in Specific Populations (8.1)] , and to monitor and evaluate long-term treatment effects of Fabrazyme. The Registry will also monitor the effect of Fabrazyme on pregnant women and their offspring. Encourage patients to participate. Advise patients that their participation is voluntary and may involve long-term follow-up. For more information, visit www. registrynxt.com or call 1-800-745-4447, extension 15500.

Manufactured by:
Genzyme Corporation
50 Binney Street
Cambridge, MA 02142
U.S. License Number: 1596

Fabrazyme and Genzyme are registered trademarks of Genzyme Corporation.

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