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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 1) [see Clinical Studies as follows].
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.
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 Pharmacodynamics as previously mentioned]. 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 1). 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 1). (See Table 1.)
Click on icon to see table/diagram/imageStudy 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 Pharmacodynamics as previously mentioned]. 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 μg/mL in the placebo group and 8.9 μg/mL in the FABRAZYME group with the overall range of 2.8 to 18.9 μg/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 Pharmacodynamics as previously mentioned]. 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).
Pharmacokinetics: The pharmacokinetics of FABRAZYME in clinical studies with adult and pediatric patients with Fabry disease is summarized in Table 2.
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 administration in pediatric patients could be due to formation of antidrug antibodies; however, such impact was not observed in adult patients [see Adverse Reactions and Use in Children under Precautions]. (See Table 2.)
Click on icon to see table/diagram/imageNonclinical Toxicology: 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.
