Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products – enzymes.
ATC code: A16AB04.

Fabry disease
Fabry disease is an inherited heterogeneous and multisystemic progressive disease, that affects both males and females. It is characterised by the deficiency of α-galactosidase. Reduced or absent α-galactosidase activity results in the presence of elevated concentrations of GL-3 and its associated soluble form lyso-GL-3 in plasma and in accumulation of GL-3 in the lysosomes of many cell types including the endothelial and parenchymal cells, ultimately leading to life-threatening clinical deteriorations as a result of renal, cardiac and cerebrovascular complications.

Mechanism of action
The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to clear the accumulating substrate in the organ tissues; thereby, preventing, stabilizing, or reversing the progressive decline in function of these organs before irreversible damage has occurred.

After intravenous infusion, agalsidase beta is rapidly removed from the circulation and taken up by vascular endothelial and parenchymal cells into lysosomes, likely through the mannose-6 phosphate, mannose and asialoglycoprotein receptors.

Clinical efficacy and safety
Efficacy and safety of Fabrazyme was evaluated in two studies with children, one dose-finding study, two double-blind placebo-controlled studies, one open-label extension study in both male and female patients and published scientific literature.


In the dose finding study, the effects of 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0 and 3.0 mg/kg once every 2 days were evaluated. A reduction in GL-3 was observed in kidney, heart, skin and plasma at all doses. Plasma GL-3 was cleared in a dose dependent manner but was less consistent at the dose of 0.3 mg/kg. In addition, infusion-associated reactions were dose dependent.

In the first placebo-controlled clinical trial of 58 Fabry patients with classic phenotype (56 males and 2 females), Fabrazyme was effective in clearing GL-3 from the vascular endothelium of the kidney after 20 weeks of treatment. This clearance was achieved in 69% (20/29) of the Fabrazyme treated patients,
but in none of the placebo patients (p<0.001). This finding was further supported by a statistically significant decrease in GL-3 inclusions in kidney, heart and skin combined and in the individual organs in patients treated with agalsidase beta compared to placebo patients (p<0.001). Sustained clearance of GL-3 from kidney vascular endothelium upon agalsidase beta treatment was demonstrated further in the open label extension of this trial. This was achieved in 47 of the 49 patients (96%) with available information at month 6, and in 8 of the 8 patients (100%) with available information at the end of the study (up to a total of 5 years of treatment). Clearance of GL-3 was also achieved in several other cell types from the kidney. Plasma GL-3 levels rapidly normalised with treatment and remained normal through 5 years.

Renal function, as measured by glomerular filtration rate and serum creatinine, as well as proteinuria, remained stable in the majority of the patients. However, the effect of Fabrazyme treatment on the kidney function was limited in some patients with advanced renal disease.

Although no specific study has been conducted to assess the effect on the neurological signs and symptoms, the results also indicate that patients may achieve reduced pain and enhanced quality of life upon enzyme replacement therapy.

Another double-blind, placebo-controlled study of 82 Fabry patients with classic phenotype (72 males and 10 females) was performed to determine whether Fabrazyme would reduce the rate of occurrence of renal, cardiac, or cerebrovascular disease or death. The rate of clinical events was substantially lower among Fabrazyme-treated patients compared to placebo-treated patients (risk reduction = 53% intent-to-treat population (p=0.0577); risk reduction = 61 % per-protocol population (p=0.0341)). This result was consistent across renal, cardiac and cerebrovascular events.

Two large observational studies followed a group of patients (n=89 to 105) who were maintained on standard-dose Fabrazyme (1.0 mg/kg every 2 weeks) or assigned to a reduced dose of Fabrazyme (0.3- 0.5 mg/kg every 2 weeks) followed by a switch to agalsidase alfa (0.2 mg/kg every 2 weeks) or directly switched to agalsidase alfa (0.2 mg/kg every 2 weeks). Due to the observational, multi-centre design of these studies based in a real-world clinical setting, there are confounding factors affecting the interpretation of the results, including the selection of patients and assignment of treatment groups and available parameters between centres over time. Due to the rarity of Fabry disease, the study populations of the observational studies overlapped and the treatment groups in respective studies were small.
Moreover, most patients with more severe disease, especially men, remained on standard dose Fabrazyme, whereas a treatment switch occurred more frequently in patients with less severe disease and women. Comparisons between the groups should therefore be cautiously interpreted.

The Fabrazyme standard-dose group demonstrated no significant changes in cardiac, renal, or neurologic organ function or in symptoms related to Fabry disease. Similarly, no significant changes in cardiac or neurologic function were observed in patients in the Fabrazyme dose-reduction group. However, deterioration in renal parameters, as measured by estimated glomerular filtration rate (eGFR), was observed in patients treated with a lower dose (p<0.05). The annual decreases in eGFR were attenuated in patients who re-switched back to standard dose Fabrazyme. These results are consistent with 10-year follow-up evidence from the Canadian Fabry Disease Initiative Registry.

In the observational studies an increase in symptoms related to Fabry disease (e.g., gastrointestinal pain, diarrhoea) was observed in patients who had received a dose reduction of agalsidase beta.
Also, in the postmarketing setting, experience was gained in patients who initiated Fabrazyme treatment at a dose of 1 mg/kg every 2 weeks and subsequently received a reduced dose for an extended period. In some of these patients, an increase of some of the following symptoms was spontaneously reported: pain, paraesthesia and diarrhoea, as well as cardiac, central nervous system and renal manifestations. These reported symptoms resemble the natural course of Fabry disease.

In an analysis conducted in the Fabry Registry, the incidence rates (95% confidence interval) of the first severe clinical event in Classic male Fabrazyme-treated patients with sustained anti-agalsidase beta IgG antibodies were 43.98 (18.99, 86.66), 48.60 (32.03, 70.70), and 56.07 (30.65, 94.07) per 1000 person- years in the low, medium, and high peak titre groups, respectively. These observed differences were not statistically significant.
Paediatric population
In one open-label paediatric study, sixteen patients with Fabry disease (8-16 years old; 14 males, 2 females) had been treated for one year at 1.0 mg/kg every 2 weeks. Clearance of GL-3 in the superficial skin vascular endothelium was achieved in all patients who had accumulated GL-3 at baseline. The 2 female patients had little or no GL-3 accumulation in the superficial skin vascular endothelium at baseline, making this conclusion applicable in male patients only.

In an additional 5-year open-label paediatric study, 31 male patients aged 5 to 18 years were randomised prior to the onset of clinical symptoms involving major organs and treated with two lower dose regimens of agalsidase beta, 0.5 mg/kg every 2 weeks or 1.0 mg/kg every 4 weeks. Results were similar between the two treatment groups. Superficial skin capillary endothelium GL-3 scores were reduced to zero or maintained at zero at all time points post-baseline upon treatment in 19/27 patients completing the study without a dose increase. Both baseline and 5-year kidney biopsies were obtained in a subset of 6 patients: in all, kidney capillary endothelium GL-3 scores were reduced to zero, but highly variable effects were observed in podocyte GL-3, with a reduction in 3 patients. Ten (10) patients met per protocol dose increase criteria, two (2) had a dose increase to the recommended dose of 1.0 mg/kg every 2 weeks.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties

Following an intravenous administration of agalsidase beta to adults at doses of 0.3 mg, 1 mg and 3 mg/kg body weight, the AUC values increased more than dose proportional, due to a decrease in clearance, indicating a saturated clearance. The elimination half-life was dose independent and ranged from 45 to 100 minutes.

After intravenous administration of agalsidase beta to adults with an infusion time of approximately 300 minutes and at a dose of 1 mg/kg body weight, biweekly, mean Cmax plasma concentrations ranged from 2000–3500 ng/ml, while the AUCinf ranged from 370–780 μg.min/ml. Vss ranged from 8.3-40.8 l, plasma clearance from 119-345 ml/min and the mean elimination half-life from 80–120 minutes.

Agalsidase beta is a protein and is expected to be metabolically degraded through peptide hydrolysis.
Consequently, impaired liver function is not expected to affect the pharmacokinetics of agalsidase beta in a clinically significant way. Renal elimination of agalsidase beta is considered to be a minor pathway for clearance.

Paediatric population
Fabrazyme pharmacokinetics was also evaluated in two paediatric studies. In one of these studies, 15 paediatric patients with available pharmacokinetics data, aged 8.5 to 16 years weighing 27.1 to 64.9 kg were treated with 1.0 mg/kg every 2 weeks. Agalsidase beta clearance was not influenced by weight in this population. Baseline CL was 77 ml/min with a Vss of 2.6 l; half-life was 55 min. After IgG seroconversion, clearance decreased to 35 ml/min, Vss increased to 5.4 l, and half-life increased to 240 min. The net effect of these changes after seroconversion was an increase in exposure of 2- to 3-fold based on AUC and Cmax. No unexpected safety issues were encountered in patients with an increase in exposure after seroconversion.
In another study with 30 paediatric patients with available pharmacokinetics data, aged 5 to 18 years, treated with two lower dose regimens of 0.5 mg/kg every 2 weeks and 1.0 mg/kg every 4 weeks, mean CL was 4.6 and 2.3 ml/min/kg, respectively, mean Vss was 0.27 and 0.22 l/kg, respectively, and mean elimination half-life was 88 and 107 minutes, respectively. After IgG seroconversion, there was no apparent change in CL (+24% and +6%, resp.), while Vss was 1.8 and 2.2-fold higher, with the net effect being a small decrease in Cmax (up to -34% and -11%, resp.) and no change in AUC (-19% and -6%, resp.).