Eng et al.,2001

Eng et al. evaluated agalsidase beta in a phase 1/2, single-center, open-label, dose-ranging study involving 15 patients with Fabry disease. The patients received one infusion of agalsidase beta at different dosage regimens for a total of five infusions. Results demonstrated a mean decrease in the GL-3 content of the liver by 84%, of the kidney by 68%, of the skin by 40%, and of the endomyocardium by 16%.

After the five infusions, patients reported significant improvements in “overall pain” and “pain intensity” scores, compared with their baseline evaluation, as assessed by the Short-Form McGill Pain Questionnaire (P = .03 and P = .004, respectively). Quality of life, as measured by the Short-Form Health Survey Questionnaire (SF-36), indicated post-treatment improvements in bodily pain, general health, and vitality. The infusions were generally well tolerated. buy antibiotics in canada

This study demonstrated the efficacy of agalsidase beta in clearing GL-3 from various tissues, and it served as a basis for the phase 3 trial.

Eng et al.,2001

A phase 3 clinical trial reported by Eng et al. evaluated the safety and efficacy of agalsidase beta in a multicenter, randomized, double-blind, placebo-controlled trial of 58 Fabry disease patients (56 male, two female). The patients were at least 16 years of age and had an enzymatically confirmed diagnosis of Fabry disease with an alpha-galactosidase A activity level less than 1.5 nmol/ml per hour in plasma or less than 4 nmol/mg per hour in leukocytes.

All patients were randomly assigned to receive treatment with IV agalsidase beta (1 mg/kg, n = 29) or placebo (n = 29) every other week for 20 weeks (11 treatments). All patients received pretreatment with 1,000 mg of acetaminophen and 25 to 50 mg of hydroxyzine.

The primary endpoint was the percentage of patients who were free of microvascular endothelial deposits of GL-3 (with a score of 0; range, 0-3) in renal biopsy specimens. Clearance of microvascular endothelial deposits of GL-3 was also evaluated in endomyocardium and skin specimens. Additional outcomes included changes in pain and quality of life and safety. Baseline characteristics between the agalsidase beta and placebo patients were similar.
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After 20 weeks, 20 of 29 (69%) patients in the agalsidase beta group were free of microvascular endothelial deposits of GL-3 in renal biopsy specimens, in contrast to none of the patients in the placebo group (P < .001, odds ratio = 0.0). Eight of the nine remaining patients (89%) had a score of 1. For one patient in the treatment group, a specimen was missing; a score of 3 was assigned.

Patients in the agalsidase beta group had significantly lower scores for endomyocardium and skin specimens than did those taking placebo (P< .001 for both comparisons). Statistically significant decreases in pain from baseline, as measured by the Short-Form McGill Pain Questionnaire, were seen at week 20 in both groups; however, no difference was seen between the groups.

Quality of life, as measured by the SF-36, was significantly improved in the agalsidase beta group for two components of the survey (physical role and emotional role). Patients in the placebo group experienced significant improvements in physical role and body pain components of the SF-36.
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An open-label, six-month extension of this trial demonstrated that treatment with agalsidase beta overall resulted in clearance of microvascular endothelial deposits of GL-3 in kidney specimens in 98% of the patients, clearance of GL-3 in skin specimens in 96%, and clearance of GL-3 in heart specimens in 75%. Those treated with agalsidase beta in the double-blind study maintained clearance of GL-3 in the kidney (in 95% of patients), skin (in 96%), and heart (in 82%) after the six-month extension.

After six months of therapy with agalsidase beta, the percentages of patients in the former placebo group who showed clearance of microvascular endothelial GL-3 deposits in the kidney, skin, and heart were 100%, 96%, and 67%, respectively.

A safety assessment of these double-blind and open-label evaluations reported mild-to-moderate infusion reactions in 59% of the patients. Rigors and fever occurred more often in the agalsidase beta group of patients (P = .004) than in the placebo patients (P = .024). Skeletal pain also occurred more frequently in the agalsidase beta group than in the placebo group (P = .02). Immunoglobulin G (IgG) seroconversion was demonstrated in 51 of 58 agalsidase patients, although this figure did not have any impact on clinical efficacy.
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This well-designed study demonstrated significant clearance of GL-3 in the kidney, heart, and skin for Fabry disease patients treated with agalsidase beta compared with placebo. For a rare disease with slow progression, this was a strong endpoint, as it is the major pathogenesis of the disease, and the FDA has accepted it as a valid surrogate endpoint.