Treatment of Fabry disease: outcome of a comparative trial with agalsidase alfa or beta at a dose of 0.2 mg/kg. Effects of enzyme replacement therapy on the cardiomyopathy of Anderson-Fabry disease: a randomised, double-blind, placebo-controlled clinical trial of agalsidase alfa. Agalsidase-beta therapy for advanced Fabry disease: a randomized trial. Efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies: a randomized, double-blind, placebo-controlled study. Randomized, dose-finding study of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Once-monthly administration of darbepoetin alfa for the treatment of patients with chronic heart failure and anemia: a pharmacokinetic and pharmacodynamic investigation.
Two different enzyme preparations, agalsidase alfa (Replagal(TM), Shire) and beta (Fabrazyme(TM), Genzyme), are registered for treatment of Fabry disease. We compared the efficacy of and tolerability towards the two agalsidase preparations administered at identical protein dose in a randomized controlled open label trial.
                Thirty-four Fabry disease patients were treated with either agalsidase alfa or agalsidase beta at equal dose of 0.2 mg/kg biweekly. Primary endpoint was reduction in left ventricular mass after 12 and 24 months of treatment. Other endpoints included occurrence of treatment failure (defined as progression of cardiac, renal or cerebral disease), glomerular filtration rate, pain, anti-agalsidase antibodies, and globotriaosylceramide levels in plasma and urine. After 12 and 24 months of treatment no reduction in left ventricular mass was seen, which was not different between the two treatment groups. Also, no differences in glomerular filtration rate, pain and decline in globotriaosylceramide levels were found. Antibodies developed only in males (4/8 in the agalsidase alfa group and 6/8 in the agalsidase beta group). Treatment failure within 24 months of therapy was seen in 8/34 patients: 6 male patients (3 in each treatment group) and 2 female patients (both agalsidase alfa). The occurrence of treatment failures did not differ between the two treatment groups; chi(2) = 0.38 p = 0.54.
                Our study revealed no difference in reduction of left ventricular mass or other disease parameters after 12 and 24 months of treatment with either agalsidase alfa or beta at a dose of 0.2 mg/kg biweekly. Treatment failure occurred frequently in both groups and seems related to age and severe pre-treatment disease.
                International Standard Randomized Clinical Trial ISRCTN45178534 [http://www.controlled-trials.com/ISRCTN45178534]. Anderson-Fabry disease is an X-linked glycosphingolipid storage disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. This leads to a progressive accumulation of globotriaosylceramide (Gb(3)) in the lysosomes of cells throughout the body that ultimately results in premature death from renal, cardiac or cerebrovascular complications. Until recently, there was no effective therapy available for this disease. The present study was designed to assess the safety and efficacy of enzyme replacement therapy with agalsidase alfa on the cardiac manifestations of Anderson-Fabry disease.
                The effects of therapy with agalsidase alfa on cardiac structure and function were assessed in a randomised, double-blind, placebo-controlled study of 15 adult male patients with Anderson-Fabry disease. The following parameters were measured at baseline and 6 months: left ventricular mass, QRS duration and levels of Gb(3) in cardiac tissue, urine sediment and plasma. After 6 months of the randomised trial patients were enrolled in a 2-year open-label extension study.
                Left ventricular mass, as measured by MRI, was significantly reduced following 6 months of treatment with agalsidase alfa compared with placebo (p = 0.041). A mean 20% reduction in myocardial Gb(3) content as assessed by serial transvenous endomyocardial biopsies was demonstrated over the 6 months of enzyme replacement compared to a mean 10% increase in patients receiving placebo (p = 0.42)
                Enzyme replacement therapy with agalsidase alfa resulted in regression of the hypertrophic cardiomyopathy associated with Anderson-Fabry disease. Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement.
                To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease.
                Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial.
                41 referral centers in 9 countries.
                82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent.
                Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months).
                The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point.
                Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group.
                The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event.
                Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit. This phase 3, randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Patients (n = 344) with lymphoma or myeloma received darbepoetin alfa 2.25 microg/kg or placebo s.c., once weekly for 12 weeks. The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group (60%) than in the placebo group (18%) (P < 0.001), regardless of baseline endogenous erythropoietin level. However, increased responsiveness was observed in patients with lower baseline erythropoietin levels. Darbepoetin alfa also resulted in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase (1.80 g/dl vs 0.19 g/dl) and after 12 weeks of treatment (2.66 g/dl vs 0.69 g/dl). A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group (P < 0.001). The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma. Improvements in quality of life were also observed with darbepoetin alfa. The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population. Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy. Darbepoetin alfa is a novel erythropoiesis-stimulating protein with a prolonged serum half-life. This randomized, double-blind, placebo-controlled, dose-finding study investigated the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies who were receiving chemotherapy. Patients were randomized in a 1:2:2:1 ratio to receive darbepoetin alfa 1.0 microg/kg (n = 11), 2.25 microg/kg (n = 22), 4.5 microg/kg (n = 22) or placebo (n = 11), administered subcutaneously once weekly for 12 weeks. No dose increases were allowed during the study. A higher proportion of patients achieved a haemoglobin response (defined as a >/= 2.0 g/dl increase from baseline) in the darbepoetin alfa 1.0 microg/kg (45%), 2.25 microg/kg (55%) and 4.5 microg/kg (62%) groups than in the placebo group (10%; P < 0.01). The mean change in haemoglobin from baseline to week 13 was 1.56 g/dl in the 1.0 microg/kg group, 1.64 g/dl in the 2.25 microg/kg group and 2.46 g/dl in the 4.5 microg/kg group, compared with a mean change of 1.00 g/dl in the placebo group. The overall safety profile of darbepoetin alfa in this study was similar to that of placebo. These results show that darbepoetin alfa effectively and safely increased haemoglobin concentrations in patients with lymphoproliferative malignancies. Confirmative studies at doses of 2.25 and/or 4.5 microg/kg/week in this population are warranted. In patients with chronic heart failure (CHF), anemia is associated with more severe symptoms and worse prognosis. Erythropoiesis-stimulating proteins (ESPs) increase hemoglobin and may be of therapeutic benefit. We investigated the pharmacokinetics and pharmacodynamics of the long-acting ESP, darbepoetin alfa, administered on 2 occasions 1 month apart to 30 healthy subjects and 33 patients with symptomatic CHF and anemia (hemoglobin<or=12.5 g/dL) in 2 randomized, double-blind, placebo-controlled studies. Subcutaneous (SC) and intravenous administration of 0.75 microg/kg of darbepoetin alfa were compared in a crossover study. The second study compared 2.0, 3.0, and 5.0 microg/kg SC doses with placebo. Darbepoetin alfa (0.75 microg/kg SC) pharmacokinetics were similar in CHF patients and healthy subjects, with a mean (+/-SD) bioavailability of 29 (+/-11)% and 37 (+/-8)%, respectively. In anemic CHF patients, mean (+/-SD) increases in hemoglobin at 4 weeks after the second monthly dose of 2.0, 3.0, and 5.0 microg/kg (SC) of darbepoetin alfa were 2.3 (+/-0.6), 1.4 (+/-1.0), and 2.4 (+/-1.9) g/dL, respectively. Darbepoetin alfa 0.75 microg/kg (SC) given twice, 1 month apart, was insufficient to increase hemoglobin in this study. No severe, drug-related adverse events occurred. Darbepoetin alfa administered once monthly elevates and maintains the hemoglobin concentration in patients with CHF and anemia.
Six small, poor quality randomised controlled trials provide no robust evidence for use of either agalsidase alfa and beta to treat Anderson-Fabry disease.