Treatment of Fabry disease with different dosing regimens of agalsidase: effects on antibody formation and GL-3.
ABSTRACT Two different enzyme preparations are used for the treatment of Fabry disease patients, agalsidase alpha (Replagal, Shire) and agalsidase beta (Fabrazyme, Genzyme). Therapeutic efficacy of both products has been variable probably due to differences in gender, severity, age and other patient characteristics. We studied the occurrence of alpha-Gal A antibodies and their effect on urinary and plasma globotriaosylceramide (GL-3), plasma chitotriosidase and clinical outcome in 52 patients after 12 months of treatment with either 0.2mg/kg agalsidase alppha (10 males, 8 females) or beta (8 males, 5 females) or 1.0mg/kg agalsidase beta (10 males, 11 females). Antibodies were detected in 18/28 male patients after 6 months. None of the females developed antibodies. Following 12 months of 0.2mg/kg treatment, urinary GL-3 decreased in antibody negative (AB-) but increased in antibody positive (AB+) patients. Treatment with 1.0mg/kg gave a reduction in urinary GL-3 in both AB- and AB+ patients. Levels of plasma GL-3 and chitotriosidase decreased in all patient groups. Twelve months of 0.2mg/kg treatment did not change renal function or left ventricular mass. Further, no change in renal function was seen following 1.0mg/kg treatment and left ventricular mass decreased in both AB- and AB+ patients. In summary, alpha-Gal A antibodies frequently develop in male Fabry disease patients and interfere with urinary GL-3 excretion. Infusion of a dose of 1.0mg/kg results in a more robust decline in GL-3, less impact, if any of antibodies, stable renal function and reduction of LVMass.
Article: Agalsidase Alfa[Show abstract] [Hide abstract]
ABSTRACT: The enzyme replacement therapy agalsidase alfa (Replagal®) has an amino acid sequence identical to that of native α-galactosidase A; intravenous agalsidase alfa 0.2 mg/kg every other week is indicated for the long-term treatment of patients with confirmed Fabry disease. This article reviews the efficacy and tolerability of agalsidase alfa in patients with Fabry disease, as well as summarizing its pharmacologic properties. Agalsidase alfa had beneficial effects in adult men with Fabry disease, according to the results of two randomized, double-blind, placebo-controlled, 6-month trials (n= 15 and 26). For example, left ventricular mass index was reduced to a significantly greater extent with agalsidase alfa than with placebo. Although the change in myocardial globotriaosylceramide content (primary endpoint in one study) did not significantly differ between agalsidase alfa and placebo recipients, the change in the Brief Pain Inventory (BPI) ‘pain at its worst’ score (reflecting neuropathic pain while without pain medications; primary endpoint in the second study) was improved to a significantly greater extent with agalsidase alfa than with placebo. In addition, the change in creatinine clearance, but not inulin clearance, significantly favored agalsidase alfa versus placebo recipients. Abnormalities in functional cerebral blood flow and cerebrovascular responses were also reversed with agalsidase alfa therapy. In extensions of these placebo-controlled trials, the reduction in left ventricular mass and improvements in BPI pain scores were maintained after longer-term agalsidase alfa therapy. The significant decline in estimated glomerular filtration rate (eGFR) seen after 48 months’ agalsidase alfa treatment was mainly driven by a marked decline in eGFR seen in four patients with stage 3 chronic kidney disease at baseline (although the progression of decline appeared slower than that seen in historic controls); renal function appeared stable in patients with stage 1 or 2 chronic kidney disease. Certain benefits of agalsidase alfa became apparent with longer-term therapy. For example, a significant reduction in cold and warm detection thresholds and a significant improvement in sweat function were seen after 3 years’ therapy. Final results from a head-to-head trial comparing the effects of agalsidase alfa and agalsidase beta at approved dosages are not yet available. The only available fully published study compared agalsidase alfa 0.2 mg/kg every other week with an off-label dosage of agalsidase beta 0.2 mg/kg every other week. This randomized, open-label, 24-month trial in adult men and women with Fabry disease generally found no significant differences in outcome between treatment arms. It should be noted that concerns were subsequently raised by the European Medicines Agency regarding the use of agalsidase beta at dosages other than the approved dosage of 1 mg/kg every other week. Preliminary results from an ongoing, randomized, open-label study suggest no differences in outcome between patients with Fabry disease receiving intravenous agalsidase alfa 0.2 mg/kg every other week and those receiving the approved regimen of agalsidase beta 1 mg/kg every other week. In three switching studies, no safety concerns were raised and disease stability was generally maintained following the switch from agalsidase beta 1 mg/kg every other week to agalsidase alfa 0.2 mg/kg every other week. Agalsidase alfa also demonstrated beneficial effects, including in women and pediatric patients, in non-comparative studies and in the Fabry Outcome Survey. Agalsidase alfa was generally well tolerated in patients with Fabry disease, with infusion reactions (e.g. rigors, pyrexia, flushing) being the most commonly occurring adverse event. IgG antibodies developed in ≈24% of male patients with Fabry disease who received agalsidase alfa. After 12–54 months of treatment, 17% of agalsidase alfa recipients were still IgG antibody positive, with immunologic tolerance developing in 7% of agalsidase alfa recipients. No IgE antibodies have been detected in any patient receiving agalsidase alfa. No antibody formation was reported in women receiving agalsidase alfa in noncomparative studies. In conclusion, agalsidase alfa is an effective and well tolerated treatment option for use in patients with Fabry disease.BioDrugs 26(5). · 2.12 Impact Factor
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ABSTRACT: Fabry disease is treated by two-weekly infusions with α-galactosidase A, which is deficient in this X-linked globotriaosylceramide (Gb3) storage disorder. Elevated plasma globotriaosylsphingosine (lysoGb3) is a hallmark of classical Fabry disease. We investigated effects of enzyme replacement therapy (ERT) on plasma levels of lysoGb3 and Gb3 in patients with classical Fabry disease treated with agalsidase alfa at 0.2mg/kg, agalsidase beta at 0.2mg/kg or at 1.0mg/kg bodyweight. Each treatment regimen led to prominent reductions of plasma lysoGb3 in Fabry males within 3 months (P=0.0313), followed by relative stability later on. Many males developed antibodies against α-galactosidase A, particularly those treated with agalsidase beta. Patients with antibodies tended towards smaller correction in plasma lysoGb3 concentration, whereas treatment with high dose agalsidase beta allowed a reduction comparable to patients without antibodies. Pre-treatment plasma lysoGb3 concentrations of Fabry females were relatively low. In all females and with each treatment regimen, ERT gave reduction or stabilisation of plasma lysoGb3. Our investigation revealed that ERT of Fabry patients reduces plasma lysoGb3, regardless of the recombinant enzyme used. This finding shows that ERT can correct a characteristic biochemical abnormality in Fabry patients.Biochimica et Biophysica Acta 01/2011; 1812(1):70-6. · 4.66 Impact Factor
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ABSTRACT: Fabry disease (FD) is an X-linked lysosomal storage disorder that affects both men and women. The manifestations of this heterogeneous disease are multisystemic and progressive. Prior to the development of enzyme replacement therapy, the management and treatment for Fabry disease was largely nonspecific and supportive. Because enzyme replacement therapy became commercially available in 2001, a variety of clinical benefits in Fabry patients have been consistently reported, including improved renal pathology and cardiac function, and reduced severity of neuropathic pain and improved pain-related quality of life. This update focuses on published data on the efficacy and tolerability of enzyme replacement therapy with agalsidase alfa, and gives a brief overview on some of the outstanding management issues in the treatment of this complex disease.Drug Design, Development and Therapy 01/2011; 5:155-73. · 3.49 Impact Factor