Treatment of Fabry disease with different dosing regimens of agalsidase: Effects on antibody formation and GL-3
Department of Internal Medicine/Endocrinology and Metabolism, Academic Medical Center, F4-224, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Molecular Genetics and Metabolism
(Impact Factor: 2.63).
08/2008; 94(3):319-25. DOI: 10.1016/j.ymgme.2008.03.003
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.
Available from: Maciej Machaczka
- "Z drugiej strony, podwyższenie aktywności chitotriozydazy w surowicy krwi nie jest specyficzne jedynie dla choroby Gauchera i jej podwyższone wartości, choć nie tak wysokie jak w chorobie Gauchera, można spotkać w innych chorobach lizosomalnych (np. chorobie Niemanna-Picka typu C) , jak również w licznych chorobach nielizosomalnych (sarkoidoza, leiszmanioza trzewna , zapalenie stawów, stwardnienie rozsiane, talasemia, przewlekła obturacyjna choroba płuc, malaria)     . Omawiając potencjalne pułapki w diagnostyce choroby Gauchera, należy na koniec wspomnieć o możliwości występowania wariantu choroby Gauchera spowodowanego niedoborem sapozyny C, białka uczestniczącego w degradacji glukocerebrozydu . "
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ABSTRACT: Gaucher disease, a rare autosomal recessive disorder caused by the deficient activity of the lysosomal enzyme glucocerebrosidase, can be difficult to diagnose in the absence of a known affected family member. This is particularly true in non-Jewish patients with mild phenotypes due to the incomplete awareness of signs and symptoms of Gaucher disease among physicians (e.g., internists). Here, we present an outline of clinical manifestations of Gaucher disease with a particular focus on hematologic symptoms. A historical outline of Gaucher disease and currently available treatment options for this disorder are briefly summarized. Last but not least, we present issues related to possible diagnostic pitfalls in non-neuropathic patients with an undiagnosed Gaucher disease.
Available from: Hsiang-Yu Lin
- "More recently, a fast and reliable LC-MS/MS assay was also developed to analyze plasma lysoGb3 levels  . Low residual enzyme activity is usually related to high plasma lysoGb3 levels . However, most of these studies were limited to classical Fabry disease; atypical variants have rarely been analyzed. "
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ABSTRACT: Previous studies revealed a high incidence of late-onset Fabry disease mutation, IVS4+919G>A, in Taiwan. However, the natural course is largely unclear and suitable biomarkers for monitoring disease progress are unavailable.
Patients carrying IVS4+919G>A or classical Fabry mutations were enrolled in this study. The subjects ranged from newborn to eighty years old adults. Plasma globotriaosylceramide (Gb3) and globotriaosylsphingosine (lysoGb3) were measured by LC-MS/MS in subjects to evaluate the sensitivity of these two biomarkers. All adult males and symptomatic females could be distinguished from healthy controls by an elevated plasma lysoGb3 level. The lysoGb3 level was also related to the left ventricular mass considering gender and age (p<0.01). Moreover, approximately 70% of male and 45% of female newborns already had an elevated plasma lysoGb3 level which increased gradually as the subjects got older (p<0.01).
Plasma lysoGb3 is a more sensitive and reliable biomarker than plasma Gb3. LysoGb3 also correlated with age and left ventricular mass index in Fabry patients with IVS4+919G>A mutation. Because lots of infants with the IVS4+919G>A mutation already had elevated lysoGb3 levels at birth, that indicates the development of hypertrophic cardiomyopathy may require a long and insidious course after lysoGb3 accumulation.
Available from: Letizia Spinelli
- "There was no increase in the clinical event incidence rate during the shortage (clinical events included neurological, renal, and cardiac events). Most, but not all (Koskenvuo et al. 2008; Kovacevic- Preradovic et al. 2008), prior studies that investigated the effects of ERT (agalsidase beta or agalsidase alfa) on cardiac functional parameters reported improvements in cardiac parameters after initiation of ERT (Weidemann et al. 2003; Beck et al. 2004; Hughes et al. 2008; Vedder et al. 2008; Imbriaco et al. 2009). Results of the current study were in agreement with the majority of these studies, i.e., LV mass and wall thickness decreased significantly from pre-ERT values after initiation of ERT, which in this case was with agalsidase beta (retrospective data; see Table 1). "
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ABSTRACT: Anderson-Fabry disease (AFD) is a multiorgan X-linked lysosomal storage disease that particularly affects the heart, kidneys, and cerebrovascular system. Current treatment is enzyme replacement therapy (ERT) with agalsidase beta (Fabrazyme(®), Genzyme Corporation, Cambridge, MA, USA) or agalsidase alfa (Replagal(®), Shire Human Genetic Therapies AB, Lund, Sweden). It was recommended that patients switch to agalsidase alfa due to a manufacturing shortage of agalsidase beta beginning in June 2009. This study assessed the effect of switching to agalsidase alfa on clinical outcomes in patients with AFD previously treated with agalsidase beta. Ten patients (seven male, three female) with genetically confirmed AFD and at least 48 months' continuous data collected during treatment with agalsidase beta 1 mg/kg every other week were switched to agalsidase alfa 0.2 mg/kg every other week for at least 20 months, with prospective clinical evaluations every 6 months. Pre-switch data was collected retrospectively from patient charts. Cardiac functional parameters were assessed using magnetic resonance imaging. Results showed that renal function was normal (estimated glomerular filtration rate ≥90 mL/min/1.73 m(2)) in 8 of 10 patients prior to agalsidase alfa and generally remained stable after the switch. Cardiac mass decreased significantly (p < 0.05 vs pre-ERT) after agalsidase beta and remained unchanged after switching to agalsidase alfa. Symptoms of pain and health status scores did not deteriorate during agalsidase alfa therapy. Adverse events were mostly mild and infusion related. In conclusion, switching to agalsidase alfa was relatively well tolerated and associated with stable clinical status and preserved renal and cardiac function.
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