In males, lysoGb3 increased with a median of 8

In males, lysoGb3 increased with a median of 8.1 nM (range 2.5 – 29.2) after 1 year of shortage (p = 0.001). unchanged: 0.15 events per person per year before Tofogliflozin versus 0.15 during the shortage (p = 0.68). In total 28 clinical events occurred in 14 patients during 4.6 treatment years, compared to Edn1 7 events in 6 patients during the 1.3 year shortage period. Tofogliflozin eGFR and BPI scores were not significantly altered. Two SF-36 subscales were significantly but minimally reduced in females. In males, lysoGb3 increased with a median of 8.1 nM (range 2.5 – 29.2) after 1 year of shortage (p = 0.001). Increases in lysoGb3 were found in both patients switching to agalsidase alpha and on a reduced agalsidase beta dose. Antibody status, treatment duration or clinical event incidence showed no obvious correlation to lysoGb3 increases. Conclusions No increase in clinical event incidence was found in the adult Dutch Fabry cohort during the agalsidase beta shortage. Increases in lysoGb3, however, suggest recurrence of disease activity. Background Fabry disease (OMIM 301500) is usually a rare inherited X-linked lysosomal storage disease. Mutations in the em GLA /em gene cause a deficiency of the lysosomal enzyme -galactosidase A. As a result glycosphingolipids with a terminal -galactosyl moiety, predominately globotriaosylceramide (Gb3), accumulate in lysosomes [1]. This accumulation is usually believed to Tofogliflozin result in the symptoms and complications of the disease. During childhood presenting symptoms consist of characteristic neuronopathic aches and pains, gastro-intestinal complaints and hypohidrosis. Complications usually occur later in life and include progressive renal insufficiency, stroke, cardiac hypertrophy or infarction, and cardiac arrhythmia [2]. The phenotype of the disease is very variable, ranging from severe end-organ damage and early death in classically affected males to less pronounced disease manifestations in some male and the majority of female patients. Enzyme replacement therapy (ERT) is currently the only approved therapy for Fabry disease and aims at restoring the defective degradation of accumulated substrates by infusion of recombinant -galactosidase A. In 2001 the European Medicines Agency (EMA) approved two recombinant enzyme preparations in Europe: agalsidase alpha (Replagal?, Shire, at a registered dose of 0.2 mg/kg/eow) and agalsidase beta (Fabrazyme, Genzyme, at a registered dose of 1 1.0 mg/kg/eow). In the USA, only agalsidase beta is usually licensed. Treatment with both preparations is reported to diminish Gb3 in tissue biopsies, decrease left ventricular hypertrophy and stabilize renal function [3-8]. These effects seem most prominent in patients with less severe organ involvement at start of therapy [9,10]. Studies on the effect of ERT on the prevention of Fabry related complications are limited. One phase IV study was conducted showing limited efficacy of treatment with agalsidase beta showing a modest decrease in incidence of complications [9]. Such a study was by no means performed for agalsidase alpha. Although one study could not demonstrate differences between agalsidase alpha and agalsidase beta at and equivalent dose of 0.2 mg/kg/eow [11], the superiority of either one of the products at their registered dose has not been proven so far. In June 2009 Genzyme recognized a computer virus (vesivirus 2117) in one of the six bioreactors at their Allston manufacturing facility. Genzyme has reported that this virus is not known to cause disease in humans. Genzyme temporarily interrupted its production, which resulted in a worldwide shortage of agalsidase beta. Assuming a quick recovery of full production, the EMA advised in an online press release on 25 June 2009 [12] that: em ‘ priority should be given to children, adolescent, and adult male patients. However, adult female patients in whom the disease is less severe may receive Fabrazyme Tofogliflozin at a reduced dose’ /em . This decision was based upon the supposition that female patients with no clinically significant end organ damage could more easily tolerate a lower dose of therapy. In a subsequent online press release on 23 April 2010 [13] the EMA advised that: ‘ em for patients on the reduced dose who demonstrate a deterioration of the disease, physicians should consider restarting the original treatment with the full dose of Fabrazyme or switching to an alternative treatment, such as Replagal /em ‘. In the beginning, in the Netherlands only less affected female patients received a reduced dose. However, from October 2009 persisting shortages forced dose reductions in all Dutch patients, including males..