Bouwien E. Smid

Long term enzyme replacement therapy for Fabry disease: effectiveness on kidney, heart and brain

BackgroundFabry disease is an X-linked lysosomal storage disorder caused by α-galactosidase A deficiency leading to renal, cardiac, cerebrovascular disease and premature death. Treatment with α-galactosidase A (enzyme replacement therapy, ERT) stabilises disease in some patients, but long term effectiveness is unclear.MethodsRenal, cardiac, and cerebral outcomes were prospectively studied in males and females with Fabry disease treated with ERT. Additionally, the occurrence of major cardiac events, stroke, end-stage renal disease and death was compared to a natural history (NH) cohort meeting treatment criteria.ResultsOf 75 patients on ERT (median treatment duration 5.2 years, range 0.05-11.0), prospective follow-up was available for 57 adult patients (30 males) and 6 adolescents. Renal function declined in males (-3.4 ml/min/1.73 m2 per year, SE 0.2; p < 0.001) despite ERT, but followed the normal course in females (-0.8 ml/min/1.73 m2 per year, SE 0.3; p = 0.001). Cardiac mass increased during ERT in males (+ 1.2 gram/m2.7, SE 0.3; p < 0.001), but remained stable in females (-0.3 gram/m2.7 per year, SE 0.4; p = 0.52). ERT did not prevent the occurrence of cerebral white matter lesions. Comparison of ERT treated to untreated patients revealed that the odds to develop a first complication increased with age (OR 1.05 (95% CI: 1.0-1.1) per year, p = 0.012). For development of a first or second complication the odds declined with longer treatment duration (OR 0.81 (95% CI: 0.68-0.96) per year of ERT, p = 0.015;OR 0.52 (0.31-0.88), p = 0.014 respectively).ConclusionsLong term ERT does not prevent disease progression, but the risk of developing a first or second complication declines with increasing treatment duration. ERT in advanced Fabry disease seems of doubtful benefit.

Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients

BackgroundEnzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzymes production facility resulted in a worldwide shortage of agalsidase beta leading to involuntary dose reductions (approved dose 1 mg/kg/eow, reduced dose 0.5 mg/kg/m), or switch to agalsidase alpha (administered dose 0.2 mg/kg/eow). An assessment report from the European Medicines Agency (EMA) raised serious concerns about an increase in adverse events at lower dosages of agalsidase beta. We determined the influence of the shortage on clinical event incidence and the most sensitive biochemical marker (lysoGb3) in Dutch Fabry patients.MethodsThe incidence of clinical events per person per year was calculated from start of agalsidase beta treatment until the shortage, and was compared to the incidence of clinical events during the shortage period. In addition, plasma lysoGb3, eGFR, quality of life (SF-36) and brief pain inventory (BPI) questionnaires were analysed.ResultsAll thirty-five Dutch Fabry patients using agalsidase beta (17 males) were included. Mean clinical event incidence was unchanged: 0.15 events per person per year before 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 7 events in 6 patients during the 1.3 year shortage period. 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 clear correlation to lysoGb3 increases.ConclusionsNo 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.

Establishing 3-nitrotyrosine as a biomarker for the vasculopathy of Fabry disease

The endothelial dysfunction of Fabry disease results from α-galactosidase A deficiency leading to the accumulation of globotriaosylceramide. Vasculopathy in the α-galactosidase A null mouse is manifested as oxidant-induced thrombosis, accelerated atherogenesis, and impaired arterial reactivity. To better understand the pathogenesis of Fabry disease in humans, we generated a human cell model by using RNA interference. Hybrid endothelial cells were transiently transfected with small interfering RNA (siRNA) specifically directed against α-galactosidase A. Knockdown of α-galactosidase A was confirmed using immunoblotting and globotriaosylceramide accumulation. Endothelial nitric oxide synthase (eNOS) activity was correspondingly decreased by >60%. Levels of 3-nitrotyrosine (3NT), a specific marker for reactive nitrogen species and quantified using mass spectrometry, increased by 40- to 120-fold without corresponding changes in other oxidized amino acids, consistent with eNOS-derived reactive nitrogen species as the source of the reactive oxygen species. eNOS uncoupling was confirmed by the observed increase in free plasma and protein-bound aortic 3NT levels in the α-galactosidase A knockout mice. Finally, 3NT levels, assayed in biobanked plasma samples from patients with classical Fabry disease, were over sixfold elevated compared with age- and gender-matched controls. Thus, 3NT may serve as a biomarker for the vascular involvement in Fabry disease.

Pharmacological small molecules for the treatment of lysosomal storage disorders

Importance of the field: Inherited lysosomal storage diseases often cause severe disability and have a devastating effect on quality of life. Enzyme replacement therapy (ERT) forms a cornerstone in the treatment of lysosomal enzyme deficiencies. Although for some lysosomal disorders ERT is lifesaving, important intrinsic restrictions of the approach are limited access of infused enzyme to less accessible body compartments such as theCNS, the burden of frequent intravenous administration, the emergence of antibodies and the high associated costs. Pharmacological small molecules may overcome these limitations. Areas covered in this review: Several novel therapeutic approaches using small molecules are emerging: substrate reduction therapy, pharmacological chaperone therapy, premature nonsense mutation suppressors and proteostasis regulators. What the reader will gain: Based on an extensive literature search up until June 2010, we here review the various therapeutic approaches with small compounds, including those currently in clinical use and those that have entered clinical trials. Compounds that are still in the preclinical phase are also briefly discussed. Take home message: pharmacological small molecules are a new class of agents that show great promise for the treatment of lysosomal storage disorders.

A revised home treatment algorithm for Fabry disease: Influence of antibody formation

BACKGROUND Enzyme replacement therapy for Fabry disease, consisting of biweekly infusions, interferes daily life. Home treatment proved beneficial. We evaluated a previously reported home treatment algorithm aiming to shorten the period of in-hospital infusions, while ascertaining patient safety. METHODS Retrospective analysis on clinical records of treated Fabry patients. Potentially predictive factors for infusion associated reactions (IARs) were studied: agalsidase antibodies, agalsidase product and dose, FOS-SSI scores, and GLA activity and mutation. A questionnaire evaluated patient satisfaction and compliance. RESULTS Seventy-nine patients were included (41 males, 46% agalsidase antibody positive (AB+)). 85% received home treatment. Home treatment complications were erroneous fast infusion rates (n=4) causing IARs and, rarely, venous access problems. The single SAE was unrelated to home treatment. IgG antibody status was significantly associated with IARs (89% vs. 26% p-value<0.01). Negative antibody status did not preclude IARs. Except for three AB+ patients, all first IARs occurred within 13 infusions. IARs occurred more frequently in patients using agalsidase beta 1.0 mg/kg/eow than agalsidase alpha or beta 0.2 mg/kg/eow, but the time to first IAR did not differ between groups. Four AB+ males experienced IARs after a dose increase. Compliance between home and in-hospital treatment was similar. Most patients preferred home treatment. CONCLUSION In this study home therapy for Fabry disease was safe and improved patient satisfaction. We propose a revised algorithm which allows safe home-treatment in all male patients after 13 instead of 26 infusions, irrespective of ERT preparation or dose. Furthermore, AB+ patients with dosage increase may experience new or increased IARs, necessitating in-hospital observations.

A systematic review on effectiveness and safety of eliglustat for type 1 Gaucher disease

Introduction: Eliglustat is a novel therapeutic agent for the treatment of Gaucher type 1 disease (GD1). GD1 is the most prevalent form of Gaucher disease, resulting from deficient activity of glucocerebrosidase. This leads to lysosomal storage of glucosylceramide, causing hepatosplenomegaly, bone disease and cytopenia. Eliglustat exerts it beneficial effects by inhibiting glucosylceramide synthesis (substrate reduction therapy), but does not cross the blood–brain barrier. Areas covered: This systematic review describes the currently available literature and data in the public domain on the clinical effectiveness and toxicity of eliglustat for the treatment of GD1 as well as the safety and tolerability in healthy controls (18 November 2013). Expert opinion: Eliglustat shows high promise as an oral treatment for GD1, with robust effectiveness on all relevant disease parameters in clinical trials. Oral treatment may offer a convenient alternative to patients who are treated lifelong with enzyme replacement therapy (ERT). Currently, insufficient data are available to establish superiority of eliglustat over ERT, especially on long-term complications and effectiveness in GD1 patients with severe disease, active bone disease or polyneuropathy. Eliglustat does not cause gastrointestinal side effects as observed with miglustat. Frequently prescribed concomitant CYP2D6-inducing medication and cardiovascular disease may restrict prescription of eliglustat.