title: Consequences of a global enzyme shortage of agalsidase beta in adult Dutch Fabry patients.
abstract: BACKGROUND
  Enzyme replacement therapy is currently the only approved therapy for Fabry disease. From June 2009 on, viral contamination of Genzyme's 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.
  
  
  METHODS
  The 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.
  
  
  RESULTS
  All 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.
  
  
  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.
authors: Department of Internal Medicine, Division of Endocrinology and Metabolism, Academic Medical Centre, PO Box 22660, 1100 DD, Amsterdam, The Netherlands.
authors: Bouwien E
authors: BE
authors: Smid
authors: Saskia M
authors: SM
authors: Rombach
authors: Johannes M F G
authors: JM
authors: Aerts
authors: Symen
authors: S
authors: Kuiper
authors: Mina
authors: M
authors: Mirzaian
authors: Hermen S
authors: HS
authors: Overkleeft
authors: Ben J H M
authors: BJ
authors: Poorthuis
authors: Carla E M
authors: CE
authors: Hollak
authors: Johanna E M
authors: JE
authors: Groener
authors: Gabor E
authors: GE
authors: Linthorst
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018450:Disease Progression; D004334:Drug Administration Schedule; D056947:Enzyme Replacement Therapy / Q000379:methods; D000795:Fabry Disease / Q000188:drug therapy* / Q000453:epidemiology / Q000503:physiopathology*; D005260:Female; D006017:Glycolipids / Q000097:blood*; D006801:Humans; D015994:Incidence; D007527:Isoenzymes / Q000008:administration & dosage* / Q000009:adverse effects / Q000600:supply & distribution* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009426:Netherlands / Q000453:epidemiology; D013107:Sphingolipids / Q000097:blood*; D016896:Treatment Outcome; D055815:Young Adult; D000519:alpha-Galactosidase / Q000008:administration & dosage* / Q000009:adverse effects / Q000600:supply & distribution* / Q000627:therapeutic use*
chemical_list: D006017:Glycolipids; D007527:Isoenzymes; D013107:Sphingolipids; C063288:globotriaosyl lysosphingolipid; D000519:alpha-Galactosidase; C459420:agalsidase beta