title: Agalsidase-beta therapy for advanced Fabry disease: a randomized trial.
abstract: BACKGROUND
  Fabry disease (alpha-galactosidase A deficiency) is a rare, X-linked lysosomal storage disorder that can cause early death from renal, cardiac, and cerebrovascular involvement.
  
  
  OBJECTIVE
  To see whether agalsidase beta delays the onset of a composite clinical outcome of renal, cardiovascular, and cerebrovascular events and death in patients with advanced Fabry disease.
  
  
  METHODS
  Randomized (2:1 treatment-to-placebo randomization), double-blind, placebo-controlled trial.
  
  
  METHODS
  41 referral centers in 9 countries.
  
  
  METHODS
  82 adults with mild to moderate kidney disease; 74 of whom were protocol-adherent.
  
  
  METHODS
  Intravenous infusion of agalsidase beta (1 mg per kg of body weight) or placebo every 2 weeks for up to 35 months (median, 18.5 months).
  
  
  METHODS
  The primary end point was the time to first clinical event (renal, cardiac, or cerebrovascular event or death). Six patients withdrew before reaching an end point: 3 to receive commercial therapy and 3 due to positive or inconclusive serum IgE or skin test results. Three patients assigned to agalsidase beta elected to transition to open-label treatment before reaching an end point.
  
  
  RESULTS
  Thirteen (42%) of the 31 patients in the placebo group and 14 (27%) of the 51 patients in the agalsidase-beta group experienced clinical events. Primary intention-to-treat analysis that adjusted for an imbalance in baseline proteinuria showed that, compared with placebo, agalsidase beta delayed the time to first clinical event (hazard ratio, 0.47 [95% CI, 0.21 to 1.03]; P = 0.06). Secondary analyses of protocol-adherent patients showed similar results (hazard ratio, 0.39 [CI, 0.16 to 0.93]; P = 0.034). Ancillary subgroup analyses found larger treatment effects in patients with baseline estimated glomerular filtration rates greater than 55 mL/min per 1.73 m2 (hazard ratio, 0.19 [CI, 0.05 to 0.82]; P = 0.025) compared with 55 mL/min per 1.73 m2 or less (hazard ratio, 0.85 [CI, 0.32 to 2.3]; P = 0.75) (formal test for interaction, P = 0.09). Most treatment-related adverse events were mild or moderate infusion-associated reactions, reported by 55% of patients in the agalsidase-beta group and 23% of patients in the placebo group.
  
  
  CONCLUSIONS
  The study sample was small. Only one third of the patients experienced clinical events, and some patients withdrew before experiencing any event.
  
  
  CONCLUSIONS
  Agalsidase-beta therapy slowed progression to the composite clinical outcome of renal, cardiac, and cerebrovascular complications and death compared with placebo in patients with advanced Fabry disease. Therapeutic intervention before irreversible organ damage may provide greater clinical benefit.
authors.affiliation: Mount Sinai School of Medicine of New York University, New York, New York, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Banikazemi
authors.forename: Jan
authors.initials: J
authors.lastname: Bultas
authors.forename: Stephen
authors.initials: S
authors.lastname: Waldek
authors.forename: William R
authors.initials: WR
authors.lastname: Wilcox
authors.forename: Chester B
authors.initials: CB
authors.lastname: Whitley
authors.forename: Marie
authors.initials: M
authors.lastname: McDonald
authors.forename: Richard
authors.initials: R
authors.lastname: Finkel
authors.forename: Seymour
authors.initials: S
authors.lastname: Packman
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Bichet
authors.forename: David G
authors.initials: DG
authors.lastname: Warnock
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology; D002561:Cerebrovascular Disorders / Q000209:etiology; D018450:Disease Progression; D004311:Double-Blind Method; D000795:Fabry Disease / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D007527:Isoenzymes / Q000009:adverse effects / Q000627:therapeutic use*; D007674:Kidney Diseases / Q000209:etiology; D008297:Male; D008875:Middle Aged; D011507:Proteinuria / Q000209:etiology; D016896:Treatment Outcome; D000519:alpha-Galactosidase / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D007527:Isoenzymes; D000519:alpha-Galactosidase; C459420:agalsidase beta