title: Evaluation of the efficacy and safety of three dosing regimens of agalsidase alfa enzyme replacement therapy in adults with Fabry disease.
abstract: OBJECTIVE
  Efficacy and safety of agalsidase alfa at 0.2 mg/kg weekly were compared with 0.2 mg/kg every other week (EOW). Exploratory analyses were performed for 0.4 mg/kg weekly.
  
  
  METHODS
  This was a 53-week, Phase III/IV, multicenter, open-label study (NCT01124643) in treatment-naïve adults (≥18 years) with Fabry disease. Inclusion criteria were left ventricular hypertrophy at baseline, defined as left ventricular mass indexed to height >50 g/m(2.7) for males and >47 g/m(2.7) for females. Primary endpoint was reduction of left ventricular mass indexed to height as assessed by echocardiography. Secondary endpoints included cardiac (peak oxygen consumption, 6-minute walk test, Minnesota Living with Heart Failure Questionnaire, New York Heart Association classification), renal (Modification of Diet in Renal Disease, estimated glomerular filtration rate), and biomarker (plasma globotriaosylceramide) assessments. Safety endpoints were adverse events and anti-agalsidase alfa antibodies.
  
  
  RESULTS
  Twenty patients were randomized to 0.2 mg/kg EOW (mean age, 50.3 years; 70% male), 19 to 0.2 mg/kg weekly (51.8 years; 53% male), and 5 to 0.4 mg/kg weekly (49.4 years; 40% male). The mean change in left ventricular mass indexed to height by Week 53 in the 0.2-mg/kg EOW and weekly groups was 3.2 g/m(2.7) and 0.5 g/m(2.7), with no significant difference between groups. No clinically meaningful changes by Week 53 were found within or between the 0.2-mg/kg groups for peak oxygen consumption, 6-minute walk test, or Minnesota Living with Heart Failure Questionnaire. Two patients in each group improved by ≥1 New York Heart Association classification. No significant differences were found between 0.2 mg/kg EOW and weekly for mean change in estimated glomerular filtration rate (-1.21 mL/min/1.73 m(2) vs -3.32 mL/min/1.73 m(2)) or plasma globotriaosylceramide (-1.05 nmol/mL vs -2.13 nmol/mL), respectively. Infusion-related adverse events were experienced by 25% and 21% in the 0.2-mg/kg EOW and weekly groups. Tachycardia, fatigue, and hypotension were experienced by two or more patients overall. Anti-agalsidase alfa antibodies were detected in 11.4% of patients and neutralizing antibodies in 6.8%. Infusion-related reactions did not appear to be correlated with antibody status.
  
  
  CONCLUSIONS
  No efficacy or safety differences were found when the approved EOW dosage of agalsidase alfa was increased to weekly administration. Exploratory analyses for 0.4 mg/kg weekly showed similar results.
authors.affiliation: First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic.
authors.forename: Lubor
authors.initials: L
authors.lastname: Goláň
authors.affiliation: Lysosomal Research and Treatment Unit, Fairfax, VA, USA.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Goker-Alpan
authors.affiliation: Stead Family Department of Pediatrics, Division of Medical Genetics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.
authors.forename: Myrl
authors.initials: M
authors.lastname: Holida
authors.affiliation: Division of Medicine, Turku University Hospital, Turku, Finland.
authors.forename: Ikka
authors.initials: I
authors.lastname: Kantola
authors.affiliation: Institute of Cardiology, Warsaw, Poland.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Klopotowski
authors.affiliation: Department of Medicine, Center for Medicine and Clinical Research, University of Eastern Finland and Kuopio University Hospital, Kuopio, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.affiliation: First Faculty of Medicine, Department of Cardiovascular Medicine, Charles University, Prague, Czech Republic.
authors.forename: Aleš
authors.initials: A
authors.lastname: Linhart
authors.affiliation: Department of Internal Medicine, Jagiellonian University Medical College, Krakow, Poland.
authors.forename: Jacek
authors.initials: J
authors.lastname: Musial
authors.affiliation: Department of Nephrology, Royal Melbourne Hospital and the University of Melbourne, VIC, Australia.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Nicholls
authors.affiliation: Instituto Privado de Hematologia E Investigacion Clinica (IPHIC), Asuncion, Paraguay.
authors.forename: Derlis
authors.initials: D
authors.lastname: Gonzalez-Rodriguez
authors.affiliation: Salford Royal NHS Foundation Trust, Salford, UK.
authors.forename: Reena
authors.initials: R
authors.lastname: Sharma
authors.affiliation: General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.
authors.forename: Bojan
authors.initials: B
authors.lastname: Vujkovac
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Chang
authors.affiliation: Shire, Lexington, MA, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Wijatyk
mesh_terms: D000328:Adult; D000368:Aged; D004305:Dose-Response Relationship, Drug; D056947:Enzyme Replacement Therapy / Q000379:methods*; D000795:Fabry Disease / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007527:Isoenzymes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D016896:Treatment Outcome; D000519:alpha-Galactosidase / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use
chemical_list: D007527:Isoenzymes; D011994:Recombinant Proteins; C000627036:agalsidase alfa; D000519:alpha-Galactosidase
keywords: adverse events; exercise tolerance; left ventricular hypertrophy; lysosomal storage disorder; quality of life; renal function