title: Eliglustat compared with imiglucerase in patients with Gaucher's disease type 1 stabilised on enzyme replacement therapy: a phase 3, randomised, open-label, non-inferiority trial.
abstract: BACKGROUND
  The mainstay of treatment for Gaucher's disease type 1 is alternate-week infusion of enzyme replacement therapy (ERT). We investigated whether patients stable on such treatment would remain so after switching to oral eliglustat, a selective inhibitor of glucosylceramide synthase.
  
  
  METHODS
  In this phase 3, randomised, multinational, open-label, non-inferiority trial, we enrolled adults (aged ≥18 years) who had received ERT for 3 years or more for Gaucher's disease. Patients were randomly allocated 2:1 at 39 clinics (stratified by ERT dose; block sizes of four; computer-generated centrally) to receive either oral eliglustat or imiglucerase infusions for 12 months. Participants and investigators were aware of treatment assignment, but the central reader who assessed organ volumes was masked. The composite primary efficacy endpoint was percentage of patients whose haematological variables and organ volumes remained stable for 12 months (ie, haemoglobin decrease not more than 15 g/L, platelet count decrease not more than 25%, spleen volume increase not more than 25%, and liver volume increase not more than 20%, in multiples of normal from baseline). The non-inferiority margin was 25% for eliglustat relative to imiglucerase, assessed in all patients who completed 12 months of treatment. This trial is registered with ClinicalTrials.gov, number NCT00943111, and EudraCT, number 2008-005223-28.
  
  
  RESULTS
  Between Sept 15, 2009, and Nov 9, 2011, we randomly allocated 106 (66%) patients to eliglustat and 54 (34%) to imiglucerase. In the per-protocol population, 84 (85%) of 99 patients who completed eliglustat treatment and 44 (94%) of 47 patients who completed imiglucerase treatment met the composite primary endpoint (between-group difference -8·8%; 95% CI -17·6 to 4·2). The lower bound of the 95% CI of -17·6% was within the prespecified threshold for non-inferiority. Dropouts occurred due to palpitations (one patient on eliglustat), myocardial infarction (one patient on eliglustat), and psychotic disorder (one patient on imiglucerase). No deaths occurred. 97 (92%) of 106 patients in the eliglustat group had treatment-emergent adverse events, as did 42 (79%) of 53 in the imiglucerase group (mostly mild or moderate in severity).
  
  
  CONCLUSIONS
  Oral eliglustat maintained haematological and organ volume stability in adults with Gaucher's disease type 1 already controlled by intravenous ERT and could be a useful therapeutic option.
  
  
  BACKGROUND
  Genzyme, a Sanofi company.
authors.affiliation: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. Electronic address: tmc12@medschl.cam.ac.uk.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Cox
authors.affiliation: Hospital de Niños 'Dr. Ricardo Gutiérrez', Buenos Aires, Argentina.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Drelichman
authors.affiliation: State Institute of Haematology 'Arthur de Siqueira Cavalcanti', Rio de Janeiro, Brazil.
authors.forename: Renata
authors.initials: R
authors.lastname: Cravo
authors.affiliation: Mount Sinai Hospital, New York, NY, USA.
authors.forename: Manisha
authors.initials: M
authors.lastname: Balwani
authors.affiliation: Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Thomas Andrew
authors.initials: TA
authors.lastname: Burrow
authors.affiliation: Universidade Federal de São Paulo, São Paulo, SP, Brazil.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Martins
authors.affiliation: Hematology Research Center, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Lukina
authors.affiliation: Cedars-Sinai Oncology, and Tower Hematology Oncology, Beverly Hills, CA, USA.
authors.forename: Barry
authors.initials: B
authors.lastname: Rosenbloom
authors.affiliation: Genzyme, a Sanofi company, Cambridge, MA, USA.
authors.forename: Leorah
authors.initials: L
authors.lastname: Ross
authors.affiliation: Genzyme, a Sanofi company, Cambridge, MA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Angell
authors.affiliation: Genzyme, a Sanofi company, Cambridge, MA, USA.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Puga
mesh_terms: D000284:Administration, Oral; D000328:Adult; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D056947:Enzyme Replacement Therapy; D005260:Female; D005776:Gaucher Disease / Q000097:blood / Q000188:drug therapy*; D005962:Glucosylceramidase / Q000627:therapeutic use*; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007262:Infusions, Intravenous; D008099:Liver / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009929:Organ Size; D010976:Platelet Count; D011759:Pyrrolidines / Q000627:therapeutic use*; D013154:Spleen / Q000473:pathology
chemical_list: D004791:Enzyme Inhibitors; D006454:Hemoglobins; D011759:Pyrrolidines; C522917:eliglustat; D005962:Glucosylceramidase; C090568:imiglucerase