ENGAGE: A phase 3, randomized, double blind, placebo controlled, multi center study to investigate the efficacy and safety of eliglustat in adults with Gaucher disease type 1: 18-month results. M. Balwani1, D. Amato2, M. Dasouki3, G. Pastores4, S. Packman5, S. Assouline6, P. Mistry7, A. Ortega8, S. Shankar9, M. Solano10, J. Angell11, L. Ross11, J. Peterschmitt11 1) Mt. Sinai Hospital, New York, NY; 2) Mount Sinai Hospital, Toronto, Canada; 3) University of Kansas Hospital, Kansas City, KS, USA; 4) New York University School of Medicine, New York, NY, USA; 5) UCSF School of Medicine, San Francisco, CA, USA; 6) Jewish General Hospital, Montreal, Quebec, Canada; 7) Yale University School of Medicine, New Haven, Connecticut, USA; 8) OCA Hospital, Monterrey, Mexico; 9) Emory University, Atlanta, GA, USA; 10) Hospital San Jose, Bogota, Colombia; 11) Genzyme, a Sanofi company, Cambridge, MA, USA.

   Introduction: Gaucher disease is an autosomal recessive disorder caused by deficient activity of the lysosomal enzyme acid -glucosidase, resulting in progressive substrate accumulation and a spectrum of debilitating visceral, hematologic, and skeletal manifestations. Eliglustat, a ceramide analogue, is a novel oral substrate-reduction therapy in development for Gaucher disease type 1 (GD1). We present 18-month results from ENGAGE (NCT00891202), a randomized, double-blind, placebo-controlled, Phase-3 trial (sponsored by Genzyme, a Sanofi company) investigating the efficacy and safety of eliglustat in untreated adults with GD1.
   Methods: Forty patients (mean age: 31.8 years; 20 males) with splenomegaly and thrombocytopenia and/or anemia were randomized 1:1 to receive eliglustat (50 or 100 mg BID depending on plasma levels) or placebo for 9 months and then entered a 9-month open-label extension phase in which all patients received eliglustat. The primary efficacy endpoint was percent change in spleen volume (multiples of normal). Other efficacy measures included hemoglobin, liver volume, and platelets. Results: In the 9-month primary analysis period, eliglustat was superior to placebo in all primary and secondary endpoints; no patients discontinued due to an adverse event. For 18/20 patients who have now received 18 months of eliglustat, mean improvements from baseline continue (spleen: -45%, hemoglobin: +1.02 g/dL; liver: -11%; platelets: +58%). For 20/20 patients previously receiving placebo, mean improvements after 9 months of eliglustat were consistent with what was seen in the primary analysis period in the eliglustat-treated patients: spleen: - 33%; hemoglobin: +0.79 g/dL; liver: -7.3%; platelets: +40%. No new safety concerns were identified. The adverse event profile for all patients after 18 months is similar to that of eliglustat patients in the primary analysis period and that of patients who switched from placebo to eliglustat after 9 months.
   Conclusion: ENGAGE met its primary and secondary efficacy endpoints. Patients from both treatment arms have showed continued improvements in the first 9 months of the extension phase.