Eliglustat, An Investigational Oral Therapy for Gaucher Disease Type 1: Phase 2 Results After 3 Years

Abstract 1104 Introduction: Gaucher disease type 1 (GD1) is an inherited lysosomal storage disorder characterized by deficient activity of the enzyme acid β-glucosidase. This enzymatic deficiency leads to accumulation of undegraded glucosylceramide primarily in tissue macrophages (Gaucher cells) and results in multisystemic manifestations, including thrombocytopenia, anemia, hepatosplenomegaly, and bone disease. The variable clinical course and progression among patients have led to the development of therapeutic goals for the different disease manifestations (Pastores, Semin Hematol . 2004;41(suppl 5):4–14). Eliglustat, a novel, small molecule, specific inhibitor of glucosylceramide synthase, is currently under clinical development as an oral substrate reduction therapy for GD1. Objective: To report long-term efficacy and safety results of eliglustat. Methods: This ongoing, open-label, uncontrolled, multicenter, Phase 2 clinical trial enrolled 26 adults with GD1 not on treatment for the previous 12 months, who had splenomegaly with thrombocytopenia and/or anemia. Efficacy outcomes included changes from baseline in hemoglobin, platelets, spleen and liver volumes, and bone mineral density (mean±SD); biomarker levels (median); and achievement of therapeutic goals for anemia, thrombocytopenia, splenomegaly, and hepatomegaly. Results: Nineteen patients completed 3 years of treatment; 7 patients discontinued the trial. After 3 years, hemoglobin increased by 2.6±1.39 g/dL (from 11.3±1.63 to 13.8±1.37); platelets increased by 91±65.9% (from 70,000±21,700 to 126,800±40,500/mm 3); and spleen and liver volumes (multiples of normal, MN) decreased by 61±12.2% (from 16.8±9.5 to 6.2±3.6 MN) and 29±15.8% (from 1.7±0.5 to 1.2±0.3 MN), respectively. Most patients met long-term therapeutic goals for hemoglobin (100%), spleen volume (100%), liver volume (89%), and platelets (63%). All patients met ≥3 therapeutic goals at 3 years. GD1 biomarkers were elevated in most patients pre-treatment. Statistically significant decreases ( P Conclusions: Eliglustat has shown promising efficacy and safety, with clinically meaningful hematologic, visceral, and bone improvements. Most patients met long-term therapeutic goals. Eliglustat was well-tolerated through 3 years and continues to have a safety profile that supports clinical investigations in Phase 3 studies. Disclosures: Peterschmitt: Genzyme: Employment. Lukina: Genzyme: Honoraria. Watman: Genzyme: Membership on an entity9s Board of Directors or advisory committees. Pastores: Protalix: Research Funding; Shire HGT: Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding; Biomarin: Research Funding; Actelion: Research Funding; Amicus: Research Funding. Arreguin: Genzyme: Research Funding. Aguzzi: Genzyme: Employment. Ross: Genzyme: Employment. Puga: Genzyme: Employment.