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: 9 Month Results

Abstract Background Gaucher disease type 1 is one of the most common lysosomal storage disorders. Deficiency of the lysosomal enzyme acid-β-glucosidase leads to accumulation of glucosylceramide (GL-1) in the spleen, liver, and bone marrow. Enzyme replacement therapy has been the mainstay of therapy for the last 20 years. Substrate reduction therapy is another treatment approach that inhibits GL-1 synthase and ultimately restores the balance between synthesis and degradation of the substrate. Eliglustat is a novel oral substrate reduction therapy that is currently in development for the treatment of Gaucher disease type 1. ENGAGE (NCT00891202) is 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 Gaucher disease type 1. Method Forty patients (mean age: 31.8 years; 20 males) with splenomegaly and thrombocytopenia and/or anemia were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg BID depending on plasma levels) or placebo for 9 months. The primary efficacy endpoint was percent change in spleen volume (multiples of normal). Other efficacy measures included hemoglobin, liver volume, and platelets. Bone endpoints included bone marrow burden (BMB) scores and bone mineral density changes (DXA). Quality of life assessments included the Gaucher Disease Severity Scoring System (DS3). Safety monitoring included adverse event reporting, and lab and electrocardiogram evaluations. Results In patients receiving eliglustat vs. placebo, mean spleen volume decreased (-28% vs. +2%, P<0.0001), mean hemoglobin increased (0.69 vs. -0.54 g/dL, P<0.0006), liver volume decreased (-5.20% vs. +1.44%, P<0.0072), and platelets increased (+32% vs. -9.06%, P<0.0001). Significant improvements (eliglustat vs. placebo) were observed for total (-1.1 vs. 0.0, p=0.002), spine (-0.6 vs. 0.1, p=0.002), and femur (-0.5 vs. 0.0, p=0.026) BMB scores. Although patients with symptomatic bone disease were excluded, absolute change in total spine DXA Z-scores approached significance (least square mean treatment difference=0.2, p=0.06). Burden of disease, as measured by the Gaucher DS3, was significantly reduced following treatment with eliglustat vs. placebo (least square mean treatment difference=-0.3, p=0.0452). No patients discontinued due to an adverse event, all of which were classified as mild to moderate, and 39/40 patients transitioned into the ongoing open-label trial. Arthralgia and nasopharyngitis occurred in >10% of eliglustat vs. placebo patients. Conclusion ENGAGE met its primary and secondary efficacy endpoints. Significant effects on bone marrow and a trend toward BMD improvement in spine were observed. Eliglustat treatment was effective and well-tolerated in untreated adults with Gaucher disease type 1. Disclosures: Shankar: Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Lukina:Genzyme, a Sanofi company: Consultancy, Honoraria, Speakers Bureau. Amato:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Packman:Genzyme, a Sanofi company: Consultancy, Research Funding. Pastores:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Balwani:Genzyme, a Sanofi company: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Mistry:Genzyme, a Sanofi company: Consultancy, Honoraria, Research Funding. Ross:Genzyme, a Sanofi company: Employment. Marulkar:Genzyme, a Sanofi company: Employment. Peterschmitt:Genzyme, a Sanofi company: Employment.

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