Abstract

Introduction: 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, Cambridge, MA) investigating the efficacy and safety of eliglustat in untreated adults with GD1.

Methods: During the primary analysis period (PAP), 40 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). Secondary endpoints included changes in hemoglobin levels, liver volume, and platelet counts. Bone efficacy endpoints included changes in bone marrow burden (BMB) scores, total bone mineral density (BMD), and T- and Z-scores.

Results: In the 9-month PAP, eliglustat was superior to placebo in all primary and secondary endpoints; no patients discontinued due to an adverse event. For 18 of 20 patients who received 18 months of eliglustat, mean improvements from baseline continued (spleen: -45%, hemoglobin: +1.02 g/dL; liver: -11%; platelets: +58%). For 20 of 20 patients previously receiving placebo for 9 months who then crossed-over to eliglustat during the extension phase, mean improvements after 9 months of eliglustat were consistent with what was seen in the PAP in the eliglustat-treated patients: spleen: -31%; hemoglobin: +0.79 g/dL; liver: -7.3%; and platelets: +40%. During the PAP, BMB scores, indicating bone marrow infiltration, decreased in eliglustat patients and were unchanged in placebo patients; changes in total BMD and in T- and Z-scores showed a positive trend with eliglustat compared with placebo, although changes were not statistically significant. Eliglustat-treated patients showed continued improvements in bone parameters during the 9-month extension period. No new safety concerns were identified.

Conclusion: ENGAGE met its primary and secondary efficacy endpoints in the PAP. Placebo cross-over patients showed improvements during the extension period similar to the eliglustat-treated patients during the PAP. Patients in the eliglustat-treatment group showed continued improvements in the first 9 months of the extension phase.

Disclosures

Amato:Protalix-Pfizer: Consultancy, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Actelion: Consultancy, Honoraria, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Shire: Consultancy, Honoraria, travel reimbursement, advisory board fees, travel reimbursement, advisory board fees Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Off Label Use: Eliglustat is an investigational drug for the treatment of Gaucher disease type 1. Dasouki:Genzyme, a Sanofi Company: Consultancy, Travel reimbursement Other. Packman:Genzyme, a Sanofi Company: Consultancy, Research Funding, Travel reimbursement Other. Pastores:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Balwani:Genzyme, a Sanofi Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Travel reimbursement Other. Mistry:Genzyme, a Sanofi Company: Consultancy, Honoraria, Research Funding, Travel reimbursement, Research grants Other. Shankar:Biomarin: Consultancy, received funds for fellowship training, for educational and patient meetings , received funds for fellowship training, for educational and patient meetings Other; Protalix-Pfizer: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Shire: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement, received funds for fellowship training, for educational and patient meetings Other; Actelion: Consultancy, received funds for fellowship training, for educational and patient meetings Other. Solano:Genzyme, a Sanofi Company: Consultancy, Honoraria, Travel reimbursement Other. Ross:Genzyme, a Sanofi Company: Employment. Angell:Genzyme, a Sanofi Company: Employment. Peterschmitt:Genzyme, a Sanofi Company: Employment.

Author notes

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Asterisk with author names denotes non-ASH members.

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