Effect of oral eliglustat on splenomegaly in patients with Gaucher disease type 1: the ENGAGE randomized clinical trial

Abstract

Importance: Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed.

Objective: To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1.

Design, setting, and participants: Phase 3, randomized, double-blind, placebo-controlled trial conducted at 18 sites in 12 countries from November 2009 to July 2012 among eligible patients with splenomegaly plus thrombocytopenia and/or anemia. Of 72 patients screened, 40 were enrolled.

Interventions: Patients were stratified by spleen volume and randomized 1:1 to receive eliglustat (50 or 100 mg twice daily; n = 20) or placebo (n = 20) for 9 months.

Main outcomes and measures: The primary efficacy end point was percentage change in spleen volume in multiples of normal from baseline to 9 months; secondary efficacy end points were change in hemoglobin level and percentage changes in liver volume and platelet count.

Results: All patients had baseline splenomegaly and thrombocytopenia (mostly moderate or severe), most had mild or moderate hepatomegaly, and 20% had mild anemia. Least-square mean spleen volume decreased by 27.77% (95% CI, -32.57% to -22.97%) in the eliglustat group (from 13.89 to 10.17 multiples of normal) vs an increase of 2.26% (95% CI, -2.54% to 7.06%) in the placebo group (from 12.50 to 12.84 multiples of normal) for an absolute treatment difference of -30.03% (95% CI, -36.82% to -23.24%; P < .001). For the secondary end points, the least-square mean absolute differences between groups all favored eliglustat, with a 1.22-g/dL increase in hemoglobin level (95% CI, 0.57-1.88 g/dL; P < .001), 6.64% decrease in liver volume (95% CI, -11.37% to -1.91%; P = .007), and 41.06% increase in platelet count (95% CI, 23.95%-58.17%; P < .001). No serious adverse events occurred. One patient in the eliglustat group withdrew (non-treatment related); 39 of the 40 patients transitioned to an open-label extension study.

Conclusions and relevance: Among previously untreated adults with Gaucher disease type 1, treatment with eliglustat compared with placebo for 9 months resulted in significant improvements in spleen volume, hemoglobin level, liver volume, and platelet count. The clinical significance of these findings is uncertain, and more definitive conclusions about clinical efficacy and utility will require comparison with the standard treatment of enzyme replacement therapy as well as longer-term follow-up.

Trial registration: clinicaltrials.gov Identifier: NCT00891202.

Conflict of interest statement

Conflict of Interest Disclosures

Principal investigators received no compensation for their role in the study or the development of this manuscript; however, their institutions as study sites received compensation to cover the costs of performing study assessments. Pramod Mistry is a principal investigator in the eliglustat ENGAGE and ENCORE trials and has received research grants, honoraria, and travel reimbursement from Genzyme.

Elena Lukina is a principal investigator in the eliglustat ENGAGE, ENCORE and EDGE trials and has received honoraria and travel reimbursement from Genzyme and Shire.

Hadhami Ben Turkia is a principal investigator in the eliglustat ENGAGE trial. She is a co-investigator in the HGT-GCB068 clinical trial at Shire.

Dominick Amato is a principal investigator in the eliglustat ENGAGE and ENCORE trials and has received honoraria from Actelion, Genzyme, and Shire; travel reimbursements from Actelion, Genzyme, Shire, and Protalix/Pfizer; operating funds from Actelion, Genzyme, and Shire; and consultant advisory board fees from Actelion, Protalix/Pfizer and Shire.

Hagit Baris is a principal investigator in the eliglustat ENGAGE trial and has no relevant relationships with industry to disclose.

Majed Dasouki is a principal investigator in the eliglustat ENGAGE trial and has received travel reimbursement from Genzyme.

Marwan Ghosn is a principal investigator in the eliglustat ENGAGE trial and has no relevant relationships with industry to disclose.

Atul Mehta is a principal investigator in the eliglustat ENGAGE trial and has received research grants, honoraria and travel reimbursement from Genzyme.

Seymour Packman is a principal investigator in the eliglustat ENGAGE and ENCORE trials and has received research grants and travel reimbursement from Genzyme.

Gregory Pastores is a principal investigator in the eliglustat ENGAGE and ENCORE trials and has received honoraria and travel reimbursement from Genzyme.

Milan Petakov is a principal investigator in the eliglustat ENGAGE trial and has no relevant relationships with industry to disclose.

Sarit Assouline is a principal investigator in the eliglustat ENGAGE trial and has no relevant relationships with industry to disclose.

Manisha Balwani is a principal investigator in the eliglustat ENGAGE and ENCORE trials and is a member of the North American advisory board for the International Collaborative Gaucher Group Registry. She has received honoraria and travel reimbursement from Genzyme.

Sumita Danda is a principal investigator in the eliglustat ENGAGE trial and has no relevant relationships with industry to disclose.

Evgueniy Hadjiev is a principal investigator in the eliglustat ENGAGE trial and has received honoraria and travel reimbursement from Genzyme.

Andres Ortega is a principal investigator in the eliglustat ENGAGE trial and has no relevant relationships with industry to disclose.

Suma P Shankar has been site primary investigator in clinical trials and received research support and educational grants sponsored by Genzyme, Shire, Protalix, Actelion and Amicus. She has also received honorarium for being a speaker for Genzyme and Shire.

Marie-Helene Solano is a principal investigator in the eliglustat ENGAGE trial and has received honoraria and travel reimbursement from Genzyme.

Jennifer Angell is an employee of Genzyme, a Sanofi company and has Sanofi stock options.

Leorah Ross is an employee of Genzyme, a Sanofi company.

M. Judith Peterschmitt is an employee of Genzyme, a Sanofi company.

Figures

Figure 1

Patient Disposition for the Double Blind Primary Analysis Period MN denotes multiples of normal.

Figure 2

Change in Spleen, Hemoglobin, Liver, and Platelets: Intent to Treat Population Panels A, B, C, and D show absolute mean changes in spleen volume, liver volume, hemoglobin level, and platelet count, respectively (error bars denote 95% confidence intervals), as well as individual baseline and 9-month values for each patient on these four parameters. All patients are shown in ascending order within each treatment group with respect to most to least normal value for that parameter (i.e., lowest to highest spleen and liver volumes, and highest to lowest values for hemoglobin level and platelet count). The asterisk (*) denotes the single patient who withdrew from the trial; this eliglustat patient withdrew for personal reasons at 3 months and had no 6- or 9-month assessments. For the final efficacy assessments, change for this patient was determined by last observation carried forward; thus for liver and spleen, the baseline value was carried forward and for hemoglobin and platelets, the 3 month value was carried forward. All other patients had both baseline and 9 month values for all parameters. MN denotes multiples of normal.