Effect of Oral Eliglustat on Splenomegaly in Patients With Gaucher Disease Type 1 The ENGAGE Randomized Clinical Trial

• Type of Material: Article
• Authors: Pramod K. Mistry, Yale University; Elena Lukina, Hematology Research Center; Hadhami Ben Turkia, Hôpital La Rabta; Dominick Amato, Mount Sinai Hospital; Hagit Baris, Rabin Medical Center; Majed Dasouki, University of Kansas; Marwan Ghosn, Hôtel-Dieu de France University Hospital; Atul Mehta, The Royal Free Hospital; Seymour Packman, University of California San Francisco; Gregory Pastores, New York University; Milan Petakov, University of Belgrade; Sarit Assouline, McGill University; Manisha Balwani, Mount Sinai Hospital; Sumita Danda, Christian Medical College; Evgueniy Hadjiev, University Hospital Alexandrovska; Andres Ortega, OCA Hospital; Suma Shankar, Emory University; Maria Helena Solano, Hospital de San Jose-Fundacion Universitaria de Ciencias de la Salud San Jose; Leorah Ross, Genzyme, a Sanofi company; Jennifer Angell, Genzyme, a Sanofi company; M. Judith Peterschmitt, Genzyme, a Sanofi company
• Language: English
• Date: 2015-02-17
• Publisher: American Medical Association (AMA): JAMA
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2015 American Medical Association. All rights reserved.
• Final Published Version (URL): http://dx.doi.org/10.1001/jama.2015.459
• Title of Journal or Parent Work: Journal of the American Medical Association
• ISSN: 0098-7484
• Volume: 313
• Issue: 7
• Start Page: 695
• End Page: 706
• Grant/Funding Information: This trial was funded by Genzyme, a Sanofi company.
• Keywords: General & Internal Medicine; SYSTEMIC-LUPUS-ERYTHEMATOSUS; Science & Technology; GLUCOCEREBROSIDASE; RECOMMENDATIONS; ENZYME REPLACEMENT THERAPY; Medicine, General & Internal; TARTRATE GENZ-112638; MIGLUSTAT; Life Sciences & Biomedicine; SAFETY; MACROPHAGE; OUTCOMES; CHITOTRIOSIDASE
• Research Categories: Health Sciences, Pathology; Health Sciences, Medicine and Surgery

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 100mg twice daily; n = 20) or placebo (n = 20) for 9 months. Main Outcomes and Measures: The primary efficacy end pointwas 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.