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

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

JAMA (2015-02-18)
Pramod K Mistry, Elena Lukina, Hadhami Ben Turkia, Dominick Amato, Hagit Baris, Majed Dasouki, Marwan Ghosn, Atul Mehta, Seymour Packman, Gregory Pastores, Milan Petakov, Sarit Assouline, Manisha Balwani, Sumita Danda, Evgueniy Hadjiev, Andres Ortega, Suma Shankar, Maria Helena Solano, Leorah Ross, Jennifer Angell, M Judith Peterschmitt
ABSTRACT

Gaucher disease type 1 is characterized by hepatosplenomegaly, anemia, thrombocytopenia, and skeletal disease. A safe, effective oral therapy is needed. To determine whether eliglustat, a novel oral substrate reduction therapy, safely reverses clinical manifestations in untreated adults with Gaucher disease type 1. 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. 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. 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. 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. 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. clinicaltrials.gov Identifier: NCT00891202.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
D-Lactose monohydrate, ACS reagent
Sigma-Aldrich
D-Lactose monohydrate, ≥99% (HPLC), BioUltra
Sigma-Aldrich
D-Lactose monohydrate, SAJ special grade
Sigma-Aldrich
D-Lactose monohydrate, ≥98.0% (HPLC)
Sigma-Aldrich
D-Lactose monohydrate, tested according to Ph. Eur.
Sigma-Aldrich
Phosphorylase b from rabbit muscle, For use as a marker in SDS-PAGE
Sigma-Aldrich
Phosphorylase b from rabbit muscle, lyophilized powder, ≥20 units/mg protein, 2× crystallization
Supelco
Lactose (Monohydrate), Pharmaceutical Secondary Standard; Certified Reference Material
USP
Lactose monohydrate, United States Pharmacopeia (USP) Reference Standard