Clinical outcomes after 4.5 years of eliglustat therapy for Gaucher disease type 1: Phase 3 ENGAGE trial final results

Abstract

Eliglustat, an oral substrate reduction therapy, is approved for eligible adults with Gaucher disease type 1. In the Phase 3 ENGAGE trial of previously untreated adults with Gaucher disease type 1, eliglustat-treated patients had statistically significant improvements in organ volumes and hematologic parameters compared with placebo in the 9-month primary analysis. We report final outcomes by time on eliglustat among all patients who participated in the ENGAGE trial and extension. No patient deteriorated clinically or withdrew due to adverse events; 39/40 patients entered the open-label extension period and 34/40 (85%) remained in the trial until completion or switching to commercial eliglustat after its approval (2.3-6 years). Clinically meaningful improvements in Gaucher disease manifestations were seen in all patients concomitant with reductions in pathological lipid substrate levels (glucosylceramide and glucosylsphingosine). Among patients with 4.5 years of eliglustat exposure, mean spleen volume decreased by 66% (from 17.1 to 5.8 multiples of normal [MN], n = 13), mean liver volume decreased by 23% (from 1.5 to 1.1 MN, n = 13), mean hemoglobin increased 1.4 g/dl (from 11.9 to 13.4 g/dl, n = 12), mean platelet count increased by 87% (from 67.6 to 122.6 × 109 /L, n = 12), median chitotriosidase decreased by 82% (from 13 394 to 2312 nmol/h/ml, n = 11), median glucosylceramide decreased by 79% (from 11.5 to 2.4 μg/ml, n = 11), median glucosylsphingosine decreased by 84% (from 518.5 to 72.1 ng/ml, n = 10), and mean spine T-score increased from -1.07 (osteopenia) to -0.53 (normal) (n = 9). The magnitude of improvement in Gaucher disease manifestations and biomarkers over time was similar among the full trial cohort. Eliglustat was well-tolerated and led to clinically significant improvements in previously untreated patients with Gaucher disease type 1 during 4.5 years of treatment.

Trial registration: ClinicalTrials.gov NCT00891202.

Conflict of interest statement

Pramod Mistry: Lead principal investigator in the eliglustat ENGAGE trial and principal investigator in the eliglustat ENCORE trial. Member of the International Collaborative Gaucher Group (ICGG) Gaucher Registry North American Advisory Board. Receives research support from Sanofi Genzyme and honoraria and travel reimbursement from Sanofi Genzyme. Elena Lukina: Lead principal investigator in the eliglustat Phase 2 trial; principal investigator in the eliglustat ENGAGE, ENCORE, and EDGE trials. Has received honoraria and travel reimbursement from Sanofi Genzyme and Shire. Hadhami Ben Turkia: Principal investigator in the eliglustat ENCORE trial. Suma P. Shankar: Principal investigator in the eliglustat ENGAGE trial. Site primary investigator in clinical trials and received research support and educational grants from Sanofi Genzyme, Shire, Protalix, Actelion, and Amicus. Hagit Baris Feldman: Principal investigator in the eliglustat ENGAGE trial. Recipient of research grants from Pfizer, Sanofi Genzyme, Shire, of honoraria from Sanofi Genzyme and Shire, of travel grants from Genzyme, Shire, Protalix and Pfizer and advisory board member of Sanofi Genzyme and Shire. Marwan Ghosn: Principal investigator in the eliglustat ENGAGE trial. Atul Mehta: Principal investigator in the eliglustat ENGAGE trial. Has received honoraria and travel reimbursement from Sanofi Genzyme. Seymour Packman: Principal investigator in the eliglustat ENGAGE trial. Received research and programmatic support from Sanofi Genzyme, Shire HGT Corporation, Amicus Corporation, Actelion Corporation, and BioMarin Pharmaceutical. Member of the speaker's bureaus of Shire and Sanofi Genzyme. Heather Lau: Principal investigator in the eliglustat ENGAGE trial. Has received honoraria and travel reimbursement from Sanofi Genzyme. Milan Petakov: Principal investigator in the eliglustat ENGAGE trial. Has received honoraria and travel reimbursement from Sanofi Genzyme. Sarit Assouline: Principal investigator in the eliglustat ENGAGE trial. Manisha Balwani: Principal investigator in the eliglustat ENGAGE and ENCORE trials. Member of the ICGG Gaucher Registry North American Advisory Board. Has received honoraria and travel reimbursement from Sanofi Genzyme. Sumita Danda: Principal investigator in the eliglustat ENGAGE trial. Evgueniy Hadjiev: Principal investigator in the eliglustat ENGAGE trial. Has received honoraria and travel reimbursement from Sanofi Genzyme. Andres Ortega: Principal investigator in the eliglustat ENGAGE trial. Meredith C. Foster: Employee of Sanofi Genzyme. Sebastiaan J.M. Gaemers: Employee of Sanofi Genzyme and holds Sanofi stock. M. Judith Peterschmitt: Employee of Sanofi Genzyme and holds Sanofi stock.

© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.

Figures

FIGURE 1

Hematologic and visceral parameters during 4.5 years of eliglustat treatment. (A), Mean (±SEM) change from baseline in hemoglobin concentration and mean (± SEM) percent change from baseline in spleen and liver volume, and platelet count. (B), Proportion of patients meeting individual long‐term therapeutic goals* after 2.5–4.5 years of eliglustat treatment (N = 33). Goal achievement for baseline values is based on value threshold. Margin of change cannot be applied to baseline values. MN, multiples of normal; SEM, standard error of the mean [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Bone mineral density and biomarkers during 4.5 years of eliglustat treatment. (A), Mean (±SEM) spine and femur T‐scores and Z‐scores. (B), Median percent reduction in Gaucher disease biomarkers. Normal ranges: glucosylceramide, wileyonlinelibrary.com]