Long-Term Hematologic Response to Eliglustat in Patients with Gaucher Disease Type 1: Results from a Phase 2 and Two Phase 3 Trials
Authors: Weinreb Neal J. , Cox Timothy M , Lukina Elena , Mistry Pramod , Angell Jennifer , Gaemers Sebastiaan , Peterschmitt M. Judith 
Published: October 2019

Introduction: Gaucher disease is caused by a deficiency in lysosomal acid β-glucosidase, which leads to accumulation of glucosylceramide primarily in macrophages. These pathogenic macrophages (Gaucher cells) deposit in the spleen, liver, bone marrow and lungs and lead to hepatosplenomegaly, pancytopenia and skeletal disease. As thrombocytopenia, anemia and splenomegaly are common presenting symptoms of Gaucher patients, hematologists are often the healthcare provider to identify, evaluate and manage the disease. The current standard of care is biweekly intravenous enzyme replacement therapy (ERT) that supplements lysosomal acid β-glucosidase in mononuclear phagocytes. Eliglustat, a ceramide analogue, is a novel oral substrate reduction therapy (SRT) that was recently approved as a first-line treatment of adults with Gaucher disease type 1 (GD1) who have a compatible CYP2D6 metabolizer phenotype (>90% of patients). Rather than supplement lysosomal acid β-glucosidase in mononuclear phagocytes, eliglustat partially inhibits glucosylceramide synthase and reduces glucosylceramide production to offset the attenuated rate of degradation.
Methods: We report on improvements in hemoglobin level and platelet counts in adults with GD1 from 3 ongoing clinical trials of eliglustat sponsored by Genzyme, a Sanofi company. Two trials are in treatment-naïve patients: an open-label Phase 2 trial (N=26, NCT00358150) for which 4-year data are available and a randomized, placebo-controlled Phase 3 trial (ENGAGE, N=40, NCT00891202) for which 18-month data are available. The third trial (ENCORE, Phase 3 imiglucerase-controlled, N=159, NCT00943111) involved patients previously stabilized on ≥3 years of ERT and 24-month data are available.
Results: In the Phase 2 study, the primary endpoint was met after 1 year, with 77% of patients improving in at least 2 of 3 main efficacy parameters (spleen volume, hemoglobin level and platelet count) (Lukina et al. Blood 2010;116:816). After 4 years, mean hemoglobin level had increased by 2.3±1.5 g/dL from the baseline mean of 11.3±1.5 g/dL, and mean platelet count had increased by 95% from the baseline mean of 69±21x109/L. In the ENGAGE study, all primary and secondary endpoints were met after 9 months, with statistically significant improvements in spleen volume, hemoglobin level, liver volume and platelet counts seen in eliglustat-treated but not placebo patients (Mistry et al. JAMA 2015;313;695). Improvements continued in patients who received eliglustat for 18 months in the trial extension; mean hemoglobin level increased by 1.02±0.84 g/dL from a baseline of 12.1±1.8 g/dL, mean platelet count increased by 58%±41 from a baseline of 75±14x109/L, and mean spleen volume decreased by 44.6%±10 from a baseline of 13.9±6.0 multiples of normal (MN). For the 20 patients who switched from placebo to eliglustat, mean hemoglobin increased by 0.79±0.82 g/dL from a baseline of 12.2±2.0 g/dL, mean platelet count increased by 40%±37 from a baseline of 71.5±25.2 x109/L and mean spleen volume decreased by 31.1%±10 from a baseline of 12.5±6.0 MN, after 9 months of eliglustat. In the ENCORE study, eliglustat was found to be non-inferior to imiglucerase in maintaining stability with respect to hemoglobin concentration, platelet count, spleen volume and liver volume after 12 months (Cox et al. Lancet 2015;385:2355). Stable hemoglobin was defined as not decreasing by more than 1.5 g/dL from baseline and stable platelet count as not decreasing by more than 25% from baseline. For patients who received eliglustat for 24 months in the ENCORE extension, hemoglobin levels remained stable in 97% of patients (mean change: -0.10±0.77 g/dL) and platelet count remained stable in 94% of patients (mean change: 2.27±17.6x109/L). In former imiglucerase patients who received eliglustat for 12 months in the ENCORE extension, hemoglobin levels remained stable in 100% of patients at 12 months and platelet counts remained stable in 90%. In all 3 trials, eliglustat was generally well tolerated with 90% of patients overall electing to continue on eliglustat. Most AEs were non-serious, considered unrelated to eliglustat, and either mild or moderate in severity.
Conclusions: Long-term use of eliglustat in adults with GD1 is associated with continued improvements over time in hematologic parameters in previously untreated patients and hematologic stability in patients previously stabilized on ERT.

Disclosures
Weinreb: Genzyme, a Sanofi company: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Shire: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Cox:Genzyme, a Sanofi company: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Shire: Consultancy, Honoraria, Other: Grant support, Speakers Bureau; Actelion: Consultancy, Honoraria, Speakers Bureau. Lukina:Shire: Honoraria, Other: Travel Reimbursement; Genzyme, a Sanofi company: Honoraria, Other: Travel Reimbursement. Mistry:Genzyme, a Sanofi company: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Shire: Consultancy, Honoraria, Other: Grant Support, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Synageva: Honoraria, Speakers Bureau; NIH NIMS: Other: Grant Support. Angell:Genzyme, a Sanofi company: Employment. Gaemers:Genzyme, a Sanofi company: Employment. Peterschmitt:Genzyme, a Sanofi company: Employment.