Long-Term Hematologic Response to Oral Eliglustat in Treatment-Naive Patients with Gaucher Disease Type 1: Final Results from a Phase 2 and the Phase 3 Engage Trials

Introduction:

Gaucher disease is caused by deficient activity of the lysosomal enzyme acid β-glucosidase, leading to accumulation of glucosylceramide primarily in macrophages (Gaucher cells). Thrombocytopenia, anemia, hepatosplenomegaly, and skeletal disease are common presenting symptoms and hematologists often identify and manage the disease. Eliglustat is an oral substrate reduction therapy approved as first-line treatment for adults with Gaucher disease type 1 (GD1) who have poor, intermediate, or extensive CYP2D6-metabolizer phenotypes (>90% of patients). Unlike enzyme replacement therapy (the historic standard of care), which supplements lysosomal acid β-glucosidase in mononuclear phagocytes and is administered in biweekly infusions, oral eliglustat reduces glucosylceramide accumulation by partially inhibiting glucosylceramide synthase.

Methods:

We report on improvements in hemoglobin concentration and platelet count in two completed clinical trials of eliglustat in treatment-naïve adults with GD1: an open-label Phase 2 trial (N=26, NCT00358150), for which 8-year data are available, and a randomized, placebo-controlled Phase 3 trial (ENGAGE, N=40, NCT00891202) for which 4.5-year data are available. Both trials were sponsored by Sanofi Genzyme.

Results:

In the Phase 2 trial, 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). Improvements continued or were maintained throughout the trial. Among patients with 8 years of data (n=19), mean (±SD) hemoglobin level and mean platelet count increased by 2.1±1.7 g/dL (from 11.3±1.6 to 13.4±1.3 g/dL) and 110% (from 67.5±21.1 to 130.7±59.8 x10⁹/L), respectively, after 8 years of eliglustat. In the Phase 3 ENGAGE trial, all primary and secondary endpoints were met, with clinically meaningful improvements from baseline in platelet and hemoglobin levels and spleen and liver volumes at 9 months in eliglustat- but not placebo-treated patients (Mistry et al. JAMA 2015;313;695). During the trial extension, in which all patients received eliglustat, patients switching from placebo had the same magnitude and time course of improvement during the first 9 months as was seen with eliglustat patients in the primary analysis and all patients continued to improve over time with continued eliglustat treatment. Among patients with 4.5 years of eliglustat treatment (n=14), mean (±SD) hemoglobin level increased by 1.4±1.31 g/dL (from 12.0±2.0 g/dL to 13.4±1.9 g/dL) and mean platelet count increased by 87% (from 69.6±18.5 to 122.6±34.1 x10⁹/L). In both trials, hematologic improvements were accompanied by clinically significant decreases in spleen and liver volumes, improvements in bone parameters, and substantive reductions in Gaucher disease biomarkers. In both trials, eliglustat was generally well-tolerated, with three withdrawals due to adverse events in the Phase 2 trial (one of which was considered related to eliglustat) and no withdrawals due to adverse events during the ENGAGE trial. Most adverse events in both trials were non-serious, considered unrelated to eliglustat, and either mild or moderate in severity.

Conclusions:

In previously untreated patients with GD1, clinically meaningful improvements in hematologic parameters continued or were maintained over time after 8 years of treatment with eliglustat in the Phase 2 trial and after 4.5 years of eliglustat in the Phase 3 ENGAGE trial.