A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1

Abstract

Eliglustat tartrate (Genz-112638), a specific inhibitor of glucosylceramide synthase, is under development as an oral substrate reduction therapy for Gaucher disease type 1 (GD1). A multinational, open-label, single-arm phase 2 study of 26 GD1 patients (16 female, 10 male; mean age, 34 years) evaluated the efficacy, safety, and pharmacokinetics of eliglustat tartrate administered twice daily by mouth at 50- or 100-mg doses based on plasma drug concentrations. Entry criteria required splenomegaly with thrombocytopenia and/or anemia. The composite primary efficacy end point required improvement after 52 weeks in at least 2 of these 3 disease manifestations and was met by 77% (95% confidence interval [CI] = 58%-89%) of all patients and 91% (95% CI = 72%-98%) of the 22 patients completing 52 weeks. Statistically significant improvements occurred in mean hemoglobin level (1.62 g/dL; 95% CI =1.05-2.18 g/dL), platelet count (40.3%; 95% CI = 23.7-57.0 g/dL), spleen volume (-38.5%; 95% CI = -43.5%--33.5%), liver volume (-17.0%; 95% CI = -21.6%-12.3%), and lumbar spine bone mineral density (0.31 Z-score; 95% CI = 0.09-0.53). Elevated biomarkers (chitotriosidase; chemokine CCL18; angiotensin-converting enzyme; tartrate-resistant acid phosphatase) decreased by 35% to 50%. Plasma glucosylceramide and ganglioside GM3 normalized. Eliglustat tartrate was well tolerated: 7 mild, transient adverse events in 6 patients were considered treatment-related. Individual pharmacokinetics varied; mean time to maximal observed concentration was 2.3 hours and mean half-life was 6.8 hours. Eliglustat tartrate appears to be a promising oral treatment for GD1.

Trial registration: ClinicalTrials.gov NCT00358150.

Figure 1

Summary of results for the composite primary efficacy end point. The ITT population includes all 26 patients; the completer population includes the 22 patients who completed 52 weeks of treatment. The percentages shown are derived from the corresponding proportions given under each column. The denominator for the 3 component end points equals the number of patients with baseline values that met the study entry criteria for abnormal for that clinical parameter, and the numerator equals the number of these patients who met the criteria for improvement during treatment. For the composite end point, the denominator equals the number of patients in the corresponding analysis population, and the numerator equals the number of these patients who met at least 2 of the 3 component end points.

Figure 2

Effect of eliglustat tartrate on hematologic parameters and organ volumes over time. Data are reported as the mean and 95% CI. P < .05; #P < .01; *P < .001 (comparison of mean change or mean percentage change from baseline).

Figure 3

Effect of eliglustat tartrate on plasma biomarker levels over time. Data are reported as the medians (for the non-normally distributed data) and 95% CI. *P < .001 for comparison of median change or median percentage change from baseline. The normal reference range is less than 2 to 6 μg/mL for plasma GL-1 and 5.0 to 9.2 μg/mL for plasma GM3.