Eliglustat, an Investigational Oral Therapy for Gaucher Disease Type 1: Phase 2 Results After 4 Years of Treatment

In Gaucher disease type 1 (GD1), genetically caused deficiency of the enzyme acid β-glucosidase results in undegraded glucosylceramide to accumulate in tissue macrophages (Gaucher cells), resulting in multisystemic manifestations that include thrombocytopenia, anemia, hepatosplenomegaly, and bone disease. A variable clinical course and progression among patients have led to the development of therapeutic goals for the different disease manifestations (Pastores et al., Semin Hematol. 2004;41[suppl 5]:4–14). Eliglustat, a potent and specific inhibitor of glucosylceramide synthase, is under late-stage development as an oral substrate reduction therapy for GD1.

To report long-term efficacy and safety results.

This ongoing, open-label, uncontrolled, multicenter Phase 2 clinical trial enrolled 26 adult patients with GD1 who were not on treatment for the previous 12 months and who had splenomegaly with thrombocytopenia and/or anemia. Patients received 50 mg or 100 mg eliglustat twice daily depending on the plasma trough level. Efficacy outcomes were assessed periodically and included changes from baseline in hemoglobin, platelets, spleen and liver volumes, skeletal manifestations, disease-related biomarker levels, and achievement of therapeutic goals.

Nineteen patients completed 4 years of eliglustat treatment; no patient discontinued in the last 2 years. After 4 years of treatment, mean hemoglobin level and platelet count increased by 2.3±1.5 g/dL (from 11.3±1.5 g/dL to 13.6±1.2 g/dL) and 95% (from 68,700±21,200/mm³ to 125,400±51,100/mm³), respectively. Mean spleen and liver volumes (multiples of normal, MN) decreased by 63% (from 17.3±9.5 to 6.1±3.4 MN) and 28% (from 1.7±0.4 MN to 1.2±0.3 MN), respectively. All patients met at least 3 of 4 long-term therapeutic goals (spleen, 100% of patients; liver, 94%; hemoglobin, 100%; platelets, 50%). Baseline platelet count was not found to be a predictive factor of response to treatment. However, a strong linear, statistically significant correlation was found between the mean plasma trough level of eliglustat and the platelet response in patients after 4 years of treatment with eliglustat (r=0.731, P=0.0004). Median chitotriosidase and CCL-18 each decreased by 82%; plasma GL-1 and GM3 normalized. Mean lumbar spine bone mineral density increased by 0.7 Z-score (from −1.2±0.9 to −0.5±1.1) and by 0.8 T-score (from −1.6±1.1 to −0.88±1.3). The greatest increases in lumbar spine T-scores occurred in patients with osteoporosis at baseline. Femur dark marrow, which is believed to reflect Gaucher cell infiltration into bone marrow, was reduced or stable in 17/18 patients. There were no bone crises. Eliglustat was well-tolerated. Most adverse events (AEs) were mild and unrelated to treatment. Ten drug-related AEs, all mild, occurred in 8 patients. No new serious AEs were reported in any patient between 3 and 4 years of treatment.

Eliglustat continues to show promising efficacy and safety, with clinically meaningful improvements across several disease parameters. Results from two controlled Phase 3 studies in untreated and enzyme replacement therapy maintenance patients will be available in 2013.

Peterschmitt:Genzyme: Employment. Lukina:Genzyme: Honoraria, Research Funding. Watman:Genzyme: Membership on an entity's Board of Directors or advisory committees. Pastores:Amicus: Research Funding; Actelion: Research Funding; Biomarin: Research Funding; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Shire HGT: Research Funding; Protalix: Research Funding. Arreguin:Genzyme: Research Funding. Rosenbaum:Pfizer: Study Investigator Other. Zimran:Protalix Biotherapeutics: Consultancy; Protalix Biotherapeutics: stock options, stock options Other; Protalix Biotherapeutics: Scientific Advisory Board, Scientific Advisory Board Other; Genzyme: Research Funding; Shire HGT: Honoraria; Actelion: Honoraria; Pfizer: Honoraria. Aguzzi:Genzyme: Employment. Ross:Genzyme: Employment. Puga:Genzyme: Employment.