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.

• Authors: Elena Lukina, Nora Watman, Elsa Avila Arreguin, Maryam Banikazemi, Marta Dragosky, Marcelo Iastrebner, Hanna Rosenbaum, Mici Phillips, Gregory M Pastores, Daniel I Rosenthal, Mathilde Kaper, Tejdip Singh, Ana Cristina Puga, Peter L Bonate, M Judith Peterschmitt
• Journal: Blood (Blood) Vol. 116 Issue 6 Pg. 893-9 (Aug 12 2010) ISSN: 1528-0020 [Electronic] United States
• PMID: 20439622 (Publication Type: Clinical Trial, Phase II, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Pyrrolidines
• eliglustat
• Glucosyltransferases
• ceramide glucosyltransferase

Topics

• Administration, Oral
• Adult
• Bone Density (drug effects)
• Enzyme Inhibitors (administration & dosage, adverse effects, pharmacokinetics)
• Female
• Gaucher Disease (drug therapy, metabolism)
• Glucosyltransferases (antagonists & inhibitors, metabolism)
• Humans
• Lumbar Vertebrae (drug effects)
• Male
• Middle Aged
• Pyrrolidines (administration & dosage, adverse effects, pharmacokinetics)
• Substrate Specificity (drug effects)
• Treatment Outcome
• Young Adult