title: 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.affiliation: Hematology Research Center, Russian Academy of Medical Sciences, Moscow, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Lukina
authors.forename: Nora
authors.initials: N
authors.lastname: Watman
authors.forename: Elsa Avila
authors.initials: EA
authors.lastname: Arreguin
authors.forename: Maryam
authors.initials: M
authors.lastname: Banikazemi
authors.forename: Marta
authors.initials: M
authors.lastname: Dragosky
authors.forename: Marcelo
authors.initials: M
authors.lastname: Iastrebner
authors.forename: Hanna
authors.initials: H
authors.lastname: Rosenbaum
authors.forename: Mici
authors.initials: M
authors.lastname: Phillips
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Pastores
authors.forename: Daniel I
authors.initials: DI
authors.lastname: Rosenthal
authors.forename: Mathilde
authors.initials: M
authors.lastname: Kaper
authors.forename: Tejdip
authors.initials: T
authors.lastname: Singh
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Puga
authors.forename: Peter L
authors.initials: PL
authors.lastname: Bonate
authors.forename: M Judith
authors.initials: MJ
authors.lastname: Peterschmitt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D015519:Bone Density / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D005776:Gaucher Disease / Q000188:drug therapy* / Q000378:metabolism; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008159:Lumbar Vertebrae / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D013379:Substrate Specificity / Q000187:drug effects; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D004791:Enzyme Inhibitors; D011759:Pyrrolidines; C522917:eliglustat; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase