title: Oral maintenance clinical trial with miglustat for type I Gaucher disease: switch from or combination with intravenous enzyme replacement.
abstract: Enzyme replacement therapy (ERT) with imiglucerase reduces hepatosplenomegaly and improves hematologic parameters in Gaucher disease type 1 within 6-24 months. Miglustat reduces organomegaly, improves hematologic parameters, and reverses bone marrow infiltration. This trial evaluates miglustat in patients clinically stable on ERT. Tolerability of miglustat and imiglucerase, alone and in combination, pharmacokinetic profile, organ reduction, and chitotriosidase activity were assessed. Thirty-six patients stable on imiglucerase were randomized into this phase II, open-label trial. Statistically significant changes from baseline were assessed (paired t test) on primary objectives with secondary analyses on biochemical and safety parameters. Liver and spleen volume were unchanged in switched patients. No significant differences were seen between groups regarding mean change in hemoglobin. Mean change in platelet counts was only significant between miglustat and imiglucerase groups (P = .035). Chitotriosidase activity remained stable. In trial extension, clinical endpoints were generally maintained. Miglustat was well tolerated alone or in combination. Miglustat's safety profile was consistent with previous trials; moreover, no new cases of peripheral neuropathy were observed. Gaucher disease type 1 (GD1) parameters were stable in most switched patients. Combination therapy did not show benefit. Findings suggest miglustat could be an effective maintenance therapy in stabilized patients with GD1.
authors.affiliation: Gaucher Clinic, Shaare Zedek Medical Center, Jerusalem, Israel. elstein@szmc.org.il
authors.forename: Deborah
authors.initials: D
authors.lastname: Elstein
authors.forename: Altoon
authors.initials: A
authors.lastname: Dweck
authors.forename: Drorit
authors.initials: D
authors.lastname: Attias
authors.forename: Irith
authors.initials: I
authors.lastname: Hadas-Halpern
authors.forename: Shoshana
authors.initials: S
authors.lastname: Zevin
authors.forename: Gheona
authors.initials: G
authors.lastname: Altarescu
authors.forename: Johannes F M G
authors.initials: JF
authors.lastname: Aerts
authors.forename: Sonja
authors.initials: S
authors.lastname: van Weely
authors.forename: Ari
authors.initials: A
authors.lastname: Zimran
mesh_terms: D017485:1-Deoxynojirimycin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D005776:Gaucher Disease / Q000145:classification / Q000188:drug therapy* / Q000473:pathology; D005962:Glucosylceramidase / Q000008:administration & dosage* / Q000627:therapeutic use*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D013997:Time Factors
chemical_list: D017485:1-Deoxynojirimycin; C059896:miglustat; D005962:Glucosylceramidase; C090568:imiglucerase