Randomized, controlled trial of miglustat in Gaucher's disease type 3 (original) (raw)
Related papers
2010
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 ran-domized 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.
Guidance on the use of miglustat for treating patients with type 1 Gaucher disease
American Journal of Hematology, 2005
Type 1 Gaucher disease (GD) is a progressive lysosomal storage disorder due to an autosomal recessive deficiency of glucocerebrosidase. Clinical manifestations include anemia, thrombocytopenia, hepatosplenomegaly, and bone and pulmonary disease. Intravenous enzyme replacement (ERT) with imiglucerase is the accepted standard for treatment of symptomatic patients. More than 3,500 patients worldwide have received ERT with well-documented beneficial effects on the hematological, visceral, skeletal, and pulmonary manifestations, and with resultant improvement in health-related quality of life. Miglustat, an imino sugar that reversibly inhibits glucosylceramide synthase and reduces intracellular substrate burden, is an oral treatment for patients with type 1 GD that was recently approved in the United States for symptomatic patients with mild to moderate clinical manifestations for whom ERT is not an option. Because responses to miglustat are slower and less robust than those observed with ERT, and because miglustat is associated with significant side effects, clinicians who care for patients with GD should become familiar with the limited indications for miglustat use and the circumstances when it may be prescribed appropriately. This review article and position statement represents the current opinion of American physicians with extensive expertise in GD regarding patient management in the context of the availability of standard imiglucerase treatment and the recent introduction of miglustat. Am.
Blood Cells, Molecules, and Diseases, 2016
We report data from a prospective, observational study (ZAGAL) evaluating miglustat 100 mg three times daily orally. in treatment-naïve patients and patients with type 1 Gaucher Disease (GD1) switched from previous enzyme replacement therapy (ERT). Clinical evolution, changes in organ size, blood counts, disease biomarkers, bone marrow infiltration (S-MRI), bone mineral density by broadband ultrasound densitometry (BMD), safety and tolerability annual reports were analysed. Between May 2004 and April 2016, 63 patients received miglustat therapy; 20 (32%) untreated and 43 (68%) switched. At the time of this report 39 patients (14 [36%] treatment-naïve; 25 [64%] switch) remain on miglustat. With over 12-year follow-up, hematologic counts, liver and spleen volumes remained stable. In total, 80% of patients achieved current GD1 therapeutic goals. Plasma chitotriosidase activity and CCL-18/PARC concentration showed a trend towards a slight increase. Reductions on S-MRI (p = 0.042) with an increase in BMD (p b 0.01) were registered. Gastrointestinal disturbances were reported in 25/63 (40%), causing miglustat suspension in 11/63 (17.5%) cases. Thirty-eight patients (60%) experienced a fine hand tremor and two a reversible peripheral neuropathy. Overall, miglustat was effective as a long
Haematologica, 2006
In a prospective, open-label study, 25 patients with mild-to-moderate type 1 Gaucher's disease (GD1) were treated with miglustat (Zavesca), an oral glucosylceramide synthase inhibitor, over 12 months. Of the 25 patients, 10 were therapy-naïve and 15 had previously received enzyme replacement therapy (ERT). Clinical status, blood parameters, biomarkers, and organomegaly were assessed at baseline at 6 months and at 12 months. At 6 months the previously untreated patients showed a mean increase in hemoglobin of 0.77 g/dL, platelet counts improved or remaining stable, chitotriosidase and CCL18 decreased. These results were similar to those observed in 40 Spanish GD1 patients on ERT. Bone marrow infiltration cleared at 12 months. In the previously treated group, clinical and hematologic parameters and biomarkers were maintained/ improved at 12 months. Miglustat was well tolerated. The efficacy of miglustat treatment after 6 months was comparable to that of ERT.
Goal-oriented therapy with miglustat in Gaucher disease
Current Medical Research and Opinion, 2009
Background: Gaucher disease (GD) is a highly heterogeneous disorder with multisystem involvement. Specific therapeutic goals for each manifestation of type 1 GD (GD1) were established in 2004 by an international panel of experts, to facilitate better management of GD1 patients. The goals were defined based on experience with enzyme replacement therapy (ERT) using imiglucerase. Miglustat, a small iminosugar, is the only commercially available substrate reduction therapy (SRT) for patients with GD1. Several clinical studies have demonstrated the beneficial effects of miglustat on cardinal disease manifestations of GD1. Objective: To review the currently available data on miglustat, and provide guidance on the attainment of the GD therapeutic goals with miglustat therapy. Methods: A literature search identified publications on miglustat using MEDLINE, HighWire Press, and Google Scholar databases. Articles were identified using the terms 'miglustat' and 'Gaucher disease type 1'. Findings: Improvements in hematological manifestations and organomegaly can be expected with miglustat therapy, with disease stabilization achievable over the long term. Recent data suggest that miglustat can maintain stability in patients with mild to moderate GD1 who have been previously treated with ERT. Miglustat may be beneficial with regards to bone manifestations, with reduction in the incidence of patients reporting bone pain and improvements in bone mineral density seen within the first 24 months of therapy. Conclusions: Several of the therapeutic goals for patients with GD1 can be achieved with miglustat therapy. In select cases, miglustat can be considered an alternative to ERT for the treatment of patients with GD1. Long-term experience with the use of miglustat will help define its overall safety and efficacy; this information will be useful in determining the role of SRT using miglustat in the management of the general adult GD1 patient population.
Upsala Journal of Medical Sciences, 2012
Introduction. Gaucher disease (GD) is an infrequent progressive multisystem lysosomal storage disorder caused by the deficient activity of the lysosomal enzyme, glucocerebrosidase. A retrospective, single-center analysis of the clinical experience concerning the use of miglustat (N-butyldeoxynojirimycin), an oral inhibitor of glucosylceramide synthase, in type 1 Gaucher disease (GD1) was conducted to evaluate the efficacy, adverse events (AE), and outcome of miglustat therapy. Patients and methods. Six adult Caucasian patients with GD1 (two women and four men), aged 21-81 years (median age 59 years), were treated with miglustat between October 2005 and April 2011. All but one patient (83%) carried at least one allele with c.1226A>G (N370S) mutation in the GBA1 gene. Results. Weight loss, diarrhea, poor appetite, and tremor were frequently reported AE by the patients. All of them experienced at least 2 AE, and three patients (50%) experienced at least 4 AE. Only two out of six patients (33%) have used miglustat longer than 12 months, of which only one used it longer than 15 months. Conclusions. The major obstacle to successful miglustat therapy in GD1 was the high proportion of patients discontinuing their treatment due to the AE and the worsened quality of life. Further efforts are needed to improve tolerability of miglustat and, in consequence, compliance of patients treated with this orphan drug.