Profile of eliglustat tartrate in the management of Gaucher disease

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Profile of eliglustat tartrate in the management of Gaucher disease

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Author(s): Annalisa Sechi , Andrea Dardis , Bruno Bembi

Publication date (Electronic): 11 January 2016

Journal: Therapeutics and Clinical Risk Management

Publisher: Dove Medical Press

Keywords: Gaucher disease, enzyme replacement therapy, substrate reduction therapy, eliglustat tartrate

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Abstract

Gaucher disease (GD) is a lysosomal storage disorder caused by the deficient activity of acid beta glucosidase, with consequent accumulation of glucosylceramide in the spleen, liver, bone marrow, and various organs and tissues. Currently, the gold standard for GD treatment is enzyme replacement therapy (ERT). The efficacy of ERT in improving or stabilizing the visceral and hematological symptoms of GD is well-proven. However, since ERT has to be administered by frequent intravenous infusions, this therapeutic approach has an important impact on the patient’s quality of life. Eliglustat tartrate is a new substrate reduction therapy for GD, which acts as a specific and potent inhibitor of glucosylceramide synthase and can be administered orally. This review summarizes the results of the preclinical and clinical trials, which experimented with eliglustat, and discusses its possible role in the management of GD, when compared to the currently available treatments and the new experimental approaches.

Most cited references 32

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Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

N Barton, R O Brady, J Dambrosia … (1991)

Gaucher's disease, the most prevalent of the sphingolipid storage disorders, is caused by a deficiency of the enzyme glucocerebrosidase (glucosylceramidase). Enzyme replacement was proposed as a therapeutic strategy for this disorder in 1966. To assess the clinical effectiveness of this approach, we infused macrophage-targeted human placental glucocerebrosidase (60 IU per kilogram of body weight every 2 weeks for 9 to 12 months) into 12 patients with type 1 Gaucher's disease who had intact spleens. The frequency of infusions was increased to once a week in two patients (children) during part of the trial because they had clinically aggressive disease. The hemoglobin concentration increased in all 12 patients, and the platelet count in 7. Serum acid phosphatase activity decreased in 10 patients during the trial, and the plasma glucocerebroside level in 9. Splenic volume decreased in all patients after six months of treatment, and hepatic volume in five. Early signs of skeletal improvements were seen in three patients. The enzyme infusions were well tolerated, and no antibody to the exogenous enzyme developed. Intravenous administration of macrophage-targeted glucocerebrosidase produces objective clinical improvement in patients with type 1 Gaucher's disease. The hematologic and visceral responses to enzyme replacement develop more rapidly than the skeletal response.

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Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease.

C. E. Hollak, S van Weely, M van Oers … (1994)

Gaucher disease (GD; glucosylceramidosis) is caused by a deficient activity of the enzyme glucocerebrosidase (GC). Clinical manifestations are highly variable and cannot be predicted accurately on the basis of the properties of mutant GC. Analysis of secondary abnormalities, such as elevated plasma levels of some hydrolases, may help to increase insight into the complicated pathophysiology of the disease and could also provide useful disease markers. The recent availability of enzyme supplementation therapy for GD increases the need for markers as early predictors of the efficacy of treatment. We report the finding of a very marked increase in chitotrisidase activity in plasma of 30 of 32 symptomatic type 1 GD patients studied: the median activity being > 600 times the median value in plasma of healthy volunteers. In three GC-deficient individuals without clinical symptoms, only slight increases were noted. Chitotriosidase activity was absent in plasma of three control subjects and two patients. During enzyme supplementation therapy, chitotriosidase activity declined dramatically. We conclude that plasma chitotriosidase levels can serve as a new diagnostic hallmark of GD and should prove to be useful in assessing whether clinical manifestations of GD are present and for monitoring the efficacy of therapeutic intervention.

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Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.

Timothy Cox, Robin Lachmann, Carla EM Hollak … (2000)

Current treatment for Gaucher's disease involves administration of intravenous glucocerebrosidase to degrade glucocerebroside stored in lysosomes. Lowering the rate of biosynthesis of glucocerebroside should decrease accumulation of this substrate. We investigated the safety and efficacy of OGT 918 (N-butyldeoxynojirimycin), an inhibitor of glucosyltransferase, as a novel oral treatment for non-neuronopathic Gaucher's disease. We recruited, into a 1-year open-label study, 28 adults (seven with previous splenectomies) from four national Gaucher's referral clinics, who were unable or unwilling to receive enzyme treatment. We measured liver and spleen volume by computed tomography or magnetic resonance imaging at baseline and at months 6 and 12, and biochemical and haematological variables monthly, including chitotriosidase activity (a sensitive marker of Gaucher's disease activity). Patients were started on 100 mg oral OGT 918 three times daily. Baseline liver volumes were 1.1-2.7 times normal and spleen volumes 5.1-24.8 times normal. At 12 months, mean liver and spleen volumes were significantly lowered by 12% (95% CI 7.8-16.4) and 19% (14.3-23.7), respectively (each p<0.001). Haematological variables improved slightly. Mean organ volume and blood counts improved continually between 6 months and 12 months of treatment. Mean chitotriosidase concentrations fell by 16.4% over 12 months (p<.0001). Six patients withdrew because of gastrointestinal complaints (two), personal reasons (two), or severe pre-existing disease (two). The most frequent adverse effect was diarrhoea, which occurred in 79% of patients shortly after the start of treatment. Decrease of substrate formation by OGT 918 improves key clinical features of non-neuronopathic Gaucher's disease. The strategy justifies further trials in this and other glycosphingolipid storage disorders.

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Author and article information

Journal

Journal ID (nlm-ta): Ther Clin Risk Manag

Journal ID (iso-abbrev): Ther Clin Risk Manag

Journal ID (publisher-id): Therapeutics and Clinical Risk Management

Title: Therapeutics and Clinical Risk Management

Publisher: Dove Medical Press

ISSN (Print): 1176-6336

ISSN (Electronic): 1178-203X

Publication date Collection: 2016

Publication date (Electronic): 11 January 2016

Volume: 12

Pages: 53-58

Affiliations

Regional Coordinator Center for Rare Diseases, Academic Hospital of Udine, Udine, Italy

Author notes

Correspondence: Annalisa Sechi, Regional Coordinator Center for Rare Diseases, Academic Hospital of Udine, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy, Email sechi.annalisa@ 123456aoud.sanita.fvg.it

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Publisher ID: tcrm-12-053

DOI: 10.2147/TCRM.S73226

PMC ID: 4714736

PubMed ID: 26811686

SO-VID: d5cf3bc2-ad6e-48b4-9399-b5bf23d023a3

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Profile of eliglustat tartrate in the management of Gaucher disease

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Abstract

Most cited references 32

Replacement therapy for inherited enzyme deficiency--macrophage-targeted glucocerebrosidase for Gaucher's disease.

Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease.

Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis.

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