Medication Summary

Several therapies have been approved by the US Food and Drug Administration (FDA) for the treatment of type 1 Gaucher disease. Enzyme replacement therapy (ERT) with glucocerebrosidase purified from human placenta was FDA approved in 1991, followed by approval in 1994 of a recombinant form of the enzyme produced in cultured Chinese hamster ovary (CHO) cells, marketed as imiglucerase (Cerezyme). Worldwide, over 4,000 patients with Gaucher disease have received ERT, which is safe and well tolerated.

In 2010, an alternate form of ERT was approved. This form of recombinant enzyme is produced in cultured human cells and is marketed as velaglucerase alfa (VPRIV).^{[16, 17]}In May 2012, taliglucerase alfa (Elelyso) was the first plant cell–based ERT approved by the FDA; it uses engineered carrot cells.^[18]

The glucosylceramide synthase inhibitors, miglustat and eliglustat, were approved for adults with type 1 Gaucher disease in 2003 and 2014 respectively.

Approximately 10-15% of patients with Gaucher disease treated with imiglucerase develop antibodies to the enzyme protein, but few develop any significant allergic reactions, which are controlled with premedication with hydrocortisone, antihistamines, or both. All antibodies have immunoglobulin G (IgG), mostly of the IgG1 subclass. A few patients with Gaucher disease have developed antibodies that impair enzyme activity.

Class Summary

In most cases, ERT is highly effective in reversing the visceral and hematologic manifestations of type 1 Gaucher disease. Recombinant beta-glucocerebrosidase (imiglucerase [Cerezyme]) has replaced the original tissue-derived product, alglucerase (Ceredase). Alglucerase is an orphan drug and still manufactured by Genzyme Corporation on an extremely limited basis for a few patients unable to tolerate the newer recombinant product. Presymptomatic use is controversial because of the high cost and the extremely variable clinical course.

Imiglucerase is approved for children aged 2 years or older. Velaglucerase and taliglucerase are both approved for children aged 4 years or older.

Imiglucerase (Cerezyme)

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A recombinant-derived analog of beta-glucocerebrosidase produced in mammalian cell culture and chemically modified by mannose termination of glycosylated amino acids. Catalyzes hydrolytic cleavage of glucocerebroside (a glycoprotein) to glucose and ceramide within the lysosomes of phagocytic cells in the reticuloendothelial system. Treatment with recombinant enzyme improves anemia and thrombocytopenia, reduces spleen and liver size, and decreases cachexia

Velaglucerase alfa (VPRIV)

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Hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy for type 1 Gaucher disease. Improves symptoms associated with the disease, including anemia, thrombocytopenia, increased spleen and liver size, and cachexia.

Taliglucerase alfa (Elelyso)

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Taliglucerase is a plant-based recombinant enzyme. It catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, which results in reduced spleen and liver enlargement and increased RBCs and platelets.

Class Summary

These agents inhibit the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. The goal of treatment is to reduce the rate of glucocerebroside biosynthesis so that the amount is reduced to a level that allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy).

Miglustat (Zavesca)

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Indicated for type 1 Gaucher disease in patients in whom ERT is not a therapeutic option. Reduces GSL production by inhibiting glucosylceramide synthase. Reduces spleen and liver volume and increases hemoglobin and platelet counts.

Eliglustat (Cerdelga)

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Eliglustat is a specific inhibitor of glucosylceramide synthase, thereby reducing production of glucosylceramide. It is indicated for the long-term treatment of adults with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EM), intermediate metabolizers (IM), or poor metabolizers (PM) as detected by an FDA-cleared test for phenotype. Dosage is based on establishing the patient's CYP2D6 metabolizer status.

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Autosomal recessive inheritance pattern.

of 1

Author

Ellen Sidransky, MD Senior Investigator, Chief, Section on Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, NIH

Ellen Sidransky, MD is a member of the following medical societies: American Society of Human Genetics, International Parkinson and Movement Disorder Society, Society for Pediatric Research, Society for Inherited Metabolic Disorders

Disclosure: Nothing to disclose.

Coauthor(s)

Emory Ryan, MSN, CPNP-PC Research Nurse Practitioner, Clinical Coordinator, Medical Genetics Branch, National Human Genome Research Institute

Emory Ryan, MSN, CPNP-PC is a member of the following medical societies: American Academy of Pediatrics, National Association of Pediatric Nurse Practitioners

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Chief Editor

Maria Descartes, MD Professor, Department of Human Genetics and Department of Pediatrics, University of Alabama at Birmingham School of Medicine

Maria Descartes, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics and Genomics, American Medical Association, American Society of Human Genetics, Society for Inherited Metabolic Disorders, International Skeletal Dysplasia Society, Southeastern Regional Genetics Group

Disclosure: Nothing to disclose.

Additional Contributors

Robert D Steiner, MD, FAAP, FACMG Professor (Clinical), Department of Pediatrics, University of Wisconsin School of Medicine and Public Health; Editor-in-Chief, Genetics in Medicine; Chief Medical Officer, PreventionGenetics

Robert D Steiner, MD, FAAP, FACMG is a member of the following medical societies: American Academy of Pediatrics, American Association for the Advancement of Science, American College of Medical Genetics and Genomics, American Society of Human Genetics, Society for Inherited Metabolic Disorders, Society for Pediatric Research, Society for the Study of Inborn Errors of Metabolism

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: PreventionGenetics-part of Exact Sciences; Acer Therapeutics; DNARx; Best Doctors; PTC Therapeutics; CTX Alliance; Leadiant' Travere<br/>Received income in an amount equal to or greater than $250 from: Marshfield Clinic; PreventionGenetics-part of Exact Sciences; Acer Therapeutics; PTC Therapeutics; DNARx; Leadiant; Travere.

Acknowledgements

The author acknosledges the assistance of Mary E. LaMarca, who co-authored the initial version of this chapter prior to her death in 2010.

Sections Gaucher Disease
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Gaucher Disease Medication

Medication Summary

Enzyme replacement therapy