Miglustat
Encyclopedia
Miglustat is a drug developed by Actelion and is used primarily to treat Type 1 Gaucher disease (GD1). It is marketed under the trade name Zavesca. Miglustat (OGT 918, N-butyl-deoxynojirimycin) is an imino sugar (molecular weight: 219 daltons), a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste. The primary pharmacological activity of miglustat is inhibition of the enzyme glucosylceramide synthase, catalyzing the first step in the biosynthesis of glycosphingolipids (GSL), i.e., the formation of glucosylceramide (GlcCer). Reduced formation of GlcCer will lead to decreased biosynthesis of more complex GSL. This therapeutic principle, called substrate reduction therapy (SRT), may be useful in disorders of intracellular (predominantly lysosomal) accumulation of GSL either due to their deficient breakdown or intracellular transport/trafficking. Miglustat exhibits a large volume of distribution and has the capacity to access deep organs such as the brain, bone and lung.
Miglustat inhibits glucosylceramide synthase, an essential enzyme
for the synthesis of most glycosphingolipids. Miglustat is a glucosylceramide synthase inhibitor. It works by inhibitting glucosylceramide synthase (the enzyme that forms glucosylceramide, which accumulates within the macrophages). Miglustat is used to treat adults with mild to moderate type 1 Gaucher disease and it is the first treatment to be approved for patients with Niemann-Pick type C disease. Miglustat may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable and it's been approved in the European Union for the treatment of progressive neurological manifestations in adult or pediatric patients with Niemann-Pick type C disease (NPC). It has also been approved for NPC treatment in Canada, Switzerland, Brazil, Australia, Turkey and Israel but not in the United States.
Type 1 Gaucher disease is an autosomal recessive disorder one gets from both parents. People with type 1 Gaucher have a defect in the enzyme called glucocerebrosidase
(also known as acid β-glucosidase) that acts on a fatty substance glucosylceramide (also known as glucocerebroside
). Accumulation of glucosylceramide causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. Treatment with miglustat is known as substrate reduction therapy
(SRT). Unlike enzyme replacement therapy (ERT), which has a direct effect on the breakdown of glycosphingolipids, the concept of SRT in Gaucher disease involves reduction of the delivery of potential storage material to the macrophage system. Patients treated with miglustat for 3 years show signicant improvements in organ volumes and haematological parameters. Miglustat was effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.
It is also being investigated to treat Tay-sachs disease
In October 2007, Actelion initiated a Phase IIa proof-of-concept clinical trial with miglustat in cystic fibrosis
(CF). It is the first time that miglustat is being tested in a clinical setting involving 25 CF patients affected by the specific delF508 mutation.
Miglustat inhibits glucosylceramide synthase, an essential enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
for the synthesis of most glycosphingolipids. Miglustat is a glucosylceramide synthase inhibitor. It works by inhibitting glucosylceramide synthase (the enzyme that forms glucosylceramide, which accumulates within the macrophages). Miglustat is used to treat adults with mild to moderate type 1 Gaucher disease and it is the first treatment to be approved for patients with Niemann-Pick type C disease. Miglustat may only be used in the treatment of type 1 Gaucher patients for whom enzyme replacement therapy is unsuitable and it's been approved in the European Union for the treatment of progressive neurological manifestations in adult or pediatric patients with Niemann-Pick type C disease (NPC). It has also been approved for NPC treatment in Canada, Switzerland, Brazil, Australia, Turkey and Israel but not in the United States.
Type 1 Gaucher disease is an autosomal recessive disorder one gets from both parents. People with type 1 Gaucher have a defect in the enzyme called glucocerebrosidase
Glucocerebrosidase
β-Glucocerebrosidase is an enzyme with glucosylceramidase activity that is needed to cleave, by hydrolysis, the beta-glucosidic linkage of the chemical glucocerebroside, an intermediate in glycolipid metabolism...
(also known as acid β-glucosidase) that acts on a fatty substance glucosylceramide (also known as glucocerebroside
Glucocerebroside
Glucocerebroside is any of the cerebrosides in which the monosaccharide head group is glucose.-Clinical significance:...
). Accumulation of glucosylceramide causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. Treatment with miglustat is known as substrate reduction therapy
Substrate reduction therapy
Substrate reduction therapy offers an approach to treatment of certain metabolic disorders, especially glycogen storage diseases and lysosomal storage disorders. In a storage disorder, a critical failure in a metabolic pathway prevents cellular breakdown and disposal of some large molecule...
(SRT). Unlike enzyme replacement therapy (ERT), which has a direct effect on the breakdown of glycosphingolipids, the concept of SRT in Gaucher disease involves reduction of the delivery of potential storage material to the macrophage system. Patients treated with miglustat for 3 years show signicant improvements in organ volumes and haematological parameters. Miglustat was effective over time and showed acceptable tolerability in patients who continued with treatment for 3 years.
It is also being investigated to treat Tay-sachs disease
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...
In October 2007, Actelion initiated a Phase IIa proof-of-concept clinical trial with miglustat in cystic fibrosis
Cystic fibrosis
Cystic fibrosis is a recessive genetic disease affecting most critically the lungs, and also the pancreas, liver, and intestine...
(CF). It is the first time that miglustat is being tested in a clinical setting involving 25 CF patients affected by the specific delF508 mutation.
See also
- Isofagomine tartrateIsofagomine tartrateIsofagomine tartrate is an experimental drug for the treatment of certain forms of Gaucher's disease, developed by Amicus Therapeutics and Shire plc....
, another orphan drug for the treatment of Gaucher's disease with a similar chemical structure, but a different mechanism of action