Miglustat


Miglustat is a drug developed by Oxford GlycoSciences and marketed by Actelion under the trade name Zavesca. It is used primarily to treat type I Gaucher disease.

Medical uses

Miglustat is used to treat adults with mild to moderate type I Gaucher disease for whom enzyme replacement therapy is unsuitable. It was approved in Europe in 2002 and by the US FDA in 2003.
Miglustat is the first treatment to be approved for treating progressive neurological complications in people with Niemann–Pick disease, type C ; it has been approved in Europe in 2009, Canada in 2010, and Japan in 2012, but not in the US where the FDA declined to approve it in 2010 and called for more data.

Contraindications

Miglustat is contraindicated for people with neurological conditions, kidney problems, women who are pregnant, and men and women planning to conceive a child.

Adverse effects

Serious side effects include pain, burning, numbness or tingling in the hands, arms, legs, or feet; shaking hands that cannot be controlled; changes in vision; and easy bruising or bleeding. Common side effects include gastrointestinal effects, dry mouth, muscular effects, back pain, dizziness, nervousness, headache, memory problems, and difficult or irregular menstruation.

Mechanism of action

Type I Gaucher's disease is an autosomal recessive disorder; parents are generally healthy carriers with one functional and one mutated copy of the Gaucher disease gene, GBA. People with type I Gaucher have a defect in the enzyme called glucocerebrosidase. Glucocerebrosidase is an enzyme, and its function is to convert glucocerebroside into ceramide and glucose. When this enzyme doesn't work, glucocerebroside accumulates, which in turn causes liver and spleen enlargement, changes in the bone marrow and blood, and bone disease. It functions as a competitive and reversible inhibitor of the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions which results in the synthesis of most glycosphingolipids.
Other treatments on the market, velaglucerase, taliglucerase alfa ) are enzyme replacement therapy - they are functioning versions of the enzyme that doesn't work. Miglustat works differently - it prevents the formation of the substance that builds up when the enzyme doesn't work; this is called substrate reduction therapy.

Chemistry

Miglustat is an iminosugar, a synthetic analogue of D-glucose and a white to off-white crystalline solid that has a bitter taste.

Research

In July 2004 Actelion started a clinical trial of miglustat to treat Tay–Sachs disease, particularly late-onset Tay–Sachs with an estimated enrollment of 10 subjects; the trial ended August 2007.
In November 2007, Actelion initiated a clinical trial with miglustat in people with cystic fibrosis who have the ΔF508 in both copies of the cystic fibrosis transmembrane conductance regulator gene; the study ended in March 2008. The cystic fibrosis trial showed no effect.