Afegostat (
INN
Inns are generally establishments or buildings where travelers can seek lodging, and usually, food and drink. Inns are typically located in the country or along a highway; before the advent of motorized transportation they also provided accommo ...
; also known as isofagomine; planned trade name Plicera) was an experimental drug for the treatment of certain forms of
Gaucher's disease
Gaucher's disease or Gaucher disease () (GD) is a genetic disorder in which glucocerebroside (a sphingolipid, also known as glucosylceramide) accumulates in cells and certain organs. The disorder is characterized by bruising, fatigue, anemia, low ...
that was being developed by
Amicus Therapeutics
Amicus Therapeutics is a public American biopharmaceutical company based in Philadelphia, PA. The company went public in 2007 under the NASDAQ trading symbol FOLD. This followed a 2006 planned offering and subsequent withdrawal, which would have ...
and
Shire plc until a failed clinical trial in 2009 led to termination of its development. The substance was used in form of the
tartrate
A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The formula of the tartrate dianion is O−OC-CH(OH)-CH(OH)-COO− or C4H4O62−.
The main forms of tartrates used commercially are pure crystalline ta ...
.
Mechanism of action
β-Glucocerebrosidase
β-Glucocerebrosidase (also called acid β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, or GCase) is an enzyme with glucosylceramidase activity () that is needed to cleave, by hydrolysis, the beta-glycosidic linkage of the chemical g ...
, an enzyme needed for the metabolisation of
glucocerebroside
Glucocerebroside (also called glucosylceramide) is any of the cerebrosides in which the monosaccharide head group is glucose.
Clinical significance
In Gaucher disease, the enzyme glucocerebrosidase is nonfunctional and cannot break down gluc ...
, is misfolded in individuals with Gaucher's disease due to various mutations, one of which is called N370S. Afegostat, an
iminosugar
An iminosugar, also known as an iminosaccharide, is any analog of a sugar where a nitrogen atom has replaced the oxygen atom in the ring of the structure.
Iminosugars are common components of plants and may be responsible for some of their medici ...
, binds selectively to N370S glucocerebrosidase and restores its correct
conformation and, consequently, enhances its activity about threefold.
Invention and development
Afegostat was invented by
Mikael Bols and Troels Skrydstrup and was first prepared by Jespersen and Bols.
Amicus Therapeutics licensed patents related to afegostat from Mt. Sinai School of Medicine, University of Maryland, and
Novo Nordisk
Novo Nordisk A/S is a Danish multinational pharmaceutical company headquartered in Bagsværd, Denmark, with production facilities in nine countries, and affiliates or offices in five countries. Novo Nordisk is controlled by majority shareholder ...
A/S. They also signed a collaboration agreement with
Shire plc related to this drug and others.
It was granted
orphan drug
An orphan drug is a pharmaceutical agent developed to treat medical conditions which, because they are so rare, would not be profitable to produce without government assistance. The conditions are referred to as orphan diseases.
The assignment o ...
status by the
European Medicines Agency (EMA)
and by the
US FDA
The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food s ...
.
[
When afegostat failed a Phase II clinical trial in 2009, Shire terminated the collaboration agreement and Amicus determined it would no longer develop the afegostat.][ The first patents in Amicus' patent portfolio on afegostat expired in 2015.][
]
See also
*Imiglucerase
Imiglucerase is a medication used in the treatment of Gaucher's disease.
It is a recombinant DNA-produced analogue of the human enzyme β-glucocerebrosidase.
Cerezyme is a freeze-dried medicine containing imiglucerase, manufactured by Genzyme Co ...
, a recombinant human β-glucocerebrosidase for enzyme replacement therapy of Gaucher's disease
*Miglustat
Miglustat, sold under the brand name Zavesca, is a medication used to treat type I Gaucher disease (GD1). It is also known as N-butyldeoxynojirimycin, and is a derivative of the anti-diabetic 1-deoxynojirimycin. It was developed by Oxford GlycoS ...
, another orphan drug for the treatment of Gaucher's disease with a different mechanism of action
*Eliglustat
Eliglustat, sold under the brand name Cerdelga, is a medication used for the treatment of Gaucher's disease. It was discovered at the University of Michigan, developed by Genzyme Corp, and was approved by the FDA in August 2014. Commonly used as ...
References
{{Reflist, 2
Orphan drugs
Piperidines