Migalastat, sold under the brand name Galafold, is a medication for the treatment of

Fabry disease Fabry disease, also known as Anderson–Fabry disease, is a rare genetic disease that can affect many parts of the body, including the kidneys, heart, and skin. Fabry disease is one of a group of conditions known as lysosomal storage diseases. T ...

, a rare genetic disorder. It was 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 ...

. The US Food and Drug Administration (FDA) granted it

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 of ...

status in 2004, and the European Commission followed in 2006. The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) granted the drug a marketing approval under the name Galafold in May 2016. The U.S. Food and Drug Administration (FDA) considers it to be a first-in-class medication.

Medical uses

Migalastat is used for the long-term treatment of Fabry disease in adults and adolescents aged 16 or older with an amenable mutation of the enzyme alpha-galactosidase A (α-GalA). An "amenable" mutation is one that leads to misfolding of the enzyme, but otherwise would not significantly impair its function. Based on an '' in vitro'' test, Amicus Therapeutics has published a list of 269 amenable and nearly 600 non-amenable mutations. About 35 to 50% of people with Fabry have an amenable mutation.

Adverse effects

The most common side effect in clinical trials was headache (in about 10% of people who take it). Less common side effects (between 1 and 10% of people) included unspecific symptoms such as dizziness,

fatigue Fatigue describes a state of tiredness that does not resolve with rest or sleep. In general usage, fatigue is synonymous with extreme tiredness or exhaustion that normally follows prolonged physical or mental activity. When it does not resolve ...

, and nausea, but also depression. Possible rare side effects could not be assessed because of the low number of subjects in the clinical trials in which adverse effects were measured.

Interactions

When combined with

intravenous Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutrie ...

agalsidase α-Galactosidase ( EC 3.2.1.22, α-GAL, α-GAL A; systematic name α-D-galactoside galactohydrolase) is a glycoside hydrolase enzyme that catalyses the following reaction: : Hydrolysis of terminal, non-reducing α-D-galactose residues in α-D- ...

alfa or beta, which are recombinant versions of the enzyme α-GalA, migalastat increases tissue concentrations of functional α-GalA compared to agalsidase given alone up to fivefold.Migalastat is not intended to be combined with agalsidase. Migalastat does not inhibit or induce

cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...

liver enzymes or transporter proteins and is therefore expected to have a low potential for interactions with other drugs.

Pharmacology

Mechanism of action

Fabry disease is a genetic disorder caused by various mutations of the enzyme α-GalA, which is responsible for breaking down the sphingolipid globotriaosylceramide (Gb3), among other

glycolipid Glycolipids are lipids with a carbohydrate attached by a glycosidic (covalent) bond. Their role is to maintain the stability of the cell membrane and to facilitate cellular recognition, which is crucial to the immune response and in the connec ...

s and

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

s. Some of these mutations result in misfolding of α-GalA, which subsequently fails protein quality control in the

endoplasmic reticulum The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough endoplasmic reticulum ( ...

and is decomposed. Lack of functional α-GalA leads to accumulation of Gb3 in blood vessels and other tissues, with a wide range of symptoms including kidney, heart, and skin problems. Migalastat is a potent, orally available

inhibitor Inhibitor or inhibition may refer to: In biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotra ...

of α-GalA ( IC₅₀: 4

μM The micrometre ( international spelling as used by the International Bureau of Weights and Measures; SI symbol: μm) or micrometer (American spelling), also commonly known as a micron, is a unit of length in the International System of Unit ...

). When binding to faulty α-GalA, it shifts the folding behaviour towards the proper conformation, resulting in a functional enzyme provided the mutation is amenable. Molecules with this type of mechanism are called

pharmacological chaperone A pharmacological chaperone or pharmacoperone is a drug that acts as a protein chaperone. That is, it contains small molecules that enter cells and serve as a molecular scaffolding in order to cause otherwise- misfolded mutant proteins to fold an ...

s. When the enzyme reaches its destination, the lysosome, migalastat dissociates because of the low pH and the relative abundance of Gb3 and other

substrate Substrate may refer to: Physical layers *Substrate (biology), the natural environment in which an organism lives, or the surface or medium on which an organism grows or is attached ** Substrate (locomotion), the surface over which an organism lo ...

s, leaving α-GalA free to fulfill its function. Depending on the mutation, the EC₅₀ is between 0.8 μM and over 1 mM in cellular models. File:PBB Protein GLA image.jpg, The enzyme alpha-galactosidase A (α-GalA) File:Globotriaosylceramide.svg, Globotriaosylceramide (Gb3), a

of α-GalA, has a terminal D- galactose structurally similar to migalastat. File:1-Deoxygalactonojirimycin 2.svg, Migalastat ("top" view)

Pharmacokinetics

Migalastat is almost completely absorbed from the gut; taking the drug together with food decreases its absorption by about 40%. Total bioavailability is about 75% when taken without food. The substance is not bound to blood

plasma proteins Blood-proteins, also termed plasma proteins, are proteins present in blood plasma. They serve many different functions, including transport of lipids, hormones, vitamins and minerals in activity and functioning of the immune system. Other blood pr ...

. Only a small fraction of a migalastat dose is metabolized, mainly to three

dehydrogenated In chemistry, dehydrogenation is a chemical reaction that involves the removal of hydrogen, usually from an organic molecule. It is the reverse of hydrogenation. Dehydrogenation is important, both as a useful reaction and a serious problem. At ...

''O''- glucuronides (4% of the dose) and a number of unspecified metabolites (10%). The drug is mainly eliminated via the urine (77%) and to a smaller extent via the faeces (20%). Practically all of the metabolites are excreted in the urine. Elimination half-life is three to five hours after a single dose.

Chemistry

Migalastat is used in form of the hydrochloride, which is a white crystalline solid and is soluble in water. The molecule has four asymmetric carbon atoms with the same

stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...

as the sugar D- galactose, but is missing the first hydroxyl group. It has a nitrogen atom in the ring instead of an oxygen, which makes it an iminosugar. The structure is formally derived from

nojirimycin Nojirimycin is the parent compound of a class of antibiotics and glycosidase enzyme inhibitor, inhibitors. Nojirimycin and its derivatives are mainly obtained from a class of ''Streptomyces'' species. Chemically, it is an iminosugar. Derivatives * ...

History

Migalastat was isolated as a

fermentation Fermentation is a metabolic process that produces chemical changes in organic substrates through the action of enzymes. In biochemistry, it is narrowly defined as the extraction of energy from carbohydrates in the absence of oxygen. In food ...

product of the bacterium ''

Streptomyces lydicus ''Streptomyces lydicus'' is a bacterium species from the genus of ''Streptomyces'' which has been isolated from soil in the United States.Deutsche Sammlung von Mikroorganismen und Zellkulturenbr>/ref> ''Streptomyces lydicus'' produces actithiaz ...

'' ( strain PA-5726) in 1988 and called ''1-deoxygalactonojirimycin''. In 2004, it was designated orphan drug status by the US FDA for the treatment of Fabry disease, and in 2006 the European CHMP did likewise. The sponsorship for the drug was transferred several times over the following years: from Amicus Therapeutics to

Shire Pharmaceuticals Shire plc was a UK-founded Jersey-registered specialty biopharmaceutical company. Originating in the United Kingdom with an operational base in the United States, its brands and products included Vyvanse, Lialda, and Adderall XR. Shire was ac ...

in 2008, back to Amicus in 2010, to Glaxo in 2011, and again to Amicus in 2014. Two phase III clinical trials with a total of about 110 subjects were conducted between 2009 and 2015, one double-blind comparing the drug to placebo, and one comparing it to recombinant α-GalA without blinding. Migalastat stabilised heart and kidney function over the 30-months period of these trials. In September 2015, Amicus announced that it would submit a new drug application (NDA) for

accelerated approval The United States Food and Drug Administration (FDA) initiated the FDA Accelerated Approval Program in 1992 to allow faster approval of drugs for serious conditions that fill an unmet medical need. The faster approval relies on use of surrogate endp ...

of migalastat to the FDA by the end of 2015. The CHMP recommended approval in April 2016, but the FDA rejected the application in November for having insufficient data in November 2016. The drug was approved in the European Union in May 2016. Germany was the first country where migalastat was launched. After

Scott Gottlieb Scott Gottlieb (born June 11, 1972) is an American physician and investor who served as the 23rd commissioner of the Food and Drug Administration (FDA) from May 2017 until April 2019. He is presently a senior fellow at the conservative think tan ...

became FDA commissioner in 2017, the CEO of Amicus began lobbying him directly for the FDA to accept the NDA and in February 2018 the FDA accepted it and promised a response by August 2018.

References

External links

* {{Portal bar , Medicine Hydrolase inhibitors Iminosugars Orphan drugs