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 ha ...

. The US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...

(FDA) granted it orphan drug status in 2004, and the European Commission followed in 2006. The European Medicines Agency's

Committee for Medicinal Products for Human Use The Committee for Medicinal Products for Human Use (CHMP), formerly known as Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regardin ...

(CHMP) granted the drug a marketing approval under the name Galafold in May 2016. The U.S.

(FDA) considers it to be a

first-in-class medication A first-in-class medication is a pharmaceutical that uses a "new and unique mechanism of action" to treat a particular medical condition. While the Food and Drug Administration's Center for Drug Evaluation and Research tracks first-in-class medicat ...

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 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 ...

A (α-GalA). An "amenable" mutation is one that leads to

misfolding Protein folding is the physical process by which a protein chain is Translation (biology), translated to its native protein tertiary structure, three-dimensional structure, typically a "folded" Protein structure, conformation by which the prote ...

of the enzyme, but otherwise would not significantly impair its function. Based on an ''

in vitro ''In vitro'' (meaning in glass, or ''in the glass'') studies are performed with microorganisms, cells, or biological molecules outside their normal biological context. Colloquially called "test-tube experiments", these studies in biology an ...

'' 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 trial Clinical trials are prospective biomedical or behavioral research studies on human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel vaccines, drugs, dietar ...

s 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 Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. While not painful, it can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the ...

, 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 protein A transport protein (variously referred to as a transmembrane pump, transporter, escort protein, acid transport protein, cation transport protein, or anion transport protein) is a protein that serves the function of moving other materials within ...

s and is therefore expected to have a low potential for interactions with other drugs.

Pharmacology

Mechanism of action

Fabry disease is a

genetic disorder A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...

caused by various mutations of the enzyme α-GalA, which is responsible for breaking down the

sphingolipid Sphingolipids are a class of lipids containing a backbone of sphingoid bases, a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sphinx because ...

globotriaosylceramide Globotriaosylceramide is a globoside. It is also known as CD77, Gb3, GL3, and ceramide trihexoside. It is one of the few clusters of differentiation that is not a protein. It is formed by the alpha linkage of galactose to lactosylceramide catalyze ...

(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 of α-GalA ( IC₅₀: 4 μM). 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 A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prot ...

, migalastat dissociates because of the low pH and the relative abundance of Gb3 and other substrates, 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

A (α-GalA) File:Globotriaosylceramide.svg,

Globotriaosylceramide Globotriaosylceramide is a globoside. It is also known as CD77, Gb3, GL3, and ceramide trihexoside. It is one of the few clusters of differentiation that is not a protein. It is formed by the alpha linkage of galactose to lactosylceramide catalyze ...

(Gb3), a substrate of α-GalA, has a terminal D-

galactose Galactose (, '' galacto-'' + '' -ose'', "milk sugar"), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epimer of glucose. A galactose molec ...

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 In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. H ...

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 p ...

. 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''-

glucuronide A glucuronide, also known as glucuronoside, is any substance produced by linking glucuronic acid to another substance via a glycosidic bond. The glucuronides belong to the glycosides. Glucuronidation, the conversion of chemical compounds to glucur ...

s (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 Biological half-life (also known as elimination half-life, pharmacologic half-life) is the time taken for concentration of a biological substance (such as a medication) to decrease from its maximum concentration ( Cmax) to half of Cmax in the bl ...

is three to five hours after a single dose.

Chemistry

Migalastat is used in form of the

hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative na ...

, which is a white crystalline solid and is soluble in water. The molecule has four

asymmetric carbon An asymmetric carbon atom (chiral carbon) is a carbon atom that is attached to four different types of atoms or groups of atoms. Le Bel-van't Hoff rule states that the number of stereoisomers of an organic compound is 2n, where n represents the num ...

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-

, but is missing the first

hydroxyl In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...

group. It has a nitrogen atom in the ring instead of an oxygen, which makes it 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 medicin ...

. 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'' (

strain Strain may refer to: Science and technology * Strain (biology), variants of plants, viruses or bacteria; or an inbred animal used for experimental purposes * Strain (chemistry), a chemical stress of a molecule * Strain (injury), an injury to a mu ...

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 in 2008, back to Amicus in 2010, to

Glaxo GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the tent ...

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 In a blind or blinded experiment, information which may influence the participants of the experiment is withheld until after the experiment is complete. Good blinding can reduce or eliminate experimental biases that arise from a participants' expec ...

comparing the drug to

placebo A placebo ( ) is a substance or treatment which is designed to have no therapeutic value. Common placebos include inert tablets (like sugar pills), inert injections (like Saline (medicine), saline), sham surgery, and other procedures. In general ...

, and one comparing it to recombinant α-GalA without blinding. Migalastat stabilised heart and

kidney function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...

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