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, brain, and skin. Fabry disease is one of a group of conditions known as lysosomal storage dis ...

, a rare genetic disorder. It was developed by

Amicus Therapeutics Amicus Therapeutics, Inc. 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 wou ...

. 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 respo ...

(FDA) granted it

orphan drug An orphan drug is a medication, pharmaceutical agent that is developed to treat certain rare medical conditions. An orphan drug would not be profitable to produce without government assistance, due to the small population of patients affected by th ...

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 the Committee for Proprietary Medicinal Products (CPMP), is the European Medicines Agency's committee responsible for elaborating the agency's opinions on all issues regar ...

(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 prototype drug 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 medic ...

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

'' 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 subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

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 is a state of tiredness (which is not sleepiness), exhaustion or loss of energy. It is a signs and symptoms, symptom of any of various diseases; it is not a disease in itself. Fatigue (in the medical sense) is sometimes associated wit ...

, and

nausea Nausea is a diffuse sensation of unease and discomfort, sometimes perceived as an urge to vomit. It can be a debilitating symptom if prolonged and has been described as placing discomfort on the chest, abdomen, or back of the throat. Over 30 d ...

, 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 nutr ...

agalsidase 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 (P450s or CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that mostly, but not exclusively, function as monooxygenases. However, they are not omnipresent; for examp ...

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 chromosome 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, which are a set of aliphatic amino alcohols that includes sphingosine. They were discovered in brain extracts in the 1870s and were named after the mythological sp ...

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 c ...

s and

glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) 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 a ...

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 a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...

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: 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 neurotransmi ...

of α-GalA ( IC₅₀: 4

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

). 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 chaperone (protein), protein chaperone. That is, it contains small molecules that enter cells and serve as a molecular scaffolding in order to cause otherwise-protein folding, ...

s. When the enzyme reaches its destination, the

lysosome A lysosome () is a membrane-bound organelle that is found in all mammalian cells, with the exception of red blood cells (erythrocytes). There are normally hundreds of lysosomes in the cytosol, where they function as the cell’s degradation cent ...

, 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 (aquatic environment), the earthy material that exi ...

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 Galactose (, ''wikt:galacto-, galacto-'' + ''wikt:-ose#Suffix 2, -ose'', ), sometimes abbreviated Gal, is a monosaccharide sugar that is about as sweetness, sweet as glucose, and about 65% as sweet as sucrose. It is an aldohexose and a C-4 epime ...

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 Plasma proteins, sometimes referred to as blood proteins, are proteins present in blood plasma. They perform many different functions, including transport of hormones, vitamins and minerals in activity and functioning of the immune system. Other b ...

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

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 (elimination half-life, pharmacological 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 blood plasma. ...

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 alternati ...

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

asymmetric carbon In stereochemistry, an asymmetric carbon is a carbon atom that is bonded to four different types of atoms or groups of atoms. The four atoms and/or groups attached to the carbon atom can be arranged in space in two different ways that are mirror ...

atoms with the same

stereochemistry Stereochemistry, a subdiscipline of chemistry, studies the spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which are defined ...

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 medic ...

. The structure is formally derived from nojirimycin.

History

Migalastat was isolated as a

fermentation Fermentation is a type of anaerobic metabolism which harnesses the redox potential of the reactants to make adenosine triphosphate (ATP) and organic end products. Organic molecules, such as glucose or other sugars, are catabolized and reduce ...

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 Zellkulturen]/ref> ''Streptomyces lydicus'' produces actithiazic ...

'' ( strain (biology), 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 in 2008, back to Amicus in 2010, to

Glaxo GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British multinational pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham, wh ...

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 ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...

, 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 medical sign, signs, as well as measurements using urine tests, blood tests, and medical imaging. Renal physiology, Functions of a healthy kidney include ...

over the 30-months period of these trials. In September 2015, Amicus announced that it would submit a

new drug application The Food and Drug Administration's (FDA) New Drug Application (NDA) is the vehicle in the United States through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing. Some 30% or less of initial ...

(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 end ...

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 previously 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 conservativ ...

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

{{Portal bar , Medicine Hydrolase inhibitors Iminosugars Orphan drugs