Diroximel fumarate, sold under the brand name Vumerity, is a

medication A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...

used for the treatment of relapsing forms of

multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

(MS). It acts as an

immunosuppressant Immunosuppressive drugs, also known as immunosuppressive agents, immunosuppressants and antirejection medications, are drugs that inhibit or prevent activity of the immune system. Classification Immunosuppressive drugs can be classified in ...

and anti-inflammatory drug. Its most common adverse effects are flushing and gastrointestinal problems. Diroximel fumarate was approved for medical use in the United States in October 2019, and in the European Union in November 2021.

Medical uses

Diroximel fumarate is used for the treatment of

relapsing-remitting multiple sclerosis Multiple (cerebral) sclerosis (MS), also known as encephalomyelitis disseminata or disseminated sclerosis, is the most common demyelinating disease, in which the insulating covers of nerve cells in the brain and spinal cord are damaged. This d ...

. In the US, it is additionally approved for other relapsing forms of MS such as clinically isolated syndrome and active secondary progressive disease.

Available forms

The drug is available as a white delayed-release capsule that is resistant to gastric acid and only dissolves in the intestine.

Contraindications

Under the European Union's label, the drug is contraindicated in people with

progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is a rare and often fatal viral disease characterized by progressive damage (''-pathy'') or inflammation of the white matter (''leuko-'') of the brain (''-encephalo-'') at multiple locations (''mu ...

(PML), a disease of the brain caused by a virus. In the US, combination with the closely related drug

dimethyl fumarate Dimethyl fumarate (DMF) is the methyl ester of fumaric acid and is named after the earth smoke plant (''Fumaria officinalis''). Dimethyl fumarate combined with three other fumaric acid esters (FAEs) is solely licensed in Germany as an oral thera ...

is contraindicated.Diroximel Fumarate on Drugs.com. Accessed 28 April 2022.

Side effects

No systematic studies of adverse effects under diroximel fumarate are available. The most common side effects in studies with ''dimethyl'' fumarate were flushing (in 34% of patients treated with the drug, versus 5% in the

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 ...

group) and gastrointestinal effects such as

diarrhoea Diarrhea, also spelled diarrhoea, is the condition of having at least three loose, liquid, or watery bowel movements each day. It often lasts for a few days and can result in dehydration due to fluid loss. Signs of dehydration often begin wi ...

(14% versus 10%),

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 ...

(12% versus 9%), abdominal pain (9% versus 4%), vomiting (8% versus 5%), and

indigestion Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier t ...

(5% versus 3%). Three percent of patients stopped the treatment because of flushing, 4% because of gastrointestinal side effects. A rare but potentially fatal adverse effect may be PML, which has been observed under treatment with dimethyl fumarate.

Overdose

No specific antidote is known. Adverse effects caused by overdosing diroximel fumarate are treated symptomatically.

Interactions

Diroximel fumarate does not interact with

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 ...

enzymes or

P-glycoprotein P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...

. Its

active metabolite An active metabolite is an active form of a drug after it has been processed by the body. Metabolites of drugs An active metabolite results when a drug is metabolized by the body into a modified form which continues to produce effects in the body ...

monomethyl fumarate Monomethyl fumarate, sold under the brand name Bafiertam is a medication for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, ...

, has a relatively low

plasma protein 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 ...

binding of 27 to 45%. Therefore, its potential for

pharmacokinetic Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

interactions is considered to be low. Inactivated vaccines can be given under diroximel fumarate therapy, based on experience with other immunosuppressant drugs, such as studies with

tetanus Tetanus, also known as lockjaw, is a bacterial infection caused by ''Clostridium tetani'', and is characterized by muscle spasms. In the most common type, the spasms begin in the jaw and then progress to the rest of the body. Each spasm usually ...

, pneumococcal and meningococcal vaccines. No studies regarding the effectiveness of these vaccines under diroximel fumarate have been conducted. No data are available regarding combination with

live vaccine An attenuated vaccine (or a live attenuated vaccine, LAV) is a vaccine created by reducing the virulence of a pathogen, but still keeping it viable (or "live"). Attenuation takes an infectious agent and alters it so that it becomes harmless or less ...

chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...

or immunosuppressants. Nephrotoxicity could be increased when the drug is combined with

aminoglycoside antibiotic Aminoglycoside is a medicinal and bacteriologic category of traditional Gram-negative antibacterial medications that inhibit protein synthesis and contain as a portion of the molecule an amino-modified glycoside (sugar). The term can also refer ...

diuretic A diuretic () is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics in ...

s, NSAIDs or

lithium Lithium (from el, λίθος, lithos, lit=stone) is a chemical element with the symbol Li and atomic number 3. It is a soft, silvery-white alkali metal. Under standard conditions, it is the least dense metal and the least dense solid el ...

Pharmacology

Mechanism of action

The drug's mechanism of action is not well understood. In preclinical studies it activated nuclear factor erythroid 2-related factor 2 (NRF2), a

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

that is up-regulated under oxidative stress.

Pharmacokinetics

The

pharmacokinetics Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...

of diroximel fumarate has been found to be practically identical to that of dimethyl fumarate. Both are

prodrug A prodrug is a medication or compound that, after intake, is metabolized (i.e., converted within the body) into a pharmacologically active drug. Instead of administering a drug directly, a corresponding prodrug can be used to improve how the drug ...

s of monomethyl fumarate. Taking the drug with a high-calorie, high-fat meal slows down absorption, but has no relevant effect on overall absorption. The US label recommends not taking the drug together with high-calorie and high-fat meals. After ingestion, the substance is cleaved by esterase enzymes before reaching the systemic circulation, resulting in monomethyl fumarate (MMF), the active metabolite, and hydroxyethyl succinimide (HES), which is inactive. Diroximel fumarate itself is not present in the bloodstream. MMF reaches highest concentrations in the

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intra ...

2.5 to 3 hours after ingestion. When in the bloodstream, 27 to 45% are bound to plasma proteins. MMF is further

metabolize Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

d to

fumarate Fumaric acid is an organic compound with the formula HO2CCH=CHCO2H. A white solid, fumaric acid occurs widely in nature. It has a fruit-like taste and has been used as a food additive. Its E number is E297. The salts and esters are known as f ...

, citrate and

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

, ultimately entering the

citric acid cycle The citric acid cycle (CAC)—also known as the Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of chemical reactions to release stored energy through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins ...

and being broken down to

carbon dioxide Carbon dioxide (chemical formula ) is a chemical compound made up of molecules that each have one carbon atom covalently double bonded to two oxygen atoms. It is found in the gas state at room temperature. In the air, carbon dioxide is transpar ...

(CO₂). About 60% of the substance leave the body as CO₂ via the lungs, 15.5% are eliminated with the urine (according to another source, less than 0.3%), and 0.9% are eliminated with the faeces. The

terminal 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 one hour. HES is eliminated mainly with the urine (58 to 63%).

Chemistry

The substance is a white to off-white powder. It is slightly soluble in water; that is, its

solubility In chemistry, solubility is the ability of a substance, the solute, to form a solution with another substance, the solvent. Insolubility is the opposite property, the inability of the solute to form such a solution. The extent of the solubil ...

is between 1:100 and 1:1000. The molecule is

achiral Chirality is a property of asymmetry important in several branches of science. The word ''chirality'' is derived from the Greek (''kheir''), "hand", a familiar chiral object. An object or a system is ''chiral'' if it is distinguishable from i ...

. The double bond of the

moiety has E configuration.

History

This drug was formulated by Alkermes in collaboration with Biogen.. Accessed 28 April 2022.

Society and culture

Legal status

Diroximel fumarate was approved for medical use in the United States in October 2019. On 16 September 2021, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vumerity, intended for the treatment of adults with relapsing remitting multiple sclerosis. The applicant for this medicinal product is Biogen Netherlands B.V. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged. It was approved for medical use in the European Union in November 2021.

References

External links

* {{DEFAULTSORT:Diroximel Fumarate Multiple sclerosis Imides Esters Methyl esters Fumarate esters