Diroximel fumarate

Identification

Summary

Diroximel fumarate is a drug used for the treatment of relapsing forms of Multiple Sclerosis (MS).

Brand Names
Vumerity
Generic Name
Diroximel fumarate
DrugBank Accession Number
DB14783
Background

Multiple Sclerosis (MS) is a chronic, debilitating neurological disease that can lead to profound cognitive and physical symptoms, severely affecting quality of life.3 It is the main cause of neurological disability not caused by trauma in the young adult population of both North America and Europe. Relapsing-remitting forms of MS lead to neurological symptoms that resolve and recur periodically. More than 80% of patients suffering from this disease have relapsing-remitting MS.4

Diroximel fumarate is a new drug from the fumarate class formulated to treat various relapsing forms of MS. This drug is bioequivalent to Dimethyl fumarate6,8(initially manufactured in 2013), but is less likely to cause gastrointestinal side effects, owing to its unique chemical structure. Diroximel fumarate was formulated by Alkermes in collaboration with Biogen, and approved by the FDA on October 30, 2019.8

Type
Small Molecule
Groups
Approved, Investigational
Structure
Thumb
Weight
Average: 255.226
Monoisotopic: 255.074287143
Chemical Formula
C11H13NO6
Synonyms
  • Diroximel fumarate
External IDs
  • ALKS 8700
  • RDC-5108

Pharmacology

Indication

Diroximel fumarate is indicated for the treatment of relapsing forms of multiple sclerosis (MS) in adults; specifically active secondary progressive disease and clinically isolated syndrome, as well as relapsing-remitting MS.7,9,10

Pharmacology
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Associated Conditions
Contraindications & Blackbox Warnings
Contraindications
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Pharmacodynamics

Diroximel fumarate relieves the neurological symptoms of relapsing MS with less gastrointestinal effects than its bioequivalent counterpart, dimethyl fumarate.2,7 It is important to note that diroximel fumarate can cause angioedema, anaphylaxis, hepatotoxicity, flushing, lymphopenia, and Progressive Multifocal Leukoencephalopathy (PML).7

Discontinue diroximel fumarate immediately if PML is suspected or if anaphylaxis or angioedema occur. Liver function and total bilirubin should be tested prior to initiating diroximel fumarate and during treatment. A complete blood count (CBC) should be obtained prior to starting diroximel fumarate, after the first 6 months of administration, and at subsequent intervals of 6 to 12 months following this period. Suspend treatment if lymphocyte counts are measured to be less than 0.5 × 109/L for more than 6 months.7

Mechanism of action

Currently, the mechanism of action of this drug in MS is not fully understood.7 Diroximel fumarate is hypothesized to regulate cell signaling pathways, causing beneficial immune and neuroprotective effects.2 Monomethyl fumarate (MMF) is the active metabolite of diroximel fumarate, and activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway in humans. This pathway occurs as a response to oxidative stress in cells.7

In addition to the above, MMF is a nicotinic acid receptor agonist in the laboratory setting. The relevance of this finding to the treatment of MS is unknown at this time.7 The mechanism by which this drug leads to less gastrointestinal effects is purported to be due to its lack of a methanol leaving group in its chemical structure, and substitution with inert 2-hydroxyethyl succinimide.2

TargetActionsOrganism
UNeuronal acetylcholine receptor subunit alpha-10
agonist
Humans
Absorption

Diroximel fumarate is rapidly absorbed in the gastrointestinal tract following administration, like its bioequivalent drug, dimethyl fumarate.6 The median Tmax of monomethyl fumarate (MMF) after oral administration ranges from 2.5-3 hours with a mean Cmax of 2.11 mg/L7. The bioequivalent drug, dimethyl fumarate, administered to healthy volunteers also shows a similar mean Tmax and Cmax.6

The average steady state concentration of this metabolite is estimated at 8.32 mg.hr/L after it is administered twice a day in patients with MS.7 The mean AUC0–∞ of the active metabolite is 88mg × min L−1. Food appears to significantly reduce the Cmax of diroximel fumarate's active metabolite, MMF, when compared to administration in the fasted state.6,7

Volume of distribution

The apparent volume of distribution ranges from 72L to 83L.7 Monomethyl fumarate (MMF), the active metabolite of diroximel fumarate, crosses the blood brain barrier.1

Protein binding

Plasma protein binding of MMF, the active metabolite of diroximel fumarate, ranges from 27-45%.7

Metabolism

Esterases heavily metabolize diroximel fumarate, as well as its bioequivalent drug, dimethyl fumarate, in the liver.6 These enzymes are present in high quantities in the gastrointestinal tract, tissues, and blood. Esterase metabolism of this drug produces the active metabolite, mono methyl fumarate (MMF), before it moves to the systemic circulation. In addition, the major inactive metabolite, 2-hydroxyethyl succinimide (HES) is produced along with small amounts of methanol, and another inactive metabolite, RDC-8439.2,7 Following esterase metabolism, the tricarboxylic acid (TCA)cycle further metabolizes MMF. The major metabolites of MMF in plasma include fumaric acid, citric acid, and glucose.6,7 It is important that methanol is a major metabolite of dimethyl fumarate metabolism, but a minor metabolite of diroximel fumarate metabolism, conferring its lower risk of gastrointestinal effects.2

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Route of elimination

Monomethyl fumarate is eliminated as carbon dioxide through expired breath. Negligible amounts, under 0.3% of the ingested dose, are measured in urine.7 The inactive metabolite, 2-hydroxyethyl succinimide (HES), representing 58-63% of the ingested dose, is excreted in urine.7

Half-life

The terminal half-life of monomethyl fumarate (MMF), diroximel fumarate's active metabolite, is estimated to be 1 hour.6,7

Clearance

No clearance information is available on the FDA label for diroximel fumarate7, however, clinical study results for its active metabolite, monomethyl fumarate show a mean apparent total clearance from the plasma after oral administration of 1.54 mgL−1.6

Adverse Effects
Adverseeffects
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Toxicity

Currently, an MSDS for diroximel fumarate is unavailable. The MSDS for its bioequivalent counterpart, dimethyl fumarate, indicates an oral LD50 of 2,240 mg/kg in rats.MSDS

There is no information regarding overdose on the FDA label for diroximel fumarate. Cases of overdose with its bioequivalent counterpart, dimethyl fumarate, have been reported in the literature, and symptoms reflect the adverse effects of this drug. These symptoms include nausea, vomiting, diarrhea, and flushing, among others.10 Currently there is no antidote to an overdose with diroximel fumarate or dimethyl fumarate. Symptomatic and supportive management are the only options up to this date if an overdose should occur.11

Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
DrugInteraction
Dimethyl fumarateThe serum concentration of Monomethyl fumarate, an active metabolite of Diroximel fumarate, can be increased when used in combination with Dimethyl fumarate.
PexidartinibDiroximel fumarate may increase the hepatotoxic activities of Pexidartinib.
Interactions
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Food Interactions
  • Avoid alcohol.
  • Take with or without food. If taken with food, the meal/snack should contain no more than 700 calories and no more than 30 g fat. Taking diroximel fumarate with food may reduce the adverse effect of flushing.

Products

Products2
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Brand Name Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing EndRegionImage
VumerityCapsule231 mg/1OralBiogen Inc.2019-10-29Not applicableUS flag

Categories

Drug Categories
Chemical TaxonomyProvided by Classyfire
Description
This compound belongs to the class of organic compounds known as fatty acid esters. These are carboxylic ester derivatives of a fatty acid.
Kingdom
Organic compounds
Super Class
Lipids and lipid-like molecules
Class
Fatty Acyls
Sub Class
Fatty acid esters
Direct Parent
Fatty acid esters
Alternative Parents
Pyrrolidine-2-ones / N-substituted carboxylic acid imides / N-alkylpyrrolidines / Dicarboxylic acids and derivatives / Methyl esters / Enoate esters / Dicarboximides / Lactams / Azacyclic compounds / Organonitrogen compounds
show 3 more
Substituents
2-pyrrolidone / Aliphatic heteromonocyclic compound / Alpha,beta-unsaturated carboxylic ester / Azacycle / Carbonyl group / Carboxylic acid derivative / Carboxylic acid ester / Carboxylic acid imide / Carboxylic acid imide, n-substituted / Dicarboximide
show 15 more
Molecular Framework
Aliphatic heteromonocyclic compounds
External Descriptors
Not Available
Affected organisms
  • Humans

Chemical Identifiers

UNII
K0N0Z40J3W
CAS number
1577222-14-0
InChI Key
YIMYDTCOUQIDMT-SNAWJCMRSA-N
InChI
InChI=1S/C11H13NO6/c1-17-10(15)4-5-11(16)18-7-6-12-8(13)2-3-9(12)14/h4-5H,2-3,6-7H2,1H3/b5-4+
IUPAC Name
1-[2-(2,5-dioxopyrrolidin-1-yl)ethyl] 4-methyl (2E)-but-2-enedioate
SMILES
COC(=O)\C=C\C(=O)OCCN1C(=O)CCC1=O

References

Synthesis Reference

Adv Ther (2019) 36:3154–3165 https://doi.org/10.1007/s12325-019-01085-3

General References
  1. Mills EA, Ogrodnik MA, Plave A, Mao-Draayer Y: Emerging Understanding of the Mechanism of Action for Dimethyl Fumarate in the Treatment of Multiple Sclerosis. Front Neurol. 2018 Jan 23;9:5. doi: 10.3389/fneur.2018.00005. eCollection 2018. [Article]
  2. Palte MJ, Wehr A, Tawa M, Perkin K, Leigh-Pemberton R, Hanna J, Miller C, Penner N: Improving the Gastrointestinal Tolerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study. Adv Ther. 2019 Nov;36(11):3154-3165. doi: 10.1007/s12325-019-01085-3. Epub 2019 Sep 19. [Article]
  3. Ghasemi N, Razavi S, Nikzad E: Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based Therapy. Cell J. 2017 Apr-Jun;19(1):1-10. Epub 2016 Dec 21. [Article]
  4. Dutta R, Trapp BD: Relapsing and progressive forms of multiple sclerosis: insights from pathology. Curr Opin Neurol. 2014 Jun;27(3):271-8. doi: 10.1097/WCO.0000000000000094. [Article]
  5. Sheikh SI, Nestorov I, Russell H, O'Gorman J, Huang R, Milne GL, Scannevin RH, Novas M, Dawson KT: Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther. 2013 Oct;35(10):1582-1594.e9. doi: 10.1016/j.clinthera.2013.08.009. [Article]
  6. Litjens NH, Burggraaf J, van Strijen E, van Gulpen C, Mattie H, Schoemaker RC, van Dissel JT, Thio HB, Nibbering PH: Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol. 2004 Oct;58(4):429-32. doi: 10.1111/j.1365-2125.2004.02145.x. [Article]
  7. Vumerity FDA label [Link]
  8. Biogen and Alkermes Announce FDA Approval of VUMERITY™ (diroximel fumarate) for Multiple Sclerosis [Link]
  9. FDA Clears More Tolerable Diroximel Fumarate (Vumerity) for MS [Link]
  10. Drugs.com: FDA approves Vumerity [Link]
  11. Dimethyl fumarate FDA Label [Link]
ChemSpider
57423290
RxNav
2261783
ChEMBL
CHEMBL3989944
ZINC
ZINC000215286156
MSDS
Download (34.9 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
4RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3Active Not RecruitingTreatmentMultiple Sclerosis1
3CompletedTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
1CompletedTreatmentMultiple Sclerosis1
Not AvailableNot Yet RecruitingNot AvailableRelapsing Forms of MS1
Not AvailableRecruitingNot AvailableRelapsing Forms of MS1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage Forms
FormRouteStrength
CapsuleOral231 mg/1
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)Region
US9090558No2015-07-282033-09-20US flag
US10080733No2018-09-252033-09-20US flag
US8669281No2014-03-112033-09-20US flag

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)102-106https://www.nwmissouri.edu/naturalsciences/sds/d/Dimethyl%20fumarate.pdf
boiling point (°C)192-193https://www.nwmissouri.edu/naturalsciences/sds/d/Dimethyl%20fumarate.pdf
logP0.74https://www.tecfidera.com/content/dam/commercial/tecfidera/pat/en_us/pdf/full-prescribing-info.pdf
Predicted Properties
PropertyValueSource
Water Solubility5.5 mg/mLALOGPS
logP-0.08ALOGPS
logP-0.22ChemAxon
logS-1.7ALOGPS
pKa (Strongest Basic)-6.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count0ChemAxon
Polar Surface Area89.98 Å2ChemAxon
Rotatable Bond Count7ChemAxon
Refractivity59.35 m3·mol-1ChemAxon
Polarizability23.89 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET Features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Targets

Drugtargets2
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Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
General Function
Receptor binding
Specific Function
Ionotropic receptor with a probable role in the modulation of auditory stimuli. Agonist binding may induce an extensive change in conformation that affects all subunits and leads to opening of an i...
Gene Name
CHRNA10
Uniprot ID
Q9GZZ6
Uniprot Name
Neuronal acetylcholine receptor subunit alpha-10
Molecular Weight
49704.295 Da
References
  1. Vumerity FDA label [Link]

Enzymes

1. Liver esterases
Kind
Group
Organism
Humans
Pharmacological action
Yes
Actions
Substrate
References
  1. Sheikh SI, Nestorov I, Russell H, O'Gorman J, Huang R, Milne GL, Scannevin RH, Novas M, Dawson KT: Tolerability and pharmacokinetics of delayed-release dimethyl fumarate administered with and without aspirin in healthy volunteers. Clin Ther. 2013 Oct;35(10):1582-1594.e9. doi: 10.1016/j.clinthera.2013.08.009. [Article]
  2. Litjens NH, Burggraaf J, van Strijen E, van Gulpen C, Mattie H, Schoemaker RC, van Dissel JT, Thio HB, Nibbering PH: Pharmacokinetics of oral fumarates in healthy subjects. Br J Clin Pharmacol. 2004 Oct;58(4):429-32. doi: 10.1111/j.1365-2125.2004.02145.x. [Article]
  3. Vumerity FDA label [Link]

Drug created on May 20, 2019 14:26 / Updated on May 05, 2021 23:20