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Diroximel fumarate | CAS No: 1577222-14-0 | GMP-certified suppliers
A medication that treats relapsing forms of multiple sclerosis in adults, including relapsing-remitting and active secondary progressive disease, offering improved gastrointestinal tolerability.
Therapeutic categories
Primary indications
- 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
Product Snapshot
- Diroximel fumarate is an oral small molecule formulated as delayed-release capsules
- It is primarily indicated for the treatment of relapsing forms of multiple sclerosis including active secondary progressive disease, clinically isolated syndrome, and relapsing-remitting MS
- The product is approved for use in the US and EU markets, with both approved and investigational status
Clinical Overview
Pharmacologically, diroximel fumarate belongs to the fumarate class of compounds and is a fatty acid ester. It is bioequivalent to dimethyl fumarate, an established MS therapy approved since 2013, but has been developed to minimize gastrointestinal adverse effects commonly associated with dimethyl fumarate. This improved tolerability is attributed to diroximel fumarate’s distinct chemical structure, which lacks a methanol leaving group and instead contains an inert 2-hydroxyethyl succinimide moiety.
The exact mechanism by which diroximel fumarate exerts its therapeutic effects in MS remains incompletely defined. Its primary active metabolite, monomethyl fumarate (MMF), activates the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, which plays a role in cellular response to oxidative stress. MMF also acts as a nicotinic acid receptor agonist in vitro, though the clinical relevance of this activity is not established.
Key safety considerations include risks of angioedema, anaphylaxis, hepatotoxicity, flushing, lymphopenia, and the potential development of progressive multifocal leukoencephalopathy (PML). Regular monitoring of liver function tests, bilirubin, and complete blood counts is recommended both prior to and during treatment. Treatment discontinuation is advised if serious adverse events such as PML, anaphylaxis, or sustained lymphopenia occur.
Diroximel fumarate was developed collaboratively by Alkermes and Biogen, with regulatory approvals granted by the FDA in 2019 and the EMA in 2021. It is categorized within acids, acyclic compounds, dicarboxylic acids, fumarates, and immunomodulating agents.
From a sourcing perspective, procurement of diroximel fumarate API necessitates adherence to stringent quality standards to ensure pharmaceutical-grade purity, stability, and compliance with regional regulatory requirements. Attention to supply chain integrity and appropriate documentation is essential to support regulatory submissions and clinical use.
Identification & chemistry
| Generic name | Diroximel fumarate |
|---|---|
| Molecule type | Small molecule |
| CAS | 1577222-14-0 |
| UNII | K0N0Z40J3W |
| DrugBank ID | DB14783 |
Pharmacology
| Summary | Diroximel fumarate is approved for the treatment of relapsing forms of multiple sclerosis, including active secondary progressive and relapsing-remitting types. Its active metabolite, monomethyl fumarate (MMF), activates the Nrf2 pathway, contributing to cellular defense against oxidative stress and modulating immune responses. Additionally, MMF acts as a nicotinic acid receptor agonist in vitro, though the clinical relevance of this interaction remains unclear. |
|---|---|
| Mechanism of action | Currently, the mechanism of action of this drug in MS is not fully understood. Diroximel fumarate is hypothesized to regulate cell signaling pathways, causing beneficial immune and neuroprotective effects. 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. 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. 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. |
| Pharmacodynamics | Diroximel fumarate relieves the neurological symptoms of relapsing MS with less gastrointestinal effects than its bioequivalent counterpart, dimethyl fumarate. It is important to note that diroximel fumarate can cause angioedema, anaphylaxis, hepatotoxicity, flushing, lymphopenia, and Progressive Multifocal Leukoencephalopathy (PML). 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. |
Targets
| Target | Organism | Actions |
|---|---|---|
| Neuronal acetylcholine receptor subunit alpha-10 | Humans | agonist |
ADME / PK
| Absorption | Diroximel fumarate is rapidly absorbed in the gastrointestinal tract following administration, like its bioequivalent drug, dimethyl fumarate. The median Tmax of monomethyl fumarate (MMF) after oral administration ranges from 2.5-3 hours with a mean Cmax of 2.11 mg/L. The bioequivalent drug, dimethyl fumarate, administered to healthy volunteers also shows a similar mean Tmax and Cmax. 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. 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. |
|---|---|
| Half-life | The terminal half-life of monomethyl fumarate (MMF), diroximel fumarate's active metabolite, is estimated to be 1 hour. |
| Protein binding | Plasma protein binding of MMF, the active metabolite of diroximel fumarate, ranges from 27-45%. |
| Metabolism | Esterases heavily metabolize diroximel fumarate, as well as its bioequivalent drug, dimethyl fumarate, in the liver. 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. 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. 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. |
| 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. The inactive metabolite, 2-hydroxyethyl succinimide (HES), representing 58-63% of the ingested dose, is excreted in urine. |
| Volume of distribution | The apparent volume of distribution ranges from 72L to 83L. Monomethyl fumarate (MMF), the active metabolite of diroximel fumarate, crosses the blood brain barrier. |
| Clearance | No clearance information is available on the FDA label for diroximel fumarate, 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. |
Formulation & handling
- Diroximel fumarate is a small molecule fatty acid ester intended for oral administration in capsule form, including delayed release formulations.
- It exhibits moderate water solubility and a low LogP, suggesting balanced hydrophilic-lipophilic properties favorable for oral absorption.
- Food intake can influence tolerability but does not significantly affect administration; dietary fat content should be limited when dosing with meals to mitigate adverse effects.
Regulatory status
| Lifecycle | The active pharmaceutical ingredient (API) is protected by patents in the United States until September 2033, with market presence in both the US and EU. Given the patent expiry timeline, the API is in a mid-to-late stage of its lifecycle in these regions. |
|---|
| Markets | US, EU |
|---|
Supply Chain
| Supply chain summary | Diroximel fumarate is primarily developed and marketed by a limited number of originator companies, with branded products available in both the US and EU markets under the brand name Vumerity. The existing patents in the United States have expiration dates around September 2033, indicating that generic competition is not expected in the near term. This patent protection supports continued exclusivity for originator manufacturers within key global markets. |
|---|
Safety
| 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. 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. |
|---|
- Oral LD50 of dimethyl fumarate, a bioequivalent to diroximel fumarate, is 2,240 mg/kg in rats
- Overdose cases of dimethyl fumarate have been associated with gastrointestinal symptoms and flushing
- No specific antidote is available
15-Epi-Treprostinil Related Substance is a type of Prostaglandin Analogues
Prostaglandin analogues are a subcategory of pharmaceutical active pharmaceutical ingredients (APIs) that play a crucial role in the field of medicine. These synthetic compounds mimic the effects of natural prostaglandins, which are hormone-like substances found in the body.
Prostaglandin analogues have gained significant attention in medical research due to their diverse therapeutic applications. They exhibit a wide range of physiological activities, such as regulating inflammation, blood flow, and hormone levels. These compounds are commonly used in the treatment of various conditions, including glaucoma, ocular hypertension, and certain types of cancer.
One notable application of prostaglandin analogues is in ophthalmology. These compounds effectively reduce intraocular pressure by increasing the outflow of aqueous humor, providing an effective treatment for glaucoma patients. Moreover, prostaglandin analogues offer the advantage of once-daily dosing, enhancing patient compliance and convenience.
In the field of oncology, prostaglandin analogues have shown promise as anticancer agents. They exert anti-proliferative effects on cancer cells and can induce apoptosis, making them valuable in the treatment of certain malignancies.
Overall, prostaglandin analogues represent a significant class of pharmaceutical APIs with diverse therapeutic applications. Continued research and development in this area hold great potential for the advancement of medicine and the improvement of patient care.
15-Epi-Treprostinil Related Substance (Prostaglandin Analogues), classified under Anti-inflammatory Agents
Anti-inflammatory agents are a crucial category of pharmaceutical active pharmaceutical ingredients (APIs) used to treat various inflammatory conditions. These agents play a vital role in alleviating pain, reducing swelling, and controlling inflammation in the body. They are widely employed in the management of diverse medical conditions, including arthritis, autoimmune disorders, asthma, and skin conditions like dermatitis.
Anti-inflammatory APIs primarily function by inhibiting the production of specific enzymes called cyclooxygenases (COX) and lipoxygenases (LOX). These enzymes are responsible for the synthesis of pro-inflammatory molecules known as prostaglandins and leukotrienes, respectively. By suppressing the activity of COX and LOX, anti-inflammatory agents effectively curtail the production of these inflammatory mediators, thereby mitigating inflammation.
Common examples of anti-inflammatory APIs include non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen, aspirin, and naproxen. These agents exhibit analgesic, antipyretic, and anti-inflammatory properties. Another group of anti-inflammatory APIs includes corticosteroids, such as prednisone and dexamethasone, which are synthetic hormones that modulate the body's immune response to control inflammation.
In conclusion, anti-inflammatory agents are a vital category of pharmaceutical APIs widely used to manage inflammation-related disorders. They target enzymes involved in the synthesis of pro-inflammatory molecules, effectively reducing pain and swelling. NSAIDs and corticosteroids are commonly prescribed anti-inflammatory APIs due to their efficacy in controlling inflammation.
