INTRODUCTION:

Multiple sclerosis (MS) is a demyelinating condition in which the myelin coating for nerve cells in the brain and spinal cord is impaired. It is categorized under the auto-immune disease. The pathogenic process involves the movement of self-reactive T cells across the blood-brain barrier to the central nervous system, causing damage to myelin, oligodendrocytes and nerve fibers and thus begin the immune cells recruitment.¹ This hinders the communication between the central nervous system and the rest of the body.²

It is pathologically described by inflammation, demyelination, and axonal and neuronal misfortune. Clinically it is characterized by intermittent backslides or movement, or both.³ In individuals with MS, the natural equilibrium between pro-inflammatory and anti-inflammatory cells in the immune system is disturbed, which results in the inflammation of both CNS and PNS.

This inﬂammatory procedure causes injuries (overwhelmingly in the cerebellum, cerebrum stem, spinal rope, optic nerves and white matter of mind ventricles) that results in the occurance of signs and symptoms of MS, including weak/hardened muscles, appendage deadness/shivering, balance issues, unsettling visual influences, and cognitive dysfunction.⁴ The lesional inﬂammatory condition likewise adds to MS pathogenesis through the age of pro inﬂammatory cytokines and oxygen and nitrogen free radicals, building up a cycle of inﬂammation and oxidative pressure.⁵

Relapsing-Remitting MS (RRMS) is more frequently seen comparing to other MS forms. Approximately 85% of patients with MS are initially diagnosed with RRMS. In RRMS, attacks usually occur when symptoms are flared up which is called as relapse and followed by remission which is the period of recovery when few symptoms appear.³

Several disease modifying-therapies are used for the management of MS commonly via the parenteral route, for example, Interferon-beta and glatiramer acetate (GA) which are administered via injection while, natalizumab and mitoxantone administered via infusion.⁶ Fortunately, some oral medications are recently developed which promote patient convenience and enhance therapeutic compliance. The oral drugs for the management of MS include fingolimod, teriflunomide, and dimethyl fumarate (DMF).⁷ These medications are effective in slowing the progression of the disease by restoring the balance of immune cells.

Diroximel fumarate (DRF) is a novel oral fumarate with a distinct chemical structure approved in the U.S. which is in development to treat patients with RRMS, to include clinically isolated syndrome, relapsing-remitting disease and active secondary progressive disease.⁸ DRF and DMF release similar active metabolite which is monomethyl fumarate (MMF).⁹ The difference relies on the onset time in which DRF has a shorter time of onset in comparison to DMF because DRF undergoes esterase cleavage in the gut before reaching systemic circulation in the blood.¹⁰ Unlike DMF, which is associated with gastrointestinal side effects including nausea, diarrhea, vomiting, and upper abdominal pain, DRF has improved gastrointestinal tolerability because of production of less irritation and reactivity toward off-target receptors in the GIT.^11-13 GI adverse reactions are a common cause of discontinuation DMF treatment.¹²

Apart from MMF, both DMF and DRF produce different metabolites. DMF is metabolized to MMF and methanol which is toxic while DRF is metabolized to MMF and inert 2-hydroxyethyl succinimide (HES).¹⁴ Two primary metabolites, MMF and HES, and two minor metabolites, RDC-8439, and methanol are formed in the first step of DRF metabolism.¹⁴ This is contrary to DMF, where MMF and methanol are produced as the primary metabolites by the first step of metabolism.¹⁴ DRF and DMF produce bioequivalent systemic exposure to MMF at therapeutic doses, which is assumed to improve efficacy in MS patients.¹⁵ Based on its chemical structure and associated metabolites, DRF is predicted to produce an effectiveness and safety profile comparable with DMF's experience but with an increased tolerability profile for GI^.15

PHARMACODYNAMICS:

The neurological signs of RRMS, are reduced by diroximel fumarate with less digestive impact than its bioequivalent analog, dimethyl fumarate.¹³ It must be remembered that angioedema, hepatotoxicity, anaphylaxis, flushing, lymphopeny, and progressive multifocal leukoencephalopathy (PML) may be induced by the administration of DRF.¹⁶ DRF should be immediately discontinued when PML, anaphylaxis or angioedema is suspected. Liver function and total bilirubin should be checked before and during therapy with diroximel fumarate. A complete blood count (CBC) should be collected before beginning DRF, after the first six months of treatment, and at corresponding periods of 6 to 12 months after that time.¹⁶ Stop the DRF therapy if the lymphocyte count is calculated to be less than 0.5 × 10⁹ /L for more than six months.¹⁶ It is to be noted that, DRF does not prolong the QTc duration to any clinically relevant degree at a dosage two times the maximum recommended dose.¹⁶ It suggested that DRF does not increase the risk of experiencing ventricular arrhythmias even in high doses.

It is evident that the pharmacodynamics of DRF and MMF are similar with higher gastrointestinal tolerability in patients undergo DRF therapy.

PHARMACOKINETICS:

Upon administration, diroximel fumarate, like its bioequivalent drug, dimethyl fumarate, is quickly absorbed in the gastrointestinal tract.¹⁷ According to EVOLVE-MS-1 Study, following oral administration, the median Tmax of monomethyl fumarate (MMF) varies from 2.5-3 hours, while the mean Cmax is of 2.11 mg/L.¹⁶ A similar mean of Tmax and Cmax is also observed in the bioequivalent drug, dimethyl fumarate, given to healthy volunteers.¹⁷ DRF metabolite's average steady-state concentration was reported at 8.32 mg.hr/L following twice-daily administration in MS patients.¹⁶ Food tends to significantly reduce MMF, the active metabolite of Cmax DRF, when compared to fasted administration.^16,17

The apparent volume of distribution of DRF varies from 72L to 83L.¹⁶ The active metabolite of DRF, MMF, crosses the blood-brain barrier which responsible for its effect.¹⁸ While the plasma protein binding of MMF ranges from 27-45%.¹⁶

Esterases metabolize both DRF and DMF in the liver.¹⁷ Throughout the gastrointestinal tract, skin, and plasma, these enzymes are found in high quantities. DRF's esterase metabolism releases the active metabolite, MMF, prior to moving into the systemic circulation.¹⁰ Moreover, together with small amounts of methanol, the main inactive metabolite, 2-hydroxyethyl succinimide (HES), and another inactive metabolite, RDC-8439, are formed during the metabolism.^16,19 Following the esterase metabolism, the tricarboxylic acid (TCA) cycle further metabolizes MMF, which produces major metabolites include fumaric acid, citric acid, and glucose.^16,17 It is important to remember that methanol is the main metabolite of DMF metabolism, but a minor metabolite of DRF metabolism, that results in a lower risk of gastrointestinal symptoms.¹⁹ Elimination of MMF, which is a major metabolite of both DMF and DRF, occurs through expired air as carbon dioxide. Negligible levels, lower than 0.3 percent of the absorbed dosage, are calculated in urine.¹⁶ The 2-hydroxyethyl succinimide (HES), an inactive metabolite of DRF, which constitutes 58-63% of the ingested dose, is excreted in urine.¹⁶ The half-life of MMF is estimated to be 1 hour. Monomethyl fumarate shows a mean apparent total plasma clearance of 1.54 mg/L following oral administration.¹⁷

GASTROINTESTINAL TOLERABILITY:

DRF was comparable in effectiveness to DMF but has a different chemical structure that may cause less gastrointestinal (GI) discomfort, as shown in the EVOLVE-MS-2 trial.¹⁹ EVOLVE-MS-2 was a 5-week study comparing the gastrointestinal tolerability of DRF(462 mg twice daily) to DMF ( 240 mg twice daily).¹⁹ The study hit its primary endpoint by demonstrating a statistically significantly lower number of gastrointestinal symptoms in patients taking DRF as compared to those who take DMF. The symptom intensity score of 2 or higher was observed with DRF on the Individual Gastrointestinal Symptom and Impact Scale (IGISIS) compared with DMF (P = .0003).¹⁹ Both DMF and DRF show gastrointestinal symptoms including flushing, diarrhea, and nausea.¹⁶ The duration and severity of gastrointestinal treatment-emergent adverse events were of similar patterns in DMF and DRF clinical trials; the difference lies in the statistics. Only 32.8% of the patients undergo DRF therapy complain of flushing in comparison to 40.6% of patients who undergo DMF therapy.¹⁶ While diarrhea was reported in 15.4% and 22.3% in patients taking DRF and DMF respectively.¹⁶ 14.6% of RRMS patients taking DRF experience nausea while 20.7% of patients taking DMF complain of it.¹⁶ The overall proportion of patients with adverse effects resulting in discontinuation of the study was 1.6% for DRF and 6% for DMF.¹⁶ Of those, the proportion of patients discontinued due to GI adverse events during the therapy phase was 0.8% for DRF and 4.8% for DMF.[16] DRF's distinct chemical structure leads to the observed low rates of gastrointestinal treatment-emergent adverse events and gastrointestinal associated discontinuation of treatment possibly due to several factors combined.¹⁹ These factors may include lower off-target protein reactivity and/or lower methanol-leaving group production which may lead to gastrointestinal irritation.¹⁹ Methanol release on the first step of DMF metabolism can contribute to the tolerability issues associated with DMF. Methanol consumption is known to cause gastrointestinal adverse effects at high systemic concentrations.²⁰ Formic acid is the main factor of side effects of methanol and is formed during methanol metabolism by the enzymes alcohol dehydrogenase (ADH) and formaldehyde dehydrogenase.^21-22 Depending on the isoform, ADHs are expressed primarily in the duodenum, small intestine, and liver (e.g., ADH1A or ADH4) or expressed in numerous tissues (ADH1C), whereas aldehyde dehydrogenases are highly expressed in most human tissues.²³ Hence, locally elevated methanol levels and GI-irritating metabolite formic acid in the small intestine can subsequently play a role in the mechanism of GI complications and contribute to GI events.²⁰ DMF's low molecular weight (144.1g/mol) and, therefore, the small physical size allows multiple receptors and proteins to be reached within the GI tract and GI wall.^13,24-26 When on target, these interactions are advantageous, thereby contributing to the drug's efficacy.¹⁹ Instead, they can cause GI problems such as diarrhea, nausea, and vomiting if they are off-target.¹⁹ DMF may react with a microbiota, similar to how antibiotics cause GI events, or may react with pre-systemic proteins/receptors, similar to how acarbose or opioids modulate GI functions.^27,28 DRF will likely have less off-target interactions with GI receptors/proteins (located either in the microbiota or GI tract) relative to DMF due to potential variations in molecular size, electrophilicity and/or molecular half-life.¹⁹ These top-level results indicate that DRF provides a distinct gastrointestinal tolerability profile and maybe an alternative for patients living with RRMS.¹⁶

SAFETY:

EVOLVE-MS-1 study evaluates long-term safety and efficacy of MMF in relapsing-remitting MS (RRMS) patients. The study shows that DRF has better safety when compare to MMF.

84.6% (589/696) of the overall patients in EVOLVE-MS-1 registered treatment-emergent adverse events.²⁹ In most patients undergo DRF therapy treatment-emergent adverse events were either mild or moderate in severity with 31.2% and 46.8% respectively^.29 Flushing was the most frequent treatment-emergent adverse event which accounts for 34.1% among the population.²⁹ 7.5% serious adverse effects were reported, and two death (0.3%) death occurred due to accidental fall and hypertensive cardiovascular events which were deemed unrelated to study drug by the investigator.²⁹

ALCs fell by about 28.4 % in the first year and then recovered, with the majority of patients(64.8%; 441/681) staying more than the lower limit of normal in EVOLVE-MS-1 Study.²⁹ A similar degree and trend of decline were found in fumarate-naïve cases, preceded by stabilization.²⁹ Incidence of prolonged moderate lymphopenia was recorded in 7.3% (50/681).²⁹

Two cases (0.3%) of severe infection, pneumonia, and sepsis were reported. However, neither were in the context of severe prolonged lymphopenia.²⁹ No severe opportunistic infections were reported.²⁹

Malignancy occurred in 0.3% (two cases) patients while there were no anaphylaxis or angioedema cases observed.²⁹

In EVOLVE-MS-1, it was found out that serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were elevated beyond the upper limit of normal in 3.6% and 2.3% patients respectively.²⁹ In 88% (14/16) and 89% (8/9) of patients, the elevations of ALT and AST were resolved respectively.²⁹ While it was 11.5 (4–144) and 13 (1–113) days the time taken for the median (range) resolution.²⁹

DOSAGE AND ADMINISTRATION:

DRF recommended starting dose is 231 mg orally twice daily.¹⁶ The dosage should be raised after 7 days to the maintenance dose of 462 mg (administered as two 231 mg capsules) given twice a day orally.¹⁶ In patients who do not withstand the maintenance dose, temporary dosage adjustments to 231 mg twice daily may be recommended.¹⁶ The prescribed dosage of 462 mg twice daily should be restored within 4 weeks.¹⁶ DRF therapy discontinuation should be considered for patients who are unable to tolerate the return of maintenance dose.¹⁶ Administration of non-enteric coated aspirin (up to a dose of 325 mg) 30 minutes prior to DRF dosing may reduce the incidence or severity of flushing.¹⁶ DRF should be shallow as a whole and intact.¹⁶ Patients should not take DRF with a high-fat and high-calorie food. Food taken together with DRF should have less than 700 calories and 30g fat.¹⁶

POTENTIAL DRUG INTERACTION:

DRF is contraindicated for individuals currently receiving DMF, which is also metabolized to MMF. This increase the risk of toxicity for which it should be avoided.¹⁶ DRF may be started the day after DMF is discontinued.¹⁶

CONCLUSION:

DRF is an innovative oral fumarate in the treatment of RRMS patients with its distinct chemical structure. DRF and DMF produce similar pharmacologically active metabolites, MMF, which cause identical mechanisms of action of both the drugs. Consequently, efficacy and safety profiles are predicted to be identical for DRF and DMF. DRF has the potential to produce a better gastrointestinal tolerability profile when compared to DMF due to less production of methanol and decreases the reactivity with off-target receptors, which are the results of its distinct chemical structure. Therefore, DRF has a promising safety and efficacy profile and seems to be a well-tolerated alternative for the treatment of RRMS.

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Received on 19.05.2020 Modified on 28.05.2020

Research J. Pharm. and Tech 2020; 13(6): 2992-2996.

DOI: 10.5958/0974-360X.2020.00529.6