Methods for treating multiple sclerosis

Abstract

To provide safer methods for treating patients with multiple sclerosis using fumarates taking into consideration of the possibility of acquiring progressive multifocal leukoencephalopathy (PML).SOLUTION: Provided is a method for treating a patient with multiple sclerosis, which comprises: (a) administering to the patient a fumarate, where the fumarate is a fumarate dialkyl, a fumarate monoalkyl, a combination of a fumarate dialkyl and a fumarate monoalkyl, a prodrug of a fumarate monoalkyl, deuterated form of any of the foregoing, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, stereoisomer of any of the foregoing, or a combination of any the foregoing; and (b) monitoring the patient for a sign or symptom suggestive of PML.SELECTED DRAWING: Figure 1

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 62 / 080,783, filed November 17, 2014; U.S. Provisional Patent Application No. 62 / 140,255, filed March 30, 2015; and U.S. Provisional Patent Application No. 62 / 232,963, filed September 25, 2015, each of which is hereby incorporated by reference in its entirety.

[0002] 1. Field Provided herein is a method for treating multiple sclerosis using fumarate compounds, such as dialkyl fumarates, monoalkyl fumarates, combinations of dialkyl fumarates and monoalkyl fumarates, prodrugs of monoalkyl fumarates, deuterated forms of any of these, and pharmaceutically acceptable salts, clathrates, solvates, tautomers, or stereoisomers of any of these, or combinations of any of these. The methods provided herein improve the safety of treatment by informing and monitoring the treated patient regarding progressive multifocal leukoencephalopathy (PML) and / or by monitoring lymphocyte counts.

Background Art

[0003] 2. Background Multiple sclerosis (MS) is an autoimmune disease in which autoimmunity against central nervous system (CNS) antigens is activated. This disease is characterized by patchy inflammation of the CNS, which leads to loss of myelin (demyelination) surrounding neuronal axons, axonal loss, and ultimately death of neurons, oligodendrocytes, and glial cells. For a comprehensive review of MS and current treatment methods, see, for example, McAlpine’s Multiple Sclerosis, by Alastair Compston et al., 4th edition, Churchill Livingstone Elsevier, 2006.

[0004] It is estimated that 2.5 million people worldwide suffer from MS. MS is one of the most common CNS diseases in young adults. MS is a chronic, progressive, and disabling disease, and patients are generally affected by the disease at some point after puberty, and the diagnosis is generally made between the ages of 20 and 40, although onset can occur earlier. This disease is not directly inherited, but genetic susceptibility plays a role in its onset. MS is a complex disease with diverse clinical, pathological, and immunological phenotypes.

[0005] There are four main clinical types of MS: 1) relapsing-remitting MS (RR-MS), characterized by distinct relapses, which may be accompanied by full recovery or residual disability upon recovery; the period between relapses is characterized by no disease progression; 2) secondary progressive MS (SP-MS), characterized by an initial relapsing-remitting course followed by disease progression, regardless of occasional relapses, mild remissions, and the presence or absence of plateaus; 3) primary progressive MS (PP-MS), characterized by disease progression from onset, with possible occasional plateaus and temporary mild improvements; and 4) progressive relapsing MS (PR-MS), characterized by the onset of a progressive disease with distinct acute relapses, regardless of full recovery; the period between relapses is characterized by continuous progression.

[0006] Clinically, this disease most often presents as a relapsing-remitting disorder, and although less often, as a progressive neurological disability. Relapsing-remitting MS (RR-MS) presents in the form of recurrent attacks of focal or multifocal neurological deficits. The attacks may occur, seemingly irregularly, over the years, with remissions and relapses. Remissions are often incomplete, and as the attacks occur one after another, the condition gradually deteriorates, resulting in an increasing permanent neurological deficit. The typical course of RR-MS is characterized by repeated relapses and, concomitantly, in the majority of patients, eventually the onset of disease progression. The subsequent course of the disease is unpredictable, but most patients with relapsing-remitting disorders will ultimately develop secondary progressive disease. During the relapsing-remitting phase, relapses occur alternately with clinically inactive periods and may or may not be characterized by sequelae depending on the presence or absence of neurological deficits between episodes. The period between relapses during the relapsing-remitting phase is clinically stable. On the other hand, patients with progressive MS show a steady increase in disability, as defined above, either from the start of the episode period or afterwards, although this nomenclature does not exclude the occurrence of further new relapses.

[0007] The MS pathology is partially reflected in the formation of focal inflammatory demyelinating lesions in the white matter, which are characteristic of patients with acute and relapsing diseases. In patients with progressive disease, the brain is affected in a more global sense, with diffuse but extensive (mainly axonal) damage in the seemingly normal white matter, and also extensive demyelination in the grey matter, particularly in the cortex.

[0008] Salts of fumaric acid esters in combination with dimethyl fumarate (DMF), such as those contained in FUMADERM®, have been proposed for the treatment of MS (see, for example, Schimrigk et al., Eur. J. Neurol., 2006, 13(6):604-610; Drugs R&D, 2005, 6(4):229-30; U.S. Patent No. 6,436,992). FUMADERM® contains dimethyl fumarate, calcium salt of ethyl hydrogen fumarate, magnesium salt of ethyl hydrogen fumarate, and zinc salt of ethyl hydrogen fumarate (see, for example, Schimrigk et al., Eur. J. Neurol., 2006, 13(6):604-610).

[0009] Tecfidera®, an oral delayed-release capsule formulation of dimethyl fumarate, was approved by the U.S. Food and Drug Administration in 2013 for the treatment of patients with relapsing multiple sclerosis. Tecfidera® contains dimethyl fumarate (DMF) having the following structure:

Chemical formula

[0010] The first Phase 3 clinical trial, DEFINE (ClinicalTrials.gov identifier NCT00420212), demonstrated that DMF significantly reduced clinical relapses, the accumulation of physical disability progression, and lesion number and volume after 2 years of treatment compared to placebo. See, for example, Gold et al., N. Engl. J. Med., 2012, 367(12):1098-1107. These findings were supported by the results of a second Phase 3 clinical trial, CONFIRM (ClinicalTrials.gov identifier NCT00451451), which additionally evaluated subcutaneous glatiramer acetate as an active comparator treatment (evaluator-blinded). See, for example, Fox et al., N. See Engl. J. Med., 2012, 367(12):1087-1097. DMF has demonstrated acceptable safety profiles in the DEFINE and CONFIRM trials.

[0011] Cases of PML have been reported in patients with psoriasis treated with FUMADERM® or compounded fumaric acid esters (Ermis et al., N. Engl. J. Med., 2013, 368(17):1657-1658; van Oosten et al., N. Engl. J. Med., 2013, 368(17):1658-1659; Sweetser et al., N. Engl. J. Med., 2013, 368(17):1659-1658; Emrich, Lisa, ‘‘Tecfidera and PML-What’s the story.’’ Multiplesclerosis.net, April 25, 2013;accessed November 10, 2014). Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection caused by a polyomavirus called the JC virus (JCV). PML typically occurs only in immunocompromised patients and usually results in death or severe physical disability. The virus is common in the general population, occurs in childhood, and persists throughout life. Studies have shown that the JCV seroprevalence rate is approximately 33-84% (see WO2011 / 085369A1, WO2007 / 100770A2, and WO2012 / 166971A2). PML is a severe and rapidly progressive viral disease of the central nervous system that destroys the myelin sheath that protects nerve cells. PML almost invariably occurs in severely immunocompromised patients and is often associated with lymphoproliferative diseases and other chronic diseases such as AIDS, Hodgkin's disease, chronic lymphocytic leukemia, sarcoidosis, tuberculosis, systemic lupus erythematosus, and organ transplantation. Cases of PML have also been reported in patients with autoimmune disorders receiving immunosuppressive therapy; among them are three patients with rheumatoid arthritis (Sponzilli et al., Neurology, 1975, 25(7):664-668; Rankin et al., J. Rheumatol., 1995, 22(4):777-779; Durez et al., Arthritis Rheum., 2002, 46(98):536), one of whom was treated with a tumor necrosis factor (TNF) antagonist (Durez et al., Arthritis Rheum., 2002, 46(98):536). PML has also been reported in patients with Crohn's disease, although the concomitant therapy was not specified (Garrels et al., Am. J. Neuroradiol., 1996, 17(3):597-600), and in patients treated with natalizumab, a humanized monoclonal antibody used in the treatment of multiple sclerosis and Crohn's disease. In 2005, the first cases of PML associated with biological immunomodulatory therapy using natalizumab followed by other agents including efalizumab, rituximab, and alemtuzumab were reported (reviewed in: Major et al., Annu. Rev. Med., 2010, 61:35-47). There is a need in the art for a safer method of treating patients with fumaric acid compounds, taking into account the possibility of developing PML.

Prior Art Documents

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Summary of the Invention

Means for Solving the Problems

[0014] 3. Summary Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, which is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) monitoring the patient for the absence of signs or symptoms suggestive of progressive multifocal leukoencephalopathy (PML).

[0015] Provided herein is a method of improving safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient being treated with a fumaric acid compound for the absence of signs or symptoms suggestive of PML, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0016] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, which is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) informing the patient that PML has occurred in a patient administered dimethyl fumarate.

[0017] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, which is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) instructing the patient on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0018] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0019] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising instructing a patient with multiple sclerosis being treated with a fumaric acid compound on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0020] In one embodiment, the method further comprises withholding treatment of the fumaric acid compound from the patient at the stage when the first signs or symptoms suggesting PML appear in the patient.

[0021] In one embodiment, the method further comprises performing a diagnostic evaluation for PML in the patient at the stage when the first signs or symptoms suggesting PML appear in the patient.

[0022] In one embodiment, the method further comprises administering a therapeutic agent to the patient for the treatment of PML if the diagnostic evaluation indicates PML in the patient.

[0023] In one embodiment, the method further comprises instructing the patient to continue to look for new signs and symptoms suggesting PML for about six months after discontinuation of treatment with the fumaric acid compound.

[0024] In one embodiment, the method further comprises instructing the patient that the typical symptoms associated with PML are diverse, progress over several days to weeks, and include progressive weakness or limb paralysis on one side of the body, visual disturbances, and changes in thinking, memory, and orientation that lead to confusion and personality changes.

[0025] In one embodiment, the method further comprises instructing the patient that the progression of a disorder associated with PML usually results in death or severe physical disability over several weeks or months.

[0026] In one embodiment, the diagnostic evaluation includes testing for the presence of JC virus DNA in the patient's cerebrospinal fluid.

[0027] In one embodiment, the signs or symptoms suggesting PML are selected from the group consisting of progressive weakness or limb paralysis on one side of the body, visual disturbances, and changes in thinking, memory, and orientation that lead to confusion and personality changes.

[0028] In one embodiment, the administration is oral.

[0029] In one embodiment, the pharmaceutical composition comprises a therapeutically effective amount of a fumaric acid compound and a pharmaceutically acceptable carrier.

[0030] In one embodiment, the pharmaceutical composition is in the form of tablets or capsules.

[0031] In one embodiment, the pharmaceutical composition is in the form of enteric-coated tablets.

[0032] In one embodiment, the pharmaceutical composition is in the form of capsules containing enteric-coated microtablets.

[0033] In one embodiment, the fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate.

[0034] In one embodiment, the fumaric acid compound is dimethyl fumarate.

[0035] In one embodiment, the administration is 240 mg of dimethyl fumarate twice a day.

[0036] In one embodiment, the administration is 120 mg of dimethyl fumarate twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose.

[0037] In one embodiment, the total amount of the fumaric acid compound administered per day is 720 mg or less.

[0038] In one embodiment, the total amount of the fumaric acid compound administered per day is 480 mg or less.

[0039] In one embodiment, the pharmaceutical composition consists essentially of dimethyl fumarate, and the total amount of the fumaric acid compound administered per day is 720 mg or less.

[0040] In one embodiment, the pharmaceutical composition consists essentially of dimethyl fumarate, and the administration is such that the total amount of fumaric acid compound per day is 480 mg or less.

[0041] In one embodiment, the pharmaceutical composition consists essentially of dimethyl fumarate.

[0042] In one embodiment, the multiple sclerosis is relapsing multiple sclerosis.

[0043] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that no fumarate is present in the pharmaceutical composition; and (b) monitoring the patient to determine whether the patient exhibits any signs or symptoms suggestive of PML.

[0044] Provided herein is a method for improving the safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient being treated with a pharmaceutical composition comprising a fumaric acid compound to determine whether the patient exhibits any signs or symptoms suggestive of PML, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that no fumarate is present in the pharmaceutical composition.

[0045] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate.

[0046] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition; and (b) instructing the patient on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0047] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition.

[0048] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising instructing the treating physician of a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound of the importance of contacting the treating physician should any symptoms suggestive of PML develop in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition.

[0049] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) monitoring the patient for the absence of signs or symptoms suggestive of PML.

[0050] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound to determine whether the patient has signs or symptoms suggestive of PML; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0051] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate.

[0052] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) instructing the patient of the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0053] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0054] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising instructing the treating physician of a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound of the importance of contacting the treating physician if any signs suggestive of PML develop in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0055] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium ethyl hydrogen fumarate, magnesium ethyl hydrogen fumarate, zinc ethyl hydrogen fumarate, and copper ethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) monitoring the patient for the absence of signs or symptoms suggestive of PML.

[0056] Provided herein is a method of improving safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound to determine whether the patient has signs or symptoms suggestive of PML; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0057] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate.

[0058] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) instructing the patient of the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0059] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0060] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising instructing the treating physician of a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound of the importance of contacting the treating physician if any symptoms suggestive of PML occur in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0061] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) monitoring the patient for the absence of signs or symptoms suggestive of PML.

[0062] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate for the absence of signs or symptoms suggestive of PML.

[0063] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate.

[0064] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) instructing the patient on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0065] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising notifying a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate that PML has occurred in patients administered dimethyl fumarate.

[0066] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising instructing a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0067] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) obtaining a complete blood count value including lymphocyte count after repeating the administration of the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0068] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter, obtaining a complete blood count value including lymphocyte count.

[0069] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter, obtaining a complete blood count value including lymphocyte count.

[0070] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0071] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) obtaining a complete blood count value including lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0072] In one embodiment, the method further comprises discontinuing administration of the pharmaceutical composition to the patient if the patient has a lymphocyte count of less than 0.5×10 9 / L for more than 6 months.

[0073] In one embodiment, the method further comprises measuring the lymphocyte count of the patient until lymphopenia is resolved in the patient.

[0074] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be below the normal range, investigating other causes of lymphopenia and taking corrective measures as appropriate with respect to such other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0075] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with this pharmaceutical composition.

[0076] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) closely monitoring the patient for signs or symptoms of the appearance of a new neurological disorder if lymphopenia occurs in the patient after administration of the pharmaceutical composition.

[0077] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has developed lymphopenia and who is being treated with a pharmaceutical composition comprising a fumaric acid compound for signs or symptoms of the appearance of a new neurological disorder; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0078] Provided herein is a method of treating multiple sclerosis in patients being treated with a multiple sclerosis disease modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; the method comprises the following steps in the order described: (a) stopping the administration of this multiple sclerosis disease modifying therapy to this patient; (b) considering the half-life and mode of action of this multiple sclerosis disease modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0079] Provided herein is a method of treating multiple sclerosis in patients being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing the administration of interferon or glatiramer acetate to the patient; and (b) immediately after this discontinuation, initiating the administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0080] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) performing a blood test and measuring the patient's white blood cell count prior to the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of the patient with this pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuing the treatment with this pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during the treatment.

[0081] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate with respect to these other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that fumarate is not present in the pharmaceutical composition.

[0082] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with this pharmaceutical composition.

[0083] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition; and (b) if the patient develops lymphopenia after administration of this pharmaceutical composition, carefully monitoring the patient for signs or symptoms of the appearance of new neurological dysfunction.

[0084] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising monitoring patients with multiple sclerosis who have been treated with a pharmaceutical composition comprising a fumaric acid compound and who have developed lymphopenia for signs or symptoms of the appearance of new neurological dysfunction; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition.

[0085] Provided herein is a method for treating multiple sclerosis in patients being treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; the method comprising, in the order described, the steps of: (a) discontinuing administration of the multiple sclerosis disease-modifying therapy to the patient; (b) considering the half-life and mode of action of the multiple sclerosis disease-modifying therapy for the purpose of avoiding further immune effects, but at the same time minimizing the risk of disease reactivation; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0086] Provided herein is a method of treating multiple sclerosis in patients being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) immediately after such discontinuation, initiating administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition.

[0087] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition; and (b) performing a blood test and measuring the patient's white blood cell count before the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of this patient with the pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuing the treatment with the pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during this treatment.

[0088] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be below the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate with respect to such other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that the ethyl hydrogen fumarate salt is not present in the pharmaceutical composition.

[0089] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that the ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with this pharmaceutical composition.

[0090] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) closely monitoring the patient for signs or symptoms of the appearance of a new neurological disorder if lymphopenia occurs in the patient after administration of the pharmaceutical composition.

[0091] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has developed lymphopenia and who is being treated with a pharmaceutical composition comprising a fumaric acid compound for signs or symptoms of the appearance of a new neurological disorder; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0092] Provided herein is a method of treating multiple sclerosis in patients being treated with a multiple sclerosis disease modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that the ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; the method comprises the following steps in the recited order: (a) discontinuing administration of this multiple sclerosis disease modifying therapy to this patient; (b) considering the half-life and mode of action of this multiple sclerosis disease modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of reactivation of the disease; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0093] Provided herein is a method of treating multiple sclerosis in patients being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) immediately after this discontinuation, initiating administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that the ethyl hydrogen fumarate salt is not present in the pharmaceutical composition.

[0094] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) performing a blood test and measuring the patient's white blood cell count prior to the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of this patient with the pharmaceutical composition comprising the fumaric acid compound; and (c) considering stopping the treatment with the pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during the treatment.

[0095] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be below the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate with respect to these other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium ethyl hydrogen fumarate, magnesium ethyl hydrogen fumarate, zinc ethyl hydrogen fumarate, and copper ethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0096] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with this pharmaceutical composition.

[0097] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) if the patient develops lymphopenia after administration of this pharmaceutical composition, carefully monitoring the patient for signs or symptoms of the appearance of a new neurological disorder.

[0098] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has been treated with a pharmaceutical composition comprising a fumaric acid compound and who has developed lymphopenia for signs or symptoms of the emergence of a new neurological disorder; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0099] Provided herein is a method for treating multiple sclerosis in a patient being treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; the method comprising the following steps in the order described: (a) discontinuing administration of the multiple sclerosis disease-modifying therapy to the patient; (b) considering the half-life and mode of action of the multiple sclerosis disease-modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of reactivation of the disease; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0100] Provided herein is a method of treating multiple sclerosis in a patient being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) immediately following such discontinuation, initiating administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0101] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) performing a blood test and measuring the patient's white blood cell count prior to the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during treatment of the patient with this pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuing the treatment with this pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during the treatment.

[0102] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate for such other causes; and (b) administering the pharmaceutical composition to the patient.

[0103] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with this pharmaceutical composition.

[0104] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) closely monitoring the patient for signs or symptoms of the appearance of new neurological dysfunction if lymphopenia occurs after administration of this pharmaceutical composition.

[0105] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has developed lymphopenia and is being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate for signs or symptoms of the appearance of new neurological dysfunction.

[0106] Provided herein is a method of treating multiple sclerosis in a patient being treated with a multiple sclerosis disease modifying therapy other than a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; the method comprising the steps in the order described: (a) discontinuing administration of the multiple sclerosis disease modifying therapy to the patient; (b) considering the half-life and mode of action of the multiple sclerosis disease modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate.

[0107] Provided herein is a method of treating multiple sclerosis in a patient being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) starting administration to the patient of a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate immediately after such discontinuation.

[0108] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; (b) performing a blood test and measuring the patient's white blood cell count before the first administration of the pharmaceutical composition to the patient and periodically during treatment of the patient with the pharmaceutical composition; and (c) considering stopping treatment with the pharmaceutical composition if the white blood cell count decreases during the treatment.

[0109] In one embodiment, the method further comprises discontinuing administration of the pharmaceutical composition to the patient if it is confirmed by repeated testing three months later that the patient's lymphocyte count is less than 0.7×10 9 / L.

[0110] In one embodiment, signs or symptoms of the appearance of a new neurological disorder include motor dysfunction and cognitive or psychiatric symptoms.

[0111] In one embodiment, the method further includes: if PML is suspected, immediately withholding treatment with this pharmaceutical composition and performing further evaluation.

[0112] In one embodiment, the method further includes performing an MRI on the patient before initiating this administration of the pharmaceutical composition comprising a fumaric acid compound to the patient. In certain embodiments, for example, the following are provided: (Item 1) A method of treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) monitoring the patient for signs or symptoms suggestive of progressive multifocal leukoencephalopathy (hereinafter "PML") in the patient The method as described above. (Item 2) A method of improving safety in the treatment of a patient with multiple sclerosis, comprising monitoring the patient for signs or symptoms suggestive of PML in a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition, the method as described above. (Item 3) The method according to item 1 or 2, further comprising withholding treatment with the fumaric acid compound in the patient at the stage when the first sign or symptom suggesting PML appears in the patient. (Item 4) The method according to any one of items 1 to 3, further comprising performing a diagnostic evaluation for PML in the patient at the stage when the first sign or symptom suggesting PML appears in the patient. (Item 5) The method according to item 4, further comprising administering a therapeutic agent to the patient for the treatment of PML if the diagnostic evaluation indicates PML in the patient. (Item 6) The method according to item 3, further comprising instructing the patient to continue to look for new signs and symptoms suggesting PML for about 6 months after discontinuation of treatment with the fumaric acid compound. (Item 7) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate comprising the said method. (Item 8) A method for treating a patient with multiple sclerosis, comprising the following (a) Administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) Instructing the patient on the importance of contacting the patient's attending physician if any symptoms suggesting PML occur in the patient. The method as described above, comprising the above. (Item 9) Furthermore, instructing the patient that the typical symptoms associated with PML are diverse, progress over several days to several weeks, and such symptoms include progressive weakness or limb impairment on one side of the body, visual impairment, and changes in thinking, memory, and orientation that lead to confusion and personality changes. The method according to Item 8, comprising the above. (Item 10) Furthermore, instructing the patient that the progression of the disorder associated with PML usually results in death or severe physical impairment over several weeks or months. The method according to Item 9, comprising the above. (Item 11) A method for improving the safety in the treatment of patients with multiple sclerosis, comprising notifying a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition. The method as described above. (Item 12) A method for improving safety in the treatment of patients with multiple sclerosis, comprising instructing the attending physician of a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound of the importance of contacting the attending physician if any symptoms suggestive of PML occur in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate is not present in the pharmaceutical composition, said method. (Item 13) Furthermore, the method according to item 12, comprising instructing the patient that the typical symptoms associated with PML are diverse, progress over several days to weeks, and include progressive weakness or limb impairment on one side of the body, visual impairment, and changes in thinking, memory, and orientation that cause confusion and personality changes. (Item 14) Furthermore, the method according to item 13, comprising instructing the patient that the progression of a disorder associated with PML usually results in death or severe physical impairment over several weeks or months. (Item 15) The method according to item 4, wherein the diagnostic evaluation includes a test for the presence of JC virus DNA in the cerebrospinal fluid of the patient. (Item 16) The method according to any one of items 1 to 6, 8, 10, 12, and 15, wherein the signs or symptoms suggestive of PML are selected from the group consisting of progressive weakness or limb impairment on one side of the body, visual impairment, and changes in thinking, memory, and orientation that cause confusion and personality changes. (Item 17) The method according to any one of items 1, 7 to 10, and any dependent claims of any one of these, wherein the administration is oral. (Item 18) The pharmaceutical composition according to any one of items 1 to 17, which comprises a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier. (Item 19) The pharmaceutical composition according to item 18, which is in the form of tablets or capsules. (Item 20) The pharmaceutical composition according to item 18, which is in the form of enteric-coated tablets. (Item 21) The pharmaceutical composition according to item 18, which is in the form of capsules containing enteric-coated microtablets. (Item 22) The fumaric acid compound according to any one of items 1 to 21, which is dimethyl fumarate and / or monomethyl fumarate. (Item 23) The fumaric acid compound according to item 22, which is dimethyl fumarate. (Item 24) The administration according to item 17, wherein 240 mg of dimethyl fumarate is administered twice a day. (Item 25) The administration according to item 17, wherein 120 mg of dimethyl fumarate is administered twice a day for 7 days, and then 240 mg of dimethyl fumarate is administered twice a day as a maintenance dose. (Item 26) The administration according to item 17, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 27) The administration according to item 17, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 28) The pharmaceutical composition according to any one of items 18 and 23 to 27, which consists essentially of dimethyl fumarate. (Item 29) The pharmaceutical composition according to any one of items 24 to 28, which is in the form of tablets or capsules. (Item 30) The pharmaceutical composition according to any one of items 24 to 28, which is in the form of enteric-coated tablets. (Item 31) The method according to any one of Items 24 to 28, wherein the pharmaceutical composition is in the form of a capsule containing enteric-coated microtablets. (Item 32) The method according to any one of Items 1 to 31, wherein the multiple sclerosis is relapsing multiple sclerosis. (Item 33) A method for treating a patient with multiple sclerosis, comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) monitoring the patient to determine whether the patient exhibits any signs or symptoms suggestive of PML. (Item 34) A method for improving the safety in the treatment of a patient with multiple sclerosis, comprising monitoring the patient being treated with a pharmaceutical composition comprising a fumaric acid compound to determine whether the patient exhibits any signs or symptoms suggestive of PML, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition. (Item 35) Furthermore, the method according to Item 33 or Item 34, comprising withholding treatment of the patient with the fumaric acid compound at the stage when the patient exhibits the first signs or symptoms suggestive of PML. (Item 36) The method according to any one of items 33 to 35, further comprising performing a diagnostic evaluation for PML in the patient at the stage when the first sign or symptom suggesting PML appears in the patient. (Item 37) The method according to item 36, further comprising administering a therapeutic agent to the patient for the treatment of PML when the diagnostic evaluation indicates PML in the patient. (Item 38) The method according to item 35, further comprising instructing the patient to continue to check for new signs and symptoms suggesting PML for about six months after discontinuation of the treatment with the fumaric acid compound. (Item 39) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) notifying the patient that PML has occurred in a patient administered dimethyl fumarate The above method. (Item 40) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) Instructing the importance of contacting the attending physician of the patient if any symptoms suggesting PML occur in the patient, regardless of what they are The method as described above, including (Item 41) Furthermore, instructing the patient that typical symptoms associated with PML are diverse, progress over several days to weeks, and include progressive weakness or limb impairment on one side of the body, visual impairment, and changes in thinking, memory, and orientation that lead to confusion and personality changes. The method according to Item 40, including (Item 42) Furthermore, instructing the patient that the progression of the disorder associated with PML usually results in death or severe physical impairment over several weeks or months. The method according to Item 41, including (Item 43) A method for improving the safety in the treatment of patients with multiple sclerosis, including notifying a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate salt does not exist in the pharmaceutical composition. The method as described above (Item 44) A method for improving the safety in the treatment of patients with multiple sclerosis, which includes instructing the importance of contacting the attending physician of a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound if any symptom suggesting PML occurs in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition, the said method. (Item 45) Furthermore, the method according to item 44, which includes instructing the patient that typical symptoms related to PML are diverse, progress over several days to several weeks, and such symptoms include progressive weakness on one side of the body or limb impairment, visual impairment, and changes in thinking, memory, and orientation that cause confusion and personality changes. (Item 46) Furthermore, the method according to item 45, which includes instructing the patient that the progression of PML-related disorders usually leads to death or severe physical impairment over several weeks or months. (Item 47) The diagnostic evaluation in the method according to item 36 includes an examination for the presence of JC virus DNA in the cerebrospinal fluid of the patient. (Item 48) The sign or symptom suggesting PML is selected from the group consisting of progressive weakness on one side of the body or limb impairment, visual impairment, and changes in thinking, memory, and orientation that cause confusion and personality changes, according to any one of items 33 - 38, 40, 42, 44, and 47. (Item 49) The administration in the method according to any one of items 33, 39 - 42, and any dependent item of any one of them is carried out orally. (Item 50) The pharmaceutical composition according to any one of items 33 to 49, which comprises a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier. (Item 51) The pharmaceutical composition according to item 50, which is in the form of a tablet or a capsule. (Item 52) The pharmaceutical composition according to item 50, which is in the form of an enteric-coated tablet. (Item 53) The pharmaceutical composition according to item 50, which is in the form of a capsule containing enteric-coated microtablets. (Item 54) The fumaric acid compound according to any one of items 33 to 53, which is dimethyl fumarate and / or monomethyl fumarate. (Item 55) The fumaric acid compound according to item 54, which is dimethyl fumarate. (Item 56) The administration according to item 49, wherein the dimethyl fumarate is 240 mg twice a day. (Item 57) The administration according to item 49, wherein the dimethyl fumarate is 120 mg twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose. (Item 58) The administration according to item 49, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 59) The administration according to item 49, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 60) The pharmaceutical composition according to any one of items 50 and 55 to 59, which consists essentially of dimethyl fumarate. (Item 61) The pharmaceutical composition according to any one of items 56 to 60, which is in the form of a tablet or a capsule. (Item 62) The pharmaceutical composition according to any one of items 56 to 60, which is in the form of an enteric-coated tablet. (Item 63) The method according to any one of Items 56 to 60, wherein the pharmaceutical composition is in the form of a capsule containing enteric-coated microtablets. (Item 64) The method according to any one of Items 33 to 63, wherein the multiple sclerosis is relapsing multiple sclerosis. (Item 65) A method for treating a patient with multiple sclerosis, comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) monitoring the patient to determine whether the patient has any signs or symptoms suggestive of PML. (Item 66) A method for improving the safety in the treatment of a patient with multiple sclerosis, comprising monitoring a patient being treated with a pharmaceutical composition comprising a fumaric acid compound to determine whether the patient has any signs or symptoms suggestive of PML, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition. (Item 67) The method according to item 65 or item 66, comprising withholding treatment with the fumaric acid compound in the patient at the stage when the first sign or symptom suggesting PML appears in the patient. (Item 68) Furthermore, the method according to any one of items 65 to 67, comprising performing a diagnostic evaluation for PML in the patient at the stage when the first sign or symptom suggesting PML appears in the patient. (Item 69) Furthermore, the method according to item 68, wherein the diagnostic evaluation comprises administering a therapeutic agent to the patient for the treatment of PML when the patient shows PML. (Item 70) Furthermore, the method according to item 67, comprising instructing the patient to continue to look for new signs and symptoms suggesting PML for about 6 months after discontinuation of treatment with the fumaric acid compound. (Item 71) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) notifying the patient that PML has occurred in patients administered dimethyl fumarate comprising the above method. (Item 72) A method for treating a patient with multiple sclerosis, comprising the following (a) Administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) instructing the patient on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient, whatever they may be. The method as described above, including. (Item 73) Furthermore, instructing the patient that the typical symptoms associated with PML are diverse, progress over several days to weeks, and include, as such symptoms, progressive weakness or limb impairment on one side of the body, visual impairment, and changes in thinking, memory, and orientation that lead to confusion and personality changes. The method according to Item 72, including. (Item 74) Furthermore, instructing the patient that the progression of the disorder associated with PML usually results in death or severe physical impairment over several weeks or months. The method according to Item 73, including. (Item 75) A method for improving safety in the treatment of patients with multiple sclerosis, comprising informing a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound that progressive multifocal leukoencephalopathy (PML) has occurred in patients administered dimethyl fumarate; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition, said method. (Item 76) A method for improving safety in the treatment of patients with multiple sclerosis, comprising instructing the importance of contacting the attending physician of a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound if any symptom suggestive of PML occurs in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition, said method. (Item 77) Furthermore, the method according to item 76, comprising instructing the patient that the typical symptoms associated with PML are diverse, progress over several days to weeks, and include progressive weakness or limb impairment on one side of the body, visual disturbances, and changes in thinking, memory, and orientation that cause confusion and personality changes. (Item 78) Furthermore, the method according to item 77, which includes instructing the patient that the progression of the disorder associated with PML usually leads to death or severe physical impairment over a period of several weeks or months. (Item 79) The diagnostic evaluation method according to item 68, which includes an examination for the presence of JC virus DNA in the cerebrospinal fluid of the patient. (Item 80) The signs or symptoms suggesting PML are selected from the group consisting of progressive weakness or limb dysfunction on one side of the body, visual impairment, and changes in thinking, memory, and orientation that cause confusion and personality changes, according to any one of items 65 - 70, 72, 74, 76, and 79. (Item 81) The administration is oral, according to any one of items 65, 71 - 74, and any dependent item of any one of them. (Item 82) The pharmaceutical composition contains a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, according to any one of items 65 - 81. (Item 83) The pharmaceutical composition is in the form of tablets or capsules, according to the method described in item 82. (Item 84) The pharmaceutical composition is in the form of enteric - coated tablets, according to the method described in item 82. (Item 85) The pharmaceutical composition is in the form of capsules containing enteric - coated micro - tablets, according to the method described in item 82. (Item 86) The fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate, according to any one of items 65 - 85. (Item 87) The fumaric acid compound is dimethyl fumarate, according to the method described in item 86. (Item 88) The administration is 240 mg of dimethyl fumarate twice a day, according to the method described in item 81. (Item 89) The administration is the method according to item 81, which is 120 mg of dimethyl fumarate twice a day for 7 days, and then 240 mg of dimethyl fumarate twice a day as a maintenance dose. (Item 90) The administration is the method according to item 81, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 91) The administration is the method according to item 81, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 92) The pharmaceutical composition consists essentially of dimethyl fumarate, and is the method according to any one of items 82 and 87 to 91. (Item 93) The pharmaceutical composition is in the form of tablets or capsules, and is the method according to items 88 to 92. (Item 94) The pharmaceutical composition is in the form of enteric-coated tablets, and is the method according to any one of items 88 to 92. (Item 95) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, and is the method according to any one of items 88 to 92. (Item 96) The multiple sclerosis is relapsing multiple sclerosis, and is the method according to any one of items 65 to 95. (Item 97) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) monitoring the patient to determine whether there are any signs or symptoms suggesting PML in the patient. (Item 98) A method for improving the safety in the treatment of a patient with multiple sclerosis, comprising monitoring the patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate to determine whether there are any signs or symptoms suggesting PML in the patient. (Item 99) The method according to item 97 or item 98, further comprising withholding treatment with the pharmaceutical composition in the patient when the first sign or symptom suggesting PML appears in the patient. (Item 100) The method according to any one of items 97 to 99, further comprising performing a diagnostic evaluation for PML in the patient when the first sign or symptom suggesting PML appears in the patient. (Item 101) The method according to item 100, further comprising administering a therapeutic agent to the patient for the treatment of PML when the diagnostic evaluation indicates PML in the patient. (Item 102) The method according to item 99, further comprising instructing the patient to continue to look for new signs and symptoms suggesting PML for about 6 months after discontinuation of treatment with the pharmaceutical composition. (Item 103) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) notifying the patient that PML has occurred in patients administered dimethyl fumarate. The method as described above. (Item 104) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) instructing the patient on the importance of contacting the patient's attending physician if any symptom suggesting PML occurs in the patient. The method as described above. (Item 105) The method according to item 104, further comprising instructing the patient that typical symptoms associated with PML are diverse, progress over several days to several weeks, and include progressive weakness or limb impairment on one side of the body, visual impairment, and changes in thinking, memory, and orientation that lead to confusion and personality changes. (Item 106) The method according to item 105, further comprising instructing the patient that the progression of the disorder associated with PML usually results in death or severe physical impairment over several weeks or months. (Item 107) A method for improving safety in the treatment of patients with multiple sclerosis, the method comprising notifying a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate that PML has occurred in patients administered dimethyl fumarate. (Item 108) A method for improving safety in the treatment of patients with multiple sclerosis, the method comprising instructing a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient. (Item 109) The method according to item 108, further comprising instructing the patient that typical symptoms associated with PML are diverse, progress over several days to several weeks, and include progressive weakness or limb impairment on one side of the body, visual impairment, and changes in thinking, memory, and orientation that lead to confusion and personality changes. (Item 110) The method according to item 109, further comprising instructing the patient that the progression of the disorder associated with PML usually results in death or severe physical impairment over several weeks or months. (Item 111) The diagnostic evaluation is the method according to item 100, including an examination for the presence of JC virus DNA in the cerebrospinal fluid of the patient. (Item 112) The signs or symptoms suggesting PML are selected from the group consisting of progressive weakness on one side of the body or limb disability, visual impairment, and changes in thinking, memory, and orientation that cause confusion and personality changes, according to any one of items 97 to 102, 104, 106, 108, and 111. (Item 113) The administration is oral, according to any one of items 97, 103 to 106, and any dependent item of any one of them. (Item 114) The pharmaceutical composition contains a pharmaceutically acceptable carrier, according to any one of items 97 to 113. (Item 115) The pharmaceutical composition is in the form of tablets or capsules, according to item 114. (Item 116) The pharmaceutical composition is in the form of enteric-coated tablets, according to item 114. (Item 117) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, according to item 114. (Item 118) The pharmaceutical composition consists essentially of dimethyl fumarate, according to any one of items 97 to 117. (Item 119) The administration is 240 mg of dimethyl fumarate twice a day, according to item 113. (Item 120) The administration is 120 mg of dimethyl fumarate twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose, according to item 113. (Item 121) The pharmaceutical composition consists essentially of dimethyl fumarate, according to item 119 or 120. (Item 122) The method according to item 113, wherein the administration is such that the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 123) The method according to item 113, wherein the administration is such that the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 124) The method according to item 113, wherein the pharmaceutical composition consists essentially of dimethyl fumarate, and the administration is such that the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 125) The method according to item 113, wherein the pharmaceutical composition consists essentially of dimethyl fumarate, and the administration is such that the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 126) The method according to any one of items 119 to 125, wherein the pharmaceutical composition is in the form of tablets or capsules. (Item 127) The method according to any one of items 119 to 125, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 128) The method according to any one of items 119 to 125, wherein the pharmaceutical composition is in the form of capsules containing enteric-coated microtablets. (Item 129) The method according to any one of items 97 to 128, wherein the multiple sclerosis is relapsing multiple sclerosis. (Item 130) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion compound, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) After repeatedly administering the pharmaceutical composition to the patient for 6 months, and then every 6 to 12 months thereafter, obtaining a complete blood count value including the lymphocyte count The method as described above, including (Item 131) Furthermore, when the state where the lymphocyte count of the patient is less than 0.5×10 9 / L continues for more than 6 months, interrupting the administration of the pharmaceutical composition to the patient, the method according to Item 130. (Item 132) Furthermore, the method according to Item 131, including measuring the lymphocyte count of the patient until lymphopenia is resolved in the patient. (Item 133) The administration is performed orally, the method according to Items 130 to 132. (Item 134) The pharmaceutical composition contains a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, the method according to any one of Items 130 to 133. (Item 135) The pharmaceutical composition is in the form of tablets or capsules, the method according to Item 134. (Item 136) The pharmaceutical composition is in the form of enteric-coated tablets, the method according to Item 134. (Item 137) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, the method according to Item 134. (Item 138) The fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate, the method according to any one of Items 130 to 137. (Item 139) The fumaric acid compound is dimethyl fumarate, the method according to Item 138. (Item 140) The administration is 240 mg of dimethyl fumarate twice a day, the method according to Item 133. (Item 141) The administration is the method according to item 133, which is 120 mg of dimethyl fumarate twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose. (Item 142) The administration is the method according to item 133, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 143) The administration is the method according to item 133, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 144) The pharmaceutical composition consists essentially of dimethyl fumarate, and is the method according to any one of items 134 and 139 to 143. (Item 145) The pharmaceutical composition is in the form of tablets or capsules, and is the method according to any one of items 140 to 144. (Item 146) The pharmaceutical composition is in the form of enteric-coated tablets, and is the method according to any one of items 140 to 144. (Item 147) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, and is the method according to any one of items 140 to 144. (Item 148) The multiple sclerosis is relapsing multiple sclerosis, and is the method according to any one of items 130 to 147. (Item 149) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition containing a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) After repeatedly administering the pharmaceutical composition to the patient for 6 months, and then every 6 to 12 months thereafter, obtaining a complete blood count value including the lymphocyte count The method as described above, including (Item 150) Furthermore, when the state where the lymphocyte count of the patient is less than 0.5×10 9 / L continues for more than 6 months, interrupting the administration of the pharmaceutical composition to the patient, the method according to Item 149. (Item 151) Furthermore, including measuring the lymphocyte count of the patient until lymphopenia is resolved in the patient, the method according to Item 150. (Item 152) The administration is oral, the method according to any one of Items 149 to 151. (Item 153) The pharmaceutical composition contains a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, the method according to any one of Items 149 to 152. (Item 154) The pharmaceutical composition is in the form of tablets or capsules, the method according to Item 153. (Item 155) The pharmaceutical composition is in the form of enteric-coated tablets, the method according to Item 153. (Item 156) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, the method according to Item 153. (Item 157) The fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate, the method according to any one of Items 149 to 156. (Item 158) The fumaric acid compound is dimethyl fumarate, the method according to Item 157. (Item 159) The administration is 240 mg of dimethyl fumarate twice a day, the method according to Item 152. (Item 160) The administration is the method according to item 152, wherein dimethyl fumarate is administered at 120 mg twice a day for 7 days, and then at 240 mg twice a day as a maintenance dose. (Item 161) The administration is the method according to item 152, wherein the total amount of fumaric acid compounds per day does not exceed 720 mg. (Item 162) The administration is the method according to item 152, wherein the total amount of fumaric acid compounds per day does not exceed 480 mg. (Item 163) The pharmaceutical composition consists essentially of dimethyl fumarate, and is the method according to any one of items 153 and 158 - 162. (Item 164) The pharmaceutical composition is in the form of tablets or capsules, and is the method according to any one of items 159 - 163. (Item 165) The pharmaceutical composition is in the form of enteric - coated tablets, and is the method according to any one of items 159 - 163. (Item 166) The pharmaceutical composition is in the form of capsules containing enteric - coated micro - tablets, and is the method according to any one of items 159 - 163. (Item 167) The multiple sclerosis is relapsing multiple sclerosis, and is the method according to any one of items 149 - 166. (Item 168) A method for treating a patient with multiple sclerosis, comprising the following (a) Administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including the lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months, and then every 6 to 12 months thereafter The method as described above, including (Item 169) Furthermore, when the state where the lymphocyte count of the patient is less than 0.5×10 9 / L persists for more than 6 months, interrupting the administration of the pharmaceutical composition to the patient, the method according to Item 168 (Item 170) Furthermore, measuring the lymphocyte count of the patient until lymphopenia is resolved in the patient, the method according to Item 169 (Item 171) The administration is performed orally, the method according to any one of Items 168 to 170 (Item 172) The pharmaceutical composition contains a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, the method according to any one of Items 168 to 171 (Item 173) The pharmaceutical composition is in the form of tablets or capsules, the method according to Item 172 (Item 174) The pharmaceutical composition is in the form of enteric-coated tablets, the method according to Item 172 (Item 175) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, the method according to Item 172 (Item 176) The method according to any one of items 168 to 175, wherein the fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate. (Item 177) The method according to item 176, wherein the fumaric acid compound is dimethyl fumarate. (Item 178) The method according to item 171, wherein the administration is 240 mg of dimethyl fumarate twice a day. (Item 179) The method according to item 171, wherein the administration is 120 mg of dimethyl fumarate twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose. (Item 180) The method according to item 171, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 181) The method according to item 171, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 182) The method according to any one of items 172 and 177 to 181, wherein the pharmaceutical composition consists essentially of dimethyl fumarate. (Item 183) The method according to any one of items 178 to 182, wherein the pharmaceutical composition is in the form of tablets or capsules. (Item 184) The method according to any one of items 178 to 182, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 185) The method according to any one of items 178 to 182, wherein the pharmaceutical composition is in the form of capsules containing enteric-coated microtablets. (Item 186) The method according to any one of items 168 to 185, wherein the multiple sclerosis is relapsing multiple sclerosis. (Item 187) A method for treating a patient with multiple sclerosis, comprising the following (a) Administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) Obtaining a complete blood count value including lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months, and then every 6 to 12 months thereafter The method as described above. (Item 188) Furthermore, when the state where the lymphocyte count of the patient is less than 0.5×10 9 / L continues for more than 6 months, interrupting the administration of the pharmaceutical composition to the patient, the method according to item 187. (Item 189) Furthermore, measuring the lymphocyte count of the patient until lymphopenia is resolved in the patient, the method according to item 188. (Item 190) The administration is performed orally, the method according to any one of items 187 to 189. (Item 191) The pharmaceutical composition contains a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, the method according to any one of items 187 to 190. (Item 192) The pharmaceutical composition is in the form of tablets or capsules, the method according to item 191. (Item 193) The pharmaceutical composition is in the form of enteric-coated tablets, the method according to item 191. (Item 194) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, the method according to item 191. (Item 195) The fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate, the method according to any one of items 187 to 194. (Item 196) The fumaric acid compound is dimethyl fumarate, the method according to item 195. (Item 197) The administration is the method according to item 190, wherein dimethyl fumarate is administered at 240 mg twice a day. (Item 198) The administration is the method according to item 190, wherein dimethyl fumarate is administered at 120 mg twice a day for 7 days, followed by dimethyl fumarate at 240 mg twice a day as a maintenance dose. (Item 199) The administration is the method according to item 190, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 200) The administration is the method according to item 190, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 201) The pharmaceutical composition consists essentially of dimethyl fumarate, and is the method according to any one of items 191 and 196 - 200. (Item 202) The pharmaceutical composition is in the form of tablets or capsules, and is the method according to any one of items 197 - 201. (Item 203) The pharmaceutical composition is in the form of enteric - coated tablets, and is the method according to any one of items 197 - 201. (Item 204) The pharmaceutical composition is in the form of capsules containing enteric - coated micro - tablets, and is the method according to any one of items 197 - 201. (Item 205) The multiple sclerosis is relapsing multiple sclerosis, and is the method according to any one of items 187 - 204. (Item 206) A method for treating a patient with multiple sclerosis, comprising the following (a) Before starting the treatment of the patient using a pharmaceutical composition containing a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) when it is found that the lymphocyte count is lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate regarding the other causes; and (b) Administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition, The method as described above, comprising (Item 207) A method for treating a patient with multiple sclerosis, comprising the following (a) Repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) Obtaining a complete blood count value including lymphocyte count every three months after starting treatment of the patient with the pharmaceutical composition, The method as described above, comprising (Item 208) Furthermore, when it is confirmed by repeated tests three months later that the lymphocyte count of the patient is less than 0.7×10 9 / L, the method according to Item 207, comprising stopping administering the pharmaceutical composition to the patient. (Item 209) A method for treating a patient with multiple sclerosis, comprising the following (a) Repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) After administration of the pharmaceutical composition, if the patient develops lymphopenia, carefully monitoring the patient for signs or symptoms of the emergence of a new neurological disorder The method as described above, comprising the above. (Item 210) A method for improving the safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has developed lymphopenia and who is being treated with a pharmaceutical composition comprising a fumaric acid compound for signs or symptoms of the emergence of a new neurological disorder; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition, the method as described above. (Item 211) The method according to item 209 or 210, wherein the signs or symptoms include motor dysfunction and cognitive or psychiatric symptoms. (Item 212) Furthermore, the following: If PML is suspected, immediately withhold treatment with the pharmaceutical composition and conduct further evaluation The method according to any one of items 209 to 211, comprising the above. (Item 213) A method for treating multiple sclerosis in patients being treated with a disease-modifying therapy for multiple sclerosis other than a pharmaceutical composition containing a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; the method comprising the following steps: (a) Stopping the administration of the disease-modifying therapy for multiple sclerosis to the patient; (b) Considering the half-life and mode of action of the disease-modifying therapy for multiple sclerosis for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) Administering to the patient the pharmaceutical composition containing the fumaric acid compound The method as described above, including in the order described. (Item 214) A method for treating multiple sclerosis in patients being treated with interferon or glatiramer acetate, the method comprising: (a) Discontinuing the administration of interferon or glatiramer acetate to the patient; and (b) Immediately after the discontinuation, starting the administration of a pharmaceutical composition containing a fumaric acid compound to the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition, the method as described above. (Item 215) Furthermore, the method according to item 213 or 214, including performing an MRI on the patient before the start of the administration of the pharmaceutical composition containing the fumaric acid compound to the patient. (Item 216) A method for treating a patient with multiple sclerosis, comprising the following: (a) Administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) Performing a blood test and measuring the patient's white blood cell count before the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of the patient with the pharmaceutical composition comprising the fumaric acid compound; and (c) Considering terminating the treatment with the pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during the treatment The method as described above. (Item 217) The method according to any one of Items 206, 207, 209, 213, 214, or 216, wherein the administration of the pharmaceutical composition is performed orally. (Item 218) The method according to any one of Items 206 to 217, wherein the pharmaceutical composition comprises a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier. (Item 219) The method according to Item 218, wherein the pharmaceutical composition is in the form of tablets or capsules. (Item 220) The method according to Item 218, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 221) The method according to Item 218, wherein the pharmaceutical composition is in the form of capsules containing enteric-coated microtablets. (Item 222) The method according to any one of Items 206 to 221, wherein the fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate. (Item 223) The method according to item 222, wherein the fumaric acid compound is dimethyl fumarate. (Item 224) The method according to item 217, wherein the administration is 240 mg of dimethyl fumarate twice a day. (Item 225) The method according to item 217, wherein the administration is 120 mg of dimethyl fumarate twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose. (Item 226) The method according to item 217, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 227) The method according to item 217, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 228) The method according to any one of items 218 and 223 to 227, wherein the pharmaceutical composition consists essentially of dimethyl fumarate. (Item 229) The method according to any one of items 224 to 228, wherein the pharmaceutical composition is in the form of tablets or capsules. (Item 230) The method according to any one of items 224 to 228, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 231) The method according to any one of items 224 to 228, wherein the pharmaceutical composition is in the form of capsules containing enteric-coated microtablets. (Item 232) The method according to any one of items 206 to 231, wherein the multiple sclerosis is relapsing multiple sclerosis. (Item 233) A method for treating a patient with multiple sclerosis, comprising the following (a) Before starting the treatment of the patient with a pharmaceutical composition containing a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) when it is found that the lymphocyte count is lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate for the other causes; and (b) Administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition, The method as described above, comprising (Item 234) A method for treating a patient with multiple sclerosis, comprising the following (a) Repeatedly administering a pharmaceutical composition containing a fumaric acid compound to the patient; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) Obtaining a complete blood count value including the lymphocyte count every three months after starting the treatment of the patient with the pharmaceutical composition, The method as described above, comprising (Item 235) Furthermore, when it is confirmed by repeated examination three months later that the lymphocyte count of the patient is less than 0.7×10 9 / L, the method according to Item 234, comprising stopping administering the pharmaceutical composition to the patient. (Item 236) A method for treating a patient with multiple sclerosis, comprising the following (a) Administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) After administration of the pharmaceutical composition, if the patient develops lymphopenia, carefully monitoring the patient for signs or symptoms of the emergence of a new neurological disorder The method as described above, comprising the above. (Item 237) A method for improving the safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has developed lymphopenia and who is being treated with a pharmaceutical composition comprising a fumaric acid compound for signs or symptoms of the emergence of a new neurological disorder; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition, the above method. (Item 238) The method according to item 236 or 237, wherein the signs or symptoms include motor dysfunction and cognitive or psychiatric symptoms. (Item 239) Furthermore, the following: If PML is suspected, immediately withhold treatment with the above pharmaceutical composition and conduct further evaluation The method according to any one of items 236 to 238, comprising the above. (Item 240) A method for treating multiple sclerosis in patients being treated with a disease-modifying therapy for multiple sclerosis other than a pharmaceutical composition containing a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; the method comprising the following steps: (a) Discontinuing administration of the disease-modifying therapy for multiple sclerosis to the patient; (b) Considering the half-life and mode of action of the disease-modifying therapy for multiple sclerosis for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) Administering to the patient the pharmaceutical composition containing the fumaric acid compound The method as described above, comprising the steps in the order described. (Item 241) A method for treating multiple sclerosis in patients being treated with interferon or glatiramer acetate, the method comprising: (a) Discontinuing administration of interferon or glatiramer acetate to the patient; and (b) Immediately after the discontinuation, starting administration of a pharmaceutical composition containing a fumaric acid compound to the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition, the method as described above. (Item 242) The method according to item 240 or 241, further comprising performing an MRI on the patient before the start of the administration of the pharmaceutical composition containing the fumaric acid compound to the patient. (Item 243) A method for treating a patient with multiple sclerosis, comprising the following: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) performing a blood test and measuring the white blood cell count of the patient before the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of the patient with the pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuing the treatment with the pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during the treatment The method as described above. (Item 244) The administration of the pharmaceutical composition is performed orally, according to the method described in any one of Items 233, 234, 236, 240, 241, or 243. (Item 245) The pharmaceutical composition comprises a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, according to the method described in any one of Items 233 to 244. (Item 246) The pharmaceutical composition is in the form of tablets or capsules, according to the method described in Item 245. (Item 247) The pharmaceutical composition is in the form of enteric-coated tablets, according to the method described in Item 245. (Item 248) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, according to the method described in Item 245. (Item 249) The fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate, according to the method described in any one of Items 233 to 248. (Item 250) The method according to item 249, wherein the fumaric acid compound is dimethyl fumarate. (Item 251) The method according to item 244, wherein the administration is twice a day with 240 mg of dimethyl fumarate. (Item 252) The method according to item 244, wherein the administration is twice a day with 120 mg of dimethyl fumarate for 7 days, followed by twice a day with 240 mg of dimethyl fumarate as a maintenance dose. (Item 253) The method according to item 244, wherein the total amount of the fumaric acid compound per day does not exceed 720 mg. (Item 254) The method according to item 244, wherein the total amount of the fumaric acid compound per day does not exceed 480 mg. (Item 255) The method according to any one of items 245 and 250 to 254, wherein the pharmaceutical composition consists essentially of dimethyl fumarate. (Item 256) The method according to any one of items 251 to 255, wherein the pharmaceutical composition is in the form of tablets or capsules. (Item 257) The method according to any one of items 251 to 255, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 258) The method according to any one of items 251 to 255, wherein the pharmaceutical composition is in the form of capsules containing enteric-coated microtablets. (Item 259) The method according to any one of items 233 to 258, wherein the multiple sclerosis is relapsing multiple sclerosis. (Item 260) A method for treating a patient with multiple sclerosis, comprising the following (a) Before starting the treatment of the patient with a pharmaceutical composition containing a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) when it is found that the lymphocyte count is lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate regarding such other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition, The method as described above. (Item 261) A method for treating a patient with multiple sclerosis, comprising the following (a) repeatedly administering to the patient a pharmaceutical composition containing a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count every three months after starting the treatment of the patient with the pharmaceutical composition, The method as described above. (Item 262) Furthermore, when the lymphocyte count of the patient is 0.7×10 9The method according to item 261, which includes discontinuing the administration of the pharmaceutical composition to the patient when it is confirmed by repeated tests after 3 months that it is less than / L. (Item 263) A method for treating a patient with multiple sclerosis, comprising the following (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) after administration of the pharmaceutical composition, if lymphopenia occurs in the patient, carefully monitoring the patient for signs or symptoms of the appearance of a new neurological disorder The above method. (Item 264) A method for improving the safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has been treated with a pharmaceutical composition containing a fumaric acid compound and has developed lymphopenia for signs or symptoms of the appearance of a new neurological disorder; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition, the above method. (Item 265) The method according to item 263 or 264, wherein the sign or symptom includes motor dysfunction and cognitive or mental symptoms. (Item 266) Furthermore, the following: When PML is suspected, immediately withhold treatment with the pharmaceutical composition and conduct further evaluation The method according to any one of items 263 to 265, including (Item 267) A method for treating multiple sclerosis in a patient being treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical composition containing a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; the method comprises the following steps: (a) Stopping the administration of the multiple sclerosis disease-modifying therapy to the patient; (b) Considering the half-life and mode of action of the multiple sclerosis disease-modifying therapy for the purpose of avoiding further immune effects, but at the same time minimizing the risk of disease reactivation; and (c) Administering the pharmaceutical composition containing the fumaric acid compound to the patient The method as described, including in the order stated. (Item 268) A method for treating multiple sclerosis in a patient being treated with interferon or glatiramer acetate, the method comprising the following: (a) Discontinuing the administration of interferon or glatiramer acetate to the patient; and (b) Immediately after such discontinuation, initiating the administration of a pharmaceutical composition containing a fumaric acid compound to the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition. The method as described above, including . (Item 269) Furthermore, the method according to Item 267 or 268, including performing an MRI on the patient before the start of the administration of the pharmaceutical composition containing the fumaric acid compound to the patient. (Item 270) A method for treating a patient with multiple sclerosis, comprising the following: (a) Administering to the patient a pharmaceutical composition containing a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) Performing a blood test and measuring the white blood cell count of the patient before the first administration of the pharmaceutical composition containing the fumaric acid compound to the patient and periodically during the treatment of the patient with the pharmaceutical composition containing the fumaric acid compound; and (c) Considering discontinuing the treatment with the pharmaceutical composition containing the fumaric acid compound if the white blood cell count decreases during the treatment. The method as described above, including the above steps. (Item 271) The administration of the pharmaceutical composition is carried out orally, by the method according to any one of Items 260, 261, 263, 267, 268, or 270. (Item 272) The pharmaceutical composition contains a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, by the method according to any one of Items 260 to 272. (Item 273) The pharmaceutical composition is in the form of tablets or capsules, by the method according to Item 272. (Item 274) The pharmaceutical composition is in the form of enteric-coated tablets, by the method according to Item 272. (Item 275) The pharmaceutical composition is in the form of capsules containing enteric-coated microtablets, by the method according to Item 272. (Item 276) The fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate, by the method according to any one of Items 260 to 275. (Item 277) The fumaric acid compound is dimethyl fumarate, by the method according to Item 276. (Item 278) The administration is 240 mg of dimethyl fumarate twice a day, by the method according to Item 271. (Item 279) The administration is 120 mg of dimethyl fumarate twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose, by the method according to Item 271. (Item 280) The administration is such that the total amount of fumaric acid compound per day does not exceed 720 mg, by the method according to Item 271. (Item 281) The administration is such that the total amount of fumaric acid compound per day does not exceed 480 mg, by the method according to Item 271. (Item 282) The method according to any one of items 272 and 277 to 281, wherein the pharmaceutical composition consists essentially of dimethyl fumarate. (Item 283) The method according to any one of items 278 to 282, wherein the pharmaceutical composition is in the form of tablets or capsules. (Item 284) The method according to any one of items 278 to 282, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 285) The method according to any one of items 278 to 282, wherein the pharmaceutical composition is in the form of capsules containing enteric-coated microtablets. (Item 286) The method according to any one of items 260 to 285, wherein the multiple sclerosis is relapsing multiple sclerosis. (Item 287) A method for treating a patient with multiple sclerosis, comprising the following (a) Before starting the treatment of the patient with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate: (i) performing a complete blood count including lymphocyte count; and (ii) when it is found that the lymphocyte count is lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate for the other causes; and (b) administering the pharmaceutical composition to the patient, The method as described above. (Item 288) A method for treating a patient with multiple sclerosis, comprising the following (a) repeatedly administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) obtaining a complete blood count value including lymphocyte count every 3 months after starting the treatment of the patient with the pharmaceutical composition, The method as described above. (Item 289) Furthermore, when the lymphocyte count of the patient is 0.7×10 9The method according to item 288, which includes discontinuing the administration of the pharmaceutical composition to the patient when it is confirmed by repeated tests after 3 months that it is less than / L. (Item 290) A method for treating a patient with multiple sclerosis, comprising the following (a) Administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) After administration of the pharmaceutical composition, if lymphopenia occurs in the patient, carefully monitoring the patient for signs or symptoms of the appearance of new neurological dysfunction The method as described above. (Item 291) A method for improving the safety in the treatment of a patient with multiple sclerosis, which includes monitoring a patient with multiple sclerosis who has been treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate and has developed lymphopenia for signs or symptoms of the appearance of new neurological dysfunction. (Item 292) The signs or symptoms include motor dysfunction and cognitive or mental symptoms, the method according to item 290 or 291. (Item 293) Furthermore, the following: If PML is suspected, immediately withhold the treatment using the pharmaceutical composition and conduct further evaluation The method according to any one of items 290 to 292, which includes the above. (Item 294) A method for treating multiple sclerosis in a patient who has been treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; the method includes the following steps: (a) Stopping the administration of the multiple sclerosis disease-modifying therapy to the patient; (b) Considering the half-life and mode of action of the multiple sclerosis disease-modifying therapy for the purpose of avoiding further immune effects, but at the same time minimizing the risk of disease reactivation; and (c) Administering the pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate The method as described above, including in the order described. (Item 295) A method for treating multiple sclerosis in a patient being treated with interferon or glatiramer acetate, the method comprising: (a) Discontinuing the administration of interferon or glatiramer acetate to the patient; and (b) Immediately after the discontinuation, initiating the administration of a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate to the patient The method as described above, including. (Item 296) Furthermore, before the start of the administration of the pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate to the patient, performing an MRI on the patient, the method according to Item 294 or 295. (Item 297) A method for treating a patient with multiple sclerosis, comprising: (a) Administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) Before the first administration of the pharmaceutical composition to the patient and periodically during the treatment of the patient with the pharmaceutical composition, performing a blood test to measure the white blood cell count of the patient; and (c) Considering stopping the treatment with the pharmaceutical composition if the white blood cell count decreases during the treatment The method as described above, including. (Item 298) The administration is oral, the method according to any one of Items 287, 288, 290, 294, 295, or 297. (Item 299) The pharmaceutical composition contains a therapeutically effective amount of the fumaric acid compound and a pharmaceutically acceptable carrier, the method according to any one of Items 287 to 298. (Item 300) The pharmaceutical composition is in the form of tablets or capsules, the method according to Item 299. (Item 301) The method according to item 299, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 302) The method according to item 299, wherein the pharmaceutical composition is in the form of a capsule containing enteric-coated microtablets. (Item 303) The method according to any one of items 287 to 302, wherein the fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate. (Item 304) The method according to item 303, wherein the fumaric acid compound is dimethyl fumarate. (Item 305) The method according to item 298, wherein the administration is 240 mg of dimethyl fumarate twice a day. (Item 306) The method according to item 298, wherein the administration is 120 mg of dimethyl fumarate twice a day for 7 days, followed by 240 mg of dimethyl fumarate twice a day as a maintenance dose. (Item 307) The method according to item 298, wherein the total amount of the fumaric acid compound administered per day does not exceed 720 mg. (Item 308) The method according to item 298, wherein the total amount of the fumaric acid compound administered per day does not exceed 480 mg. (Item 309) The method according to any one of items 299 and 304 to 308, wherein the pharmaceutical composition consists essentially of dimethyl fumarate. (Item 310) The method according to any one of items 305 to 309, wherein the pharmaceutical composition is in the form of tablets or capsules. (Item 311) The method according to any one of items 305 to 309, wherein the pharmaceutical composition is in the form of enteric-coated tablets. (Item 312) The method according to any one of items 305 to 309, wherein the pharmaceutical composition is in the form of a capsule containing enteric-coated microtablets. (Item 313) The method according to any one of items 287 to 312, wherein the multiple sclerosis is relapsing multiple sclerosis.

[0113] 3.1 Terms To make the understanding of the specification and claims clear and consistent, the following definitions are provided:

[0114] As used herein, the term "alkanediyl" refers to a straight or branched alkyl chain having, for example, 1 to 6 carbon atoms. Representative examples of alkanediyl groups include, but are not limited to, -CH2-, -(CH2)2, -CH(CH3)-, -(CH2)3-, -CH2CH(CH3)-, -CH(CH3)CH2-, -CH(C2H5)-, -C(CH3)2-, -(CH2)4-, -(CH2)2CH(CH3)-, -CH2CH(CH3)CH2-, -CH(CH3)(CH2)2-, -CH(C2H5)CH2-, -CH2CH(C2H5)-, -C(CH3)2CH2-, -CH2C(CH3)2-, -CH(CH3)CH(CH3), -CH(C3H7)-, -(CH2)5, -(CH2)3CH(CH3), -(CH2)2CH(CH3)CH2-, -CH2CHCH3(CH2)2-, -CH2C(CH3)2CH2-, -(CH2)2C(CH3)2-, -(CH2)6-, -(CH2)4CH(CH3)-, -(CH2)3CH(CH3)CH2-, -CH2CHCH3(CH2)3-, -(CH2)3C(CH3)2-, and -(CH2)2C(CH3)2CH2-.

[0115] As used herein, the term "alkenyl" refers to a monovalent straight or branched hydrocarbon having 2 to 6 carbons and at least one carbon-carbon double bond. Representative examples of alkenyl groups include, but are not limited to, -CH=CH2, -CH=CH-CH3, -CH2-CH=CH-CH3, or -CH(CH3)-CH=CH-CH3.

[0116] As used herein, the term "alkyl" refers to a fully saturated, branched or unbranched hydrocarbon moiety. In one embodiment, alkyl contains 1 to 20 carbon atoms, 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Representative examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, or n-decyl.

[0117] As used herein, the term "alkynyl" refers to a monovalent straight or branched chain hydrocarbon having 2 to 6 carbons and at least one carbon-carbon triple bond. Representative examples of alkynyl groups include, but are not limited to, 2-propynyl, 3-butynyl, 2-butynyl, 4-pentynyl, 3-pentynyl.

[0118] As used herein, the term "aryl" refers to a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having, for example, 5 to 14 carbon atoms in the ring moiety. In one embodiment, aryl refers to monocyclic and bicyclic aromatic hydrocarbon groups having 6 to 10 carbon atoms. Representative examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthracenyl.

[0119] As used herein, the term "arylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms in the group, typically the terminal or sp 3 hydrogen atom bonded to a carbon atom is replaced by an aryl group. Representative examples of arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, or 2-naphthophenylethan-1-yl. In certain embodiments, the arylalkyl group is C7-30 Arylalkyl, for example, the alkyl moiety of the arylalkyl group is C 1-10 and the aryl moiety is C 6-20 In certain embodiments, the arylalkyl group is C 6-18 Arylalkyl, for example, the alkyl moiety of the arylalkyl group is C 1-8 and the aryl moiety is C 6-10 In certain embodiments, the arylalkyl group is C 7-12 arylalkyl.

[0120] As used herein, the term "alkyl linker" refers to a C1, C2, C3, C4, C5, or C6 straight-chain (linear) saturated aliphatic hydrocarbon group and a C3, C4, C5, or C6 branched-chain saturated aliphatic hydrocarbon group. In one embodiment, the C 1-6 alkyl linker is a C1, C2, C3, C4, C5, or C6 alkyl linker group. Representative examples of alkyl linkers include moieties having 1 to 6 carbon atoms, such as methyl (-CH2-), ethyl (-CH2CH2-), n-propyl (-CH2CH2CH2-), i-propyl (-CHCH3CH2-), n-butyl (-CH2CH2CH2CH2-), s-butyl (-CHCH3CH2CH2-), i-butyl (-C(CH3)2CH2-), n-pentyl (-CH2CH2CH2CH2CH2-), s-pentyl (-CHCH3CH2CH2CH2-), or n-hexyl (-CH2CH2CH2CH2CH2CH2-), etc., but are not limited thereto. The term "substituted alkyl linker" refers to an alkyl linker in which one or more hydrogens on one or more carbons of the hydrocarbon backbone are replaced by substituents. Such substituents do not change the sp 3 hybridization of the carbon atoms to which they are attached, and such substituents include those listed below in the definition of the term "substituted".

[0121] As used herein, the term "carbocyclic ring" refers to any stable monocyclic, bicyclic, or tricyclic ring having the specified number of carbons, which may be saturated or unsaturated. In one embodiment, C 3-14 The carbocyclic ring is intended to include monocyclic, bicyclic, tricyclic, or spirocyclic (monocyclic or polycyclic) rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 carbon atoms. Representative examples of carbocyclic rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl, cyclooctyl, cyclooctenyl, cyclooctadienyl, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, tetrahydronaphthyl, octahydropentalene, octahydro-1H-indene, bicyclo[2.2.2]octane, spiro[3.4]octane, spiro[4.5]decane, spiro[4.5]deca-1,6-diene, and dispiro[2.2.4.2]dodecane. In one embodiment, the bridge that connects non-adjacent carbon atoms to form a tricyclic ring is a C1 or C2 bridge. When the ring is bridged, substituents described for the ring may also be present on the bridge.

[0122] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated cyclic alkyl group. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, or cyclohexane. In one embodiment, the cycloalkyl group is C 3-15 cycloalkyl, C 3-12 cycloalkyl, or C 3-8 cycloalkyl.

[0123] As used herein, the term "cycloalkylalkyl" refers to a carbon atom in the group, typically a terminal or sp 3An acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom is replaced by a cycloalkyl group is shown. In certain embodiments, the cycloalkylalkyl group is C 4-30 cycloalkylalkyl, for example, the alkyl portion of the cycloalkylalkyl group is C 1-10 and the cycloalkyl portion is C 3-20 Another embodiment, the cycloalkylalkyl group is C 3-20 cycloalkylalkyl, for example, the alkyl portion of the cycloalkylalkyl group is C 1-8 and the cycloalkyl portion is C 3-12 In certain embodiments, the cycloalkylalkyl group is C 4-12 cycloalkylalkyl.

[0124] As used herein, the term "deuterium enrichment" refers to the ratio of the isotopic abundance of deuterium to the natural abundance in a given sample of a compound.

[0125] As used herein, the term "deuterium incorporation percentage" refers to the percentage of molecules having deuterium at a specific position among the total amount of molecules including deuteration and non-deuteration in a given sample of a compound.

[0126] As used herein, the terms "deuterated methyl" and "deuterated ethyl" refer to a methyl group and an ethyl group having at least one deuterium atom, respectively. Examples of deuterated methyl include -CDH2, -CD2H, and -CD3. Examples of deuterated ethyl include, but are not limited to, -CHDCH3, -CD2CH3, -CHDCDH2, -CH2CD3.

[0127] As used herein, the term "halogen" refers to fluoro, chloro, bromo, or iodo.

[0128] As used herein, the term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and certain associated hydrogen atoms) in the group are independently replaced by heteroatom groups, either by itself or as part of another substituent. Examples of heteroatom groups include, but are not limited to, -O-, -S-, -O-O-, -S-S-, -O-S-, -NR', =N-N=, -N=N-, -N=N-NR'-,-PR'-, -P(O)2-, -POR'-, -O-P(O)2-, -SO-, -SO2-, and -Sn(R')2-, where each R' is independently hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 6-12 aryl, substituted C 6-12 aryl, C 7-18 arylalkyl, substituted C 7-18 arylalkyl, C 3-7 cycloalkyl, substituted C 3-7 cycloalkyl, C 3-7 heterocycloalkyl, substituted C 3-7 heterocycloalkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 6-12 heteroaryl, substituted C 6-12 heteroaryl, C 7-18 heteroarylalkyl, or substituted C 7-18 heteroarylalkyl. In one embodiment, C 1-6 heteroalkyl is, for example, a C where at least one carbon atom (and certain associated hydrogen atoms) in the group is replaced by a heteroatom group 1-6 alkyl group. In certain embodiments, C 1-6 heteroalkyl includes, for example, groups having 5 carbon atoms and 1 heteroatom, groups having 4 carbon atoms and 2 heteroatoms, and the like. In one embodiment, each R' is independently hydrogen or C 1-3 alkyl. In another embodiment, the heteroatom group is -O-, -S-, -NH-, -N(CH3)-, or -SO2-. In certain embodiments, the heteroatom group is -O-.

[0129] As used herein, the term "heteroaryl" refers to, for example, a monocyclic, bicyclic, or tricyclic ring system having 5 to 14 members, which ring system has 1 to 10 heteroatoms independently selected from N, O, or S, where N and S may optionally be oxidized to various oxidation states, and at least one ring of the ring system is aromatic. In one embodiment, heteroaryl is monocyclic and is a 5- or 6-membered ring. Representative examples of monocyclic heteroaryl groups include, but are not limited to, pyridyl, thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, and tetrazolyl. In another embodiment, heteroaryl is bicyclic and is an 8- to 10-membered ring. Representative examples of bicyclic heteroaryl groups include, but are not limited to, indolyl, benzofuranyl, quinolyl, isoquinolyl, indazolyl, indolinyl, isoindryl, indolizinyl, benzimidazolyl, quinolinyl, 5,6,7,8-tetrahydroquinoline, and 6,7-dihydro-5H-pyrrolo[3,2-d]pyrimidine.

[0130] As used herein, the term "heteroarylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms, typically a terminal or sp 3 hydrogen atom bonded to a carbon atom is replaced by a heteroaryl group. In certain embodiments, the heteroarylalkyl group is C 7-12 heteroarylalkyl, for example, where the alkyl portion of the heteroarylalkyl group is C 1-2 and the heteroaryl portion is C 6-10 is.

[0131] As used herein, the term "heterocyclic ring" refers to any (saturated or partially unsaturated) ring structure having at least one ring heteroatom (e.g., N, O, or S). Examples of heterocyclic rings include, but are not limited to, morpholine, pyrrolidine, tetrahydrothiophene, piperidine, piperazine, and tetrahydrofuran.

[0132] As used herein, the term "heterocycloalkyl" refers to a saturated or unsaturated cyclic alkyl group in which one or more carbon atoms (and certain attendant hydrogen atoms) in the group are independently replaced by one or more heteroatom groups; or a group in which one or more carbon atoms (and certain attendant hydrogen atoms) in the parent aromatic ring system are independently replaced by one or more heteroatom groups such that the ring system no longer has even a single aromatic ring. Representative examples of heteroatoms replacing carbon atoms (s) include, but are not limited to, N, P, O, S, and Si. Representative examples of heterocycloalkyl groups include, but are not limited to, epoxide, azirine, thiulane, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidine, and quinuclidine. In one embodiment, the heterocycloalkyl group is C 5-10 heterocycloalkyl, C 5-8 is heterocycloalkyl. In certain embodiments, the heterocycloalkyl group is C 5-6 is heterocycloalkyl.

[0133] As used herein, the term "heterocycloalkylalkyl" refers to an acyclic alkyl group in which one of the carbon atoms, typically a terminal or sp 3 hydrogen atom bonded to the carbon atom is replaced by a heterocycloalkyl group. In certain embodiments, the heterocycloalkylalkyl group is C 7-12 is heterocycloalkylalkyl, e.g., the alkyl portion of the heterocycloalkylalkyl group is C 1-2 and the heterocycloalkyl portion is C 6-10 is.

[0134] The term "isotopically substituted" as used herein refers to an isotopically enriched fumaric acid compound.

[0135] The term "isotopically enriched" as used herein refers to an atom having an isotopic composition different from the natural isotopic composition. In one embodiment, an "isotopically enriched" fumaric acid compound has at least one atom having an isotopic composition different from the natural isotopic composition.

[0136] The term "isotopic composition" as used herein refers to the amount of each isotope present in a given atom.

[0137] The term "pharmaceutically acceptable salt", as used herein, refers to salts formed from pharmaceutically acceptable non-toxic acids or bases, such inorganic acids and bases as well as organic acids and bases being examples of such acids or bases. Suitable pharmaceutically acceptable base addition salts of the fumaric acid compounds provided herein include metal salts made from aluminum, calcium, lithium, magnesium, potassium, sodium, and zinc, or organic salts made from lysine, Ν,Ν'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine, but are not limited thereto. Suitable non-toxic acids include inorganic acids and organic acids, such as acetic acid, alginic acid, anthranilic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, phthalic acid, galacturonic acid, gluconic acid, glucuronic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid, but are not limited thereto. Specific examples of non-toxic acids include hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and methanesulfonic acid. Others are well known in the art, for example, see Remington’s Pharmaceutical Sciences, 18th eds., Mack Publishing, Easton PA (1990) or Remington: The Science and Practice of Pharmacy, 19th eds., Mack Publishing, Easton PA (1995).

[0138] As used herein, the term "stereoisomer" refers to one stereoisomer of a fumaric acid compound and substantially excludes other stereoisomers of that fumaric acid compound. For example, a "stereochemically pure" fumaric acid compound having one chiral center will substantially exclude the opposite enantiomer of that fumaric acid compound. A "stereochemically pure" fumaric acid compound having two chiral centers will substantially exclude the other diastereomers of that fumaric acid compound. A typical "stereochemically pure" fumaric acid compound contains more than about 80% by weight of one stereoisomer of the fumaric acid compound and less than about 20% by weight of the other stereoisomers of the fumaric acid compound, or more than about 90% by weight of one stereoisomer of the fumaric acid compound and less than about 10% by weight of the other stereoisomers of the fumaric acid compound, or more than about 95% by weight of one stereoisomer of the fumaric acid compound and less than about 5% by weight of the other stereoisomers of the fumaric acid compound, or more than about 97% by weight of one stereoisomer of the fumaric acid compound and less than about 3% by weight of the other stereoisomers of the fumaric acid compound. The fumaric acid compounds can have multiple chiral centers and can occur as racemates, individual enantiomers or diastereomers, and mixtures thereof. All such isomeric forms, including mixtures thereof, are included in the embodiments disclosed herein. The use of such fumaric acid compounds in stereochemically pure form, as well as the use of mixtures of such forms, are encompassed by the embodiments disclosed herein. For example, mixtures containing equal or unequal amounts of enantiomers of a particular fumaric acid compound may be used in the methods and compositions disclosed herein. These isomers may be synthesized asymmetrically or may be resolved using standard techniques such as chiral columns or chiral resolving agents.For example, Jacques, J., et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E.L., Stereochemistry of Carbon Compounds (McGraw Hill, NY, 1962); and Wilen, S. H., Tables of Resolving Agents and Optical. See Resolutions p.268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN, 1972).

[0139] As used herein, the term "substituted" refers to a group in which one or more hydrogen atoms in the group are independently replaced by the same or different substituent(s). In certain embodiments, each substituent is independently halogen, -OH, -CN, -CF3, =O, -NO2, benzyl, -C(O)NH2, -R'', -OR'', -C(O)R'', -COOR'', -S(O)2R'', or -NR2'', where each R'' is independently hydrogen or C 1-6 alkyl. In certain embodiments, each substituent is independently halogen, -OH, -CN, -CF3, -NO2, benzyl, -R'', -OR'', or -NR2'', where each R'' is independently hydrogen or C 1-4 alkyl. In certain embodiments, each substituent is independently halogen, -OH, -CN, -CF3, =O, -NO2, benzyl, -C(O)NR2'', -R'', -OR'', -C(O)R'', -COOR'', or -NR2'', where each R'' is independently hydrogen or C 1-4 alkyl. In certain embodiments, each substituent is independently -OH, C 1-4 alkyl, and -NH2.

[0140] The number of carbon atoms therein is, in this specification, specified by the prefix "C" x-xx ", where x and xx are integers. For example, "C 1-4 alkyl" is an alkyl group having 1 to 4 carbon atoms; "C 1-6 alkyl" is an alkyl group having 1 to 6 carbon atoms; and "C 6-10 aryl" is an aryl group having 6 to 10 carbon atoms.

Brief Description of the Drawings

[0141]

Figure 1

Figure 2

Figure 3

Figure 4A

Figure 4B

Mode for Carrying Out the Invention

[0142] 5. Detailed Description Based on the fact that PML is observed as a complication of treatment with fumaric acid compounds described herein in some patients, the present invention provides a method for treating patients with MS and a method for improving safety in the treatment of MS. A fatal case of progressive multifocal leukoencephalopathy (PML) occurred in a patient with MS who had been administered Tecfidera® for 4 years during the period of registration in a clinical trial. The patient who received Tecfidera® had not been previously treated with immunosuppressive therapy or natalizumab, which is known to be associated with PML, and there was no systemic condition identified that caused immune system dysfunction. This patient was not receiving any immunosuppressive or immunomodulatory medications concurrently. During the clinical trial, long-term lymphopenia (lymphocyte counts were mainly less than 0.5×10 9 / L for 3.5 years) developed in the patient while receiving Tecfidera®.

[0143] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) monitoring the patient to determine whether the patient exhibits any signs or symptoms suggestive of PML.

[0144] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis being treated with a fumaric acid compound for the absence of signs or symptoms suggestive of PML, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0145] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) informing the patient of the occurrence of PML in patients administered dimethyl fumarate.

[0146] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) instructing the patient on the importance of contacting the patient's physician if any symptoms suggestive of PML occur in the patient.

[0147] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0148] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising instructing the treating physician of a patient with multiple sclerosis being treated with a fumaric acid compound on the importance of contacting the physician if any symptoms suggestive of PML develop in the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0149] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that fumarate salts are not present in the pharmaceutical composition; and (b) monitoring the patient for the absence or presence of signs or symptoms suggestive of PML.

[0150] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound for the absence of signs or symptoms suggestive of PML; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition.

[0151] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) informing the patient of the occurrence of PML in patients who have received dimethyl fumarate.

[0152] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) instructing the patient on the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0153] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition.

[0154] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising instructing the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in a patient with multiple sclerosis being treated with a pharmaceutical composition containing a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition.

[0155] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) monitoring the patient to determine whether the patient exhibits any signs or symptoms suggestive of PML.

[0156] Provided herein is a method for improving the safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient being treated with a pharmaceutical composition comprising a fumaric acid compound to determine whether the patient exhibits any signs or symptoms suggestive of PML, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0157] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate.

[0158] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) instructing the patient of the importance of contacting the patient's physician if any symptoms suggestive of PML occur in the patient.

[0159] Provided herein is a method of improving safety in the treatment of a patient with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0160] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising instructing the treating physician of a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound of the importance of contacting the treating physician if any symptoms suggestive of PML develop in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0161] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium ethyl hydrogen fumarate, magnesium ethyl hydrogen fumarate, zinc ethyl hydrogen fumarate, and copper ethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) monitoring the patient for the absence or presence of signs or symptoms suggestive of PML.

[0162] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound to determine whether the patient has any signs or symptoms suggestive of PML; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0163] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate.

[0164] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) instructing the patient of the importance of contacting the patient's attending physician if any symptoms suggestive of PML occur in the patient.

[0165] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising informing a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound that PML has occurred in patients administered dimethyl fumarate; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0166] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising instructing the treating physician of a patient with multiple sclerosis being treated with a pharmaceutical composition comprising a fumaric acid compound of the importance of contacting the treating physician if any symptoms suggestive of PML occur in the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0167] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) monitoring the patient for signs or symptoms suggestive of PML.

[0168] Provided herein is a method for improving the safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate for signs or symptoms suggestive of PML.

[0169] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) informing the patient that PML has occurred in patients administered dimethyl fumarate.

[0170] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) instructing the patient on the importance of contacting their attending physician if any symptoms suggestive of PML occur in the patient.

[0171] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising notifying a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate that PML has occurred in patients administered dimethyl fumarate.

[0172] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising instructing a patient with multiple sclerosis being treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate on the importance of contacting their attending physician if any symptoms suggestive of PML occur in the patient.

[0173] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) obtaining a complete blood count value including lymphocyte count after repeating administration of the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0174] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0175] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0176] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0177] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) obtaining a complete blood count value including lymphocyte count after repeatedly administering the pharmaceutical composition to the patient for 6 months and then every 6 to 12 months thereafter.

[0178] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be below the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate with respect to such other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0179] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiation of treatment of the patient with this pharmaceutical composition.

[0180] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) carefully monitoring the patient for signs or symptoms of the appearance of a new neurological disorder if the patient develops lymphopenia after administration of this pharmaceutical composition.

[0181] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has been treated with a pharmaceutical composition comprising a fumaric acid compound and who has developed lymphopenia for signs or symptoms of the emergence of a new neurological disorder; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0182] Provided herein is a method for treating multiple sclerosis in a patient being treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; the method comprising the following steps in the order described: (a) discontinuing administration of the multiple sclerosis disease-modifying therapy to the patient; (b) considering the half-life and mode of action of the multiple sclerosis disease-modifying therapy for the purpose of avoiding further immune effects, but at the same time minimizing the risk of disease reactivation; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0183] Provided herein is a method of treating multiple sclerosis in a patient being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) immediately after such discontinuation, initiating administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; the fumaric acid compound comprising a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these.

[0184] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; and (b) performing a blood test to measure the patient's white blood cell count prior to the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of the patient with this pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuation of the treatment with this pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during the treatment.

[0185] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be below the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate with respect to such other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition.

[0186] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with this pharmaceutical composition.

[0187] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that fumarate salts are not present in the pharmaceutical composition; and (b) after administration of the pharmaceutical composition, if the patient develops lymphopenia, carefully monitoring the patient for signs or symptoms of the appearance of a new neurological disorder.

[0188] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has developed lymphopenia and who is being treated with a pharmaceutical composition comprising a fumaric acid compound for signs or symptoms of the appearance of a new neurological disorder, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that fumarate salts are not present in the pharmaceutical composition.

[0189] Provided herein is a method of treating multiple sclerosis in patients being treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; the method comprising the following steps in the order recited: (a) discontinuing administration of this multiple sclerosis disease-modifying therapy to this patient; (b) considering the half-life and mode of action of this multiple sclerosis disease-modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0190] Provided herein is a method of treating multiple sclerosis in patients being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) immediately following this discontinuation, initiating administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition.

[0191] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or an inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that fumarate salts are not present in the pharmaceutical composition; and (b) performing a blood test and measuring the patient's white blood cell count prior to the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of the patient with this pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuing the treatment with this pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during the treatment.

[0192] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if it is found that the lymphocyte count is lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate with respect to these other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0193] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with the pharmaceutical composition.

[0194] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these, provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) if the patient develops lymphopenia after administration of the pharmaceutical composition, carefully monitoring the patient for signs or symptoms of the appearance of a new neurological disorder.

[0195] Provided herein is a method for improving safety in the treatment of patients with multiple sclerosis, the method comprising monitoring patients with multiple sclerosis who have been treated with a pharmaceutical composition comprising a fumaric acid compound and who have developed lymphopenia for signs or symptoms of the emergence of new neurological dysfunction; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that the ethyl hydrogen fumarate salt is not present in the pharmaceutical composition.

[0196] Provided herein is a method for treating multiple sclerosis in patients being treated with a multiple sclerosis disease modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that the ethyl hydrogen fumarate salt is not present in the pharmaceutical composition; the method comprising the following steps in the order described: (a) stopping administration of this multiple sclerosis disease modifying therapy to this patient; (b) considering the half-life and mode of action of this multiple sclerosis disease modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0197] Provided herein is a method of treating multiple sclerosis in patients being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) immediately after such discontinuation, initiating administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition.

[0198] Provided herein is a method of treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound being a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that ethyl hydrogen fumarate is not present in the pharmaceutical composition; and (b) performing a blood test and measuring the patient's white blood cell count before the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of this patient with this pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuing the treatment with this pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during this treatment.

[0199] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) prior to initiating treatment of the patient with a pharmaceutical composition comprising a fumaric acid compound: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be below the normal range, investigating other causes of lymphopenia and taking corrective measures as appropriate with respect to such other causes; and (b) administering the pharmaceutical composition to the patient, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0200] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of the patient with this pharmaceutical composition.

[0201] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) after administration of the pharmaceutical composition, if the patient develops lymphopenia, carefully monitoring the patient for signs or symptoms of the appearance of a new neurological disorder.

[0202] Provided herein is a method for improving safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis who has developed lymphopenia and who is being treated with a pharmaceutical composition comprising a fumaric acid compound for signs or symptoms of the appearance of a new neurological disorder, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0203] Provided herein is a method of treating multiple sclerosis in a patient being treated with a multiple sclerosis disease modifying therapy other than a pharmaceutical composition comprising a fumaric acid compound; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; the method comprises the following steps in the order described: (a) stopping administration of this multiple sclerosis disease modifying therapy to this patient; (b) considering the half-life and mode of action of this multiple sclerosis disease modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) administering to the patient a pharmaceutical composition comprising a fumaric acid compound.

[0204] Provided herein is a method of treating multiple sclerosis in a patient being treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing administration of interferon or glatiramer acetate to the patient; and (b) immediately after this discontinuation, initiating administration of a pharmaceutical composition comprising a fumaric acid compound to the patient; the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition.

[0205] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition comprising a fumaric acid compound, wherein the fumaric acid compound is a dialkyl fumarate, a monoalkyl fumarate, a combination of a dialkyl fumarate and a monoalkyl fumarate, a prodrug of a monoalkyl fumarate, a deuterated form of any of these, or a pharmaceutically acceptable salt, inclusion complex, solvate, tautomer, or stereoisomer of any of these, or a combination of any of these; provided that calcium monoethyl hydrogen fumarate, magnesium monoethyl hydrogen fumarate, zinc monoethyl hydrogen fumarate, and copper monoethyl hydrogen fumarate are not present in the pharmaceutical composition; and (b) performing a blood test and measuring the patient's white blood cell count before the first administration of the pharmaceutical composition comprising the fumaric acid compound to the patient and periodically during the treatment of this patient with this pharmaceutical composition comprising the fumaric acid compound; and (c) considering discontinuing the treatment with this pharmaceutical composition comprising the fumaric acid compound if the white blood cell count decreases during this treatment.

[0206] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) before initiating treatment of the patient with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate: (i) performing a complete blood count including lymphocyte count; and (ii) if the lymphocyte count is found to be lower than the normal range, examining other causes of lymphopenia and taking corrective measures as appropriate for this other cause; and (b) administering this pharmaceutical composition to the patient.

[0207] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) repeatedly administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) obtaining a complete blood count value including lymphocyte count every three months after initiating treatment of this patient with this pharmaceutical composition.

[0208] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; and (b) after administration of the pharmaceutical composition, if the patient develops lymphopenia, closely monitoring the patient for signs or symptoms of the appearance of new neurological dysfunction.

[0209] Provided herein is a method for improving the safety in the treatment of a patient with multiple sclerosis, the method comprising monitoring a patient with multiple sclerosis, who has been treated with a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate and has developed lymphopenia, for signs or symptoms of the appearance of new neurological dysfunction.

[0210] Provided herein is a method for treating multiple sclerosis in a patient who has been treated with a multiple sclerosis disease-modifying therapy other than a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; the method comprising the following steps in the recited order: (a) stopping the administration of the multiple sclerosis disease-modifying therapy to the patient; (b) considering the half-life and mode of action of the multiple sclerosis disease-modifying therapy for the purpose of avoiding further immune effects but at the same time minimizing the risk of disease reactivation; and (c) administering a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate.

[0211] Provided herein is a method for treating multiple sclerosis in a patient who has been treated with interferon or glatiramer acetate, the method comprising: (a) discontinuing the administration of interferon or glatiramer acetate to the patient; and (b) immediately after such discontinuation, initiating the administration of a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate to the patient.

[0212] Provided herein is a method for treating a patient with multiple sclerosis, the method comprising: (a) administering to the patient a pharmaceutical composition consisting essentially of dimethyl fumarate and / or monomethyl fumarate; (b) performing a blood test and measuring the patient's white blood cell count before the first administration of the pharmaceutical composition to the patient and periodically during the treatment of the patient with the pharmaceutical composition; and (c) considering discontinuing the treatment with the pharmaceutical composition if the white blood cell count decreases during the treatment.

[0213] All of the various aspects, embodiments, and options disclosed herein can be combined in any and all combinations. The provided compositions and methods are illustrative and are not intended to limit the scope of the claimed embodiments.

[0214] 5.1 Active agents for use in the methods provided herein The active agent (i.e., drug) for use in the methods and compositions of the present invention is a fumaric acid compound. Such fumaric acid compounds can be dialkyl fumarates (e.g., dimethyl fumarate), monoalkyl fumarates (e.g., monomethyl fumarate), combinations of dialkyl fumarates and monoalkyl fumarates (e.g., dimethyl fumarate and monomethyl fumarate), prodrugs of monoalkyl fumarates (e.g., monomethyl), deuterated forms of any of these, or pharmaceutically acceptable salts, inclusion complexes, solvates, tautomers, or stereoisomers of any of these, or combinations of any of these. In one embodiment, the fumaric acid compound used in the methods, compositions, and products described herein is dimethyl fumarate. In certain embodiments, the fumaric acid compound is (i) a monoalkyl fumarate or a prodrug thereof, or (ii) a dialkyl fumarate. In one embodiment, the monoalkyl fumarate is monomethyl fumarate (“MMF”). In another embodiment, the dialkyl fumarate is dimethyl fumarate (“DMF”).

[0215] 5.1.1 Monoalkyl fumarate and dialkyl fumarate Specifically, provided herein are monoalkyl fumarates and dialkyl fumarates, or pharmaceutically acceptable salts, inclusion complexes, solvates, or stereoisomers thereof, for use in the methods provided herein.

[0216] In one embodiment, the fumaric acid compound is a monoalkyl fumarate of formula I below: [Chemical formula] or a pharmaceutically acceptable salt, inclusion complex, solvate, or stereoisomer thereof, wherein R 1 is C 1-6 alkyl.

[0217] In certain embodiments of the compound of formula (I), R 1 is methyl (monomethyl fumarate, "MMF").

[0218] In one embodiment, the compound of formula I can be prepared using methods known to those skilled in the art, for example, as disclosed in U.S. Patent No. 4,959,389.

[0219] In another embodiment, the fumaric acid compound is a dialkyl fumarate of formula II: [Chemical formula] or a pharmaceutically acceptable salt, inclusion complex, solvate, or stereoisomer thereof, wherein each R 2 is C 1-6 alkyl.

[0220] In certain embodiments of the compound of formula (II), each R 2is methyl (dimethyl fumarate, "DMF"). In certain embodiments, the agent is administered as a pharmaceutical composition, which is Tecfidera®. In another specific embodiment, the agent is present as a pharmaceutical composition, which is FUMADERM®. FUMADERM® contains the following active ingredients: dimethyl fumarate, calcium salt of ethyl hydrogen fumarate, magnesium salt of ethyl hydrogen fumarate, and zinc salt of ethyl hydrogen fumarate.

[0221] In one embodiment, the compound of formula (II) can be prepared using methods known to those skilled in the art, for example, as disclosed in U.S. Patent No. 4,959,389.

[0222] In one embodiment, the fumaric acid compound is dimethyl fumarate and / or monomethyl fumarate.

[0223] In one embodiment, the fumaric acid compound is dimethyl fumarate.

[0224] 5.1.2 Prodrugs of Monoalkyl Fumarates Further provided herein are prodrugs of monoalkyl fumarates, or pharmaceutically acceptable salts, inclusion complexes, solvates, or stereoisomers thereof, for use in the methods provided herein.

[0225] Specifically, the prodrugs of monoalkyl fumarates are the prodrugs disclosed in WO2013 / 119677, such as the compounds of the following formula (III):

Chemical formula

[0226] In certain embodiments of the compound of formula (III), when R 3 is ethyl; R 6 and R 7 are each independently hydrogen, C 1-6 alkyl, or substituted C 1-6 alkyl.

[0227] In certain embodiments of the compound of formula (III), each substituent is independently halogen, -OH, -CN, -CF3, -R 8 , -OR 8or -NR 8 is 2, and in the formula, each R 8 is, independently, hydrogen or C 1-4 alkyl. In certain embodiments, each substituent is independently -OH or -COOH.

[0228] In certain embodiments of the compound of formula (III), each substituent is, independently, =O, C 1-4 alkyl, or -COOR 8 wherein R 8 is hydrogen or C 1-4 alkyl.

[0229] In certain embodiments of the compound of formula (III), R 3 is methyl.

[0230] In certain embodiments of the compound of formula (III), R 3 is ethyl.

[0231] In certain embodiments of the compound of formula (III), R 3 is C 3-6 alkyl.

[0232] In certain embodiments of the compound of formula (III), R 3 is methyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0233] In certain embodiments of the compound of formula (III), R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0234] In certain embodiments of the compound of formula (III), R 4 and R 5 are each hydrogen.

[0235] In certain embodiments of the compound of formula (III), R4 and R 5 one of which is hydrogen, and R 4 and R 5 the other of which is C 1-4 alkyl.

[0236] In certain embodiments of the compound of formula (III), R 4 and R 5 one of which is hydrogen, and R 4 and R 5 the other of which is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl.

[0237] In certain embodiments of the compound of formula (III), R 4 and R 5 one of which is hydrogen, and R 4 and R 5 the other of which is methyl.

[0238] In certain embodiments of the compound of formula (III), R 6 and R 7 are each independently hydrogen or C 1-6 alkyl.

[0239] In certain embodiments of the compound of formula (III), R 6 and R 7 are each independently hydrogen or C 1-4 alkyl.

[0240] In certain embodiments of the compound of formula (III), R 6 and R 7 are each independently hydrogen, methyl, or ethyl.

[0241] In certain embodiments of the compound of formula (III), R 6 and R 7 are each hydrogen; in certain embodiments, R 6 and R 7is methyl, respectively; and in certain embodiments, R 6 and R 7 are ethyl, respectively.

[0242] In certain embodiments of the compound of formula (III), R 6 is hydrogen; and R 7 is C 1-4 alkyl, substituted C 1-4 alkyl, wherein each substituent is independently =O, -OR 8 , -COOR 8 , or -NR 8 2, and wherein each R 8 is independently hydrogen or C 1-4 alkyl.

[0243] In certain embodiments of the compound of formula (III), R 6 is hydrogen; and R 7 is C 1-4 alkyl, benzyl, 2-methoxyethyl, carboxymethyl, carboxypropyl, 1,3,4-thiadiazolyl, methoxy, -COOCH3, 2-oxo-1,3-oxazolidinyl, 2-(methylethoxy)ethyl, 2-ethoxyethyl, (tert-butyloxycarbonyl)methyl, (ethoxycarbonyl)methyl, (methylethyl)oxycarbonylmethyl, or ethoxycarbonylmethyl.

[0244] In certain embodiments of the compound of formula (III), R 6 and R 7 together with the nitrogen to which they are attached form a ring selected from C 5-6 heterocycloalkyl, substituted C 5-6 heterocycloalkyl, C 5-6 heteroaryl, and substituted C 5-6 heteroaryl rings. In certain embodiments of the compound of formula (III), R 6 and R 7together with the nitrogen to which they are attached form a ring selected from C5 heterocycloalkyl, substituted C5 heterocycloalkyl, C5 heteroaryl, and substituted C5 heteroaryl rings. In certain embodiments of the compounds of formula (III), R 6 and R 7 together with the nitrogen to which they are attached form a ring selected from C6 heterocycloalkyl, substituted C6 heterocycloalkyl, C6 heteroaryl, and substituted C6 heteroaryl rings. In certain embodiments of the compounds of formula (III), R 6 and R 7 together with the nitrogen to which they are attached form a ring selected from piperazine, 1,3-oxazolidinyl, pyrrolidine, and morpholine rings.

[0245] In certain embodiments of the compounds of formula (III), R 6 and R 7 together with the nitrogen to which they are attached form a C 5-10 heterocycloalkyl ring.

[0246] In certain embodiments of the compounds of formula (III), one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is C 1-6 alkyl; R 6 is hydrogen; R 7 is hydrogen, C 1-6 alkyl, or benzyl.

[0247] In certain embodiments of the compounds of formula (III), R 3 is methyl; one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is C 1-6 alkyl; R 6 is hydrogen; and R 7 is hydrogen, C 1-6 alkyl, or benzyl.

[0248] In certain embodiments of the compound of formula (III), R 4 and R 5 one of which is hydrogen, and R 4 and R 5 the other is hydrogen or C 1-6 alkyl; and R 6 and R 7 are each C 1-6 alkyl.

[0249] In certain embodiments of the compound of formula (III), R 3 is methyl; one of R 4 and R 5 is hydrogen, and the other of R 4 and R 5 is hydrogen or C 1-6 alkyl; and R 6 and R 7 are each C 1-6 alkyl. In certain embodiments of the compound of formula (III), R 5 is methyl; R 4 and R 5 are each hydrogen; and R 6 and R 7 are each C 1-6 alkyl.

[0250] In certain embodiments of the compound of formula (III), R 3 is methyl; one of R 4 and R 5 is hydrogen, and the other of R 4 and R 5 is hydrogen or C 1-4 alkyl; R 6 is hydrogen; and R 7 is C 1-4 alkyl or substituted C 1-4 alkyl, wherein the substituent is =O, -OR 8 , -COOR 8 or -NR 8 2, wherein each R 8 is independently hydrogen or C 1-4is alkyl. In certain embodiments of the compound of formula (III), R 3 is methyl; one of R 4 and R 5 is hydrogen, and the other of R 4 and R 5 is methyl; R 6 is hydrogen; and R 7 is C 1-4 alkyl or substituted C 1-4 alkyl, wherein the substituent is ═O, -OR 8 , -COOR 8 , or -NR 8 2, wherein each R 8 is independently hydrogen or C 1-4 alkyl. In certain embodiments of the compound of formula (III), R 3 is methyl; R 4 and R 5 are each hydrogen; R 6 is hydrogen; and R 7 is C 1-4 alkyl or substituted C 1-4 alkyl, wherein the substituent is ═O, -OR 11 , -COOR 11 , or -NR 11 2, wherein each R 11 is independently hydrogen or C 1-4 alkyl.

[0251] In certain embodiments of the compound of formula (III), R 6 and R 7 together with the nitrogen to which they are attached form a C 5-10 heterocycloalkyl ring.

[0252] In certain embodiments of the compound of formula (III), R 3 is methyl; one of R 4 and R 5 is hydrogen, and the other of R 4 and R 5 is hydrogen or C 1-6 alkyl; and R 6 and R7 combines with the nitrogen to which they are attached to form a ring selected from C 5-6 heterocycloalkyl, substituted C 5-6 heterocycloalkyl, C 5-6 heteroaryl, and substituted C 5-6 heteroaryl rings. In certain embodiments of the compounds of formula (III), R 3 is methyl; one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is methyl; R 6 and R 7 combine with the nitrogen to which they are attached to form a ring selected from C 5-6 heterocycloalkyl, substituted C 5-6 heterocycloalkyl, C 5-6 heteroaryl, and substituted C 5-6 heteroaryl rings. In certain embodiments of the compounds of formula (III), R 3 is methyl; R 4 and R 5 are each hydrogen; and R 6 and R 7 combine with the nitrogen to which they are attached to form a ring selected from C 5-6 heterocycloalkyl, substituted C 5-6 heterocycloalkyl, C 5-6 heteroaryl, and substituted C 5-6 heteroaryl rings.

[0253] In certain embodiments of the compounds of formula (III), one of R 4 and R 5 is hydrogen and the other of R 4 and R 5 is hydrogen or C 1-6 alkyl; and R 6 and R 7 combine with the nitrogen to which they are attached to form a ring selected from morpholine, piperazine, and N-substituted piperazines.

[0254] In certain embodiments of the compound of formula (III), R 3 is methyl; one of R 4 and R 5 is hydrogen, and the other of R 4 and R 5 is hydrogen or C 1-6 alkyl; and R 6 and R 7 together with the nitrogen to which they are attached form a ring selected from morpholine, piperazine, and N-substituted piperazine.

[0255] In certain embodiments of the compound of formula (III), R 3 is not methyl.

[0256] In certain embodiments of the compound of formula (III), R 4 is hydrogen, and in certain embodiments, R 5 is hydrogen.

[0257] In certain embodiments of the compound of formula (III), R 6 and R 7 are independently hydrogen, C 1-6 alkyl, substituted C 1-6 alkyl, C 6-10 aryl, substituted C 6-10 aryl, C 4-12 cycloalkylalkyl, substituted C 4-12 cycloalkylalkyl, C 7-12 arylalkyl, substituted C 7-12 arylalkyl, C 1-6 heteroalkyl, substituted C 1-6 heteroalkyl, C 6-10 heteroaryl, substituted C 6-10 heteroaryl, C 4-12 heterocycloalkylalkyl, substituted C 4-12 heterocycloalkylalkyl, C 7-12 heteroarylalkyl, substituted C 7-12 heteroarylalkyl; or R 6 and R 7together with the nitrogen to which they are attached, C 5-10 heteroaryl, substituted C 5-10 heteroaryl, C 5-10 heterocycloalkyl, and substituted C 5-10 form a ring selected from heterocycloalkyl.

[0258] In certain embodiments of the compounds of formula (III), the compounds are as follows: (N,N-diethylcarbamoyl)methyl = methyl (2E) but-2-ene-1,4-dioate; methyl [N-benzylcarbamoyl]methyl (2E) but-2-ene-1,4-dioate; methyl = 2-morpholin-4-yl-2-oxoethyl (2E) but-2-ene-1,4-dioate; (N-butylcarbamoyl)methyl = methyl (2E) but-2-ene-1,4-dioate; [N-(2-methoxyethyl)carbamoyl]methyl = methyl (2E) but-2-ene-1,4-dioate; 2-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}acetic acid; 4-{2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic acid; methyl (N-(1,3,4-thiadiazol-2-yl)carbamoyl)methyl (2E) but-2-ene-1,4-dioate; (N,N-dimethylcarbamoyl)methyl = methyl (2E) but-2-ene-1,4-dioate; (N-methoxy-N-methylcarbamoyl)methyl = methyl (2E) but-2-ene-1,4-dioate; bis-(2-methoxyethylamino)carbamoyl]methyl = methyl (2E) but-2-ene-1,4-dioate; [N-(methoxycarbonyl)carbamoyl]methyl = methyl (2E) but-2-ene-1,4-dioate; 4-{2-[(2E)-3-(Methoxycarbonyl)prop-2-enoyloxy]acetylamino}butanoic acid, sodium salt; Methyl = 2-oxo-2-piperazinylethyl (2E) but-2-ene-1,4-dioate; Methyl = 2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl (2E) but-2-ene-1,4-dioate; {N-[2-(Dimethylamino)ethyl]carbamoyl}methyl = methyl (2E) but-2-ene-1,4-dioate; Methyl = 2-(4-methylpiperazinyl)-2-oxoethyl (2E) but-2-ene-1,4-dioate; Methyl = {N-[(propylamino)carbonyl]carbamoyl}methyl (2E) but-2-ene-1,4-dioate; 2-(4-acetylpiperazinyl)-2-oxoethyl = methyl (2E) but-2-ene-1,4-dioate; {N,N-bis[2-(methylethoxy)ethyl]carbamoyl}methyl = methyl (2E) but-2-ene-1,4-dioate; Methyl = 2-(4-benzylpiperazinyl)-2-oxoethyl (2E) but-2-ene-1,4-dioate; [N,N-bis(2-ethoxyethyl)carbamoyl]methyl = methyl (2E) but-2-ene-1,4-dioate; 2-{(2S)-2-[(tert-butyl)oxycarbonyl]pyrrolidinyl}-2-oxoethyl = methyl (2E) but-2-ene-1,4-dioate; 1-{2-{(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetyl}(2S)pyrrolidine-2-carboxylic acid; (N-{[(tert-butyl)oxycarbonyl]methyl}-N-methylcarbamoyl)methyl = methyl (2E) but-2-ene-1,4-dioate; {N-(ethoxycarbonyl)methyl]-N-methylcarbamoyl}methyl = methyl (2E) but-2-ene-1,4-dioate; Methyl = 1 - methyl - 2 - morpholin - 4 - yl - 2 - oxoethyl (2E) but - 2 - ene - 1,4 - dioate; [N,N - Bis(2 - methoxyethyl)carbamoyl]ethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; (N,N - Dimethylcarbamoyl)ethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; 2 - {2 - [(2E) - 3 - (methoxycarbonyl)prop - 2 - enoyloxy] - N - methylacetylamino}acetic acid; (N - {[(tert - butyl)oxycarbonyl]methyl}carbamoyl)methyl = methyl (2E) but - 2 - ene - 1,4 - dioate; (2E)but - methyl - N - {[(methylethyl)oxycarbonyl]methyl}carbamoyl)methyl (2E) but - 2 - ene - 1,4 - dioate; {N - [(ethoxycarbonyl)methyl] - N - benzylcarbamoyl}methyl = methyl (2E) but - 2 - ene - 1,4 - dioate; {N - [(ethoxycarbonyl)methyl] - N - benzylcarbamoyl}ethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; {N - [(ethoxycarbonyl)methyl] - N - methylcarbamoyl}ethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; (1S) - 1 - methyl - 2 - morpholin - 4 - yl - 2 - oxoethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; (1S) - 1 - [N,N - bis(2 - methoxyethyl)carbamoyl]ethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; (1R) - 1 - (N,N - diethylcarbamoyl)ethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; or (1S) - 1 - (N,N - diethylcarbamoyl)ethyl = methyl (2E) but - 2 - ene - 1,4 - dioate; or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof.

[0259] In certain embodiments of the compound of formula (III), the compound is as follows:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0260] In certain embodiments of the compound of formula (III), the compound is as follows: (N,N - Diethylcarbamoyl)methyl = methyl (2E)but - 2 - ene - 1,4 - dioate; Methyl [N - benzylcarbamoyl]methyl (2E)but - 2 - ene - 1,4 - dioate; methyl = 2 - morpholin - 4 - yl - 2 - oxoethyl (2E)but - 2 - ene - 1,4 - dioate; (N - Butylcarbamoyl)methyl = methyl (2E)but - 2 - ene - 1,4 - dioate; [N - (2 - Methoxyethyl)carbamoyl]methyl = methyl (2E)but - 2 - ene - 1,4 - dioate; 2 - {2 - [(2E)-3 - (Methoxycarbonyl)prop - 2 - enoyloxy]acetylamino}acetic acid; {2 - [(2E)-3 - (Methoxycarbonyl)prop - 2 - enoyloxy]acetylamino}butanoic acid; Methyl (N - (1,3,4 - thiadiazol - 2 - yl)carbamoyl)methyl (2E)but - 2 - ene - 1,4 - dioate; (N,N - Dimethylcarbamoyl)methyl = methyl (2E)but - 2 - ene - 1,4 - dioate; (N-Methoxy-N-methylcarbamoyl)methyl = methyl (2E)but-2-ene-1,4-dioate; Bis-(2-methoxyethylamino)carbamoyl]methyl = methyl (2E)but-2-ene-1,4-dioate; [N-(Methoxycarbonyl)carbamoyl]methyl = methyl (2E)but-2-ene-1,4-dioate; Methyl = 2-oxo-2-piperazinylethyl (2E)but-2-ene-1,4-dioate; Methyl = 2-oxo-2-(2-oxo(1,3-oxazolidin-3-yl)ethyl (2E)but-2-ene-1,4-dioate; {N-[2-(Dimethylamino)ethyl]carbamoyl}methyl = methyl (2E)but-2-ene-1,4-dioate; (N-[(Methoxycarbonyl)ethyl]carbamoyl)methyl = methyl (2E)but-2-ene-1,4-dioate; or 2-{2-[(2E)-3-(Methoxycarbonyl)prop-2-enoyloxy]acetylamino}propanoic acid; or a pharmaceutically acceptable salt, clathrate, solvate, tautomer, or stereoisomer thereof.

[0261] In certain embodiments of the compound of formula (III), the compound is as follows:

Chemical formula

Chemical formula

Chemical formula

[0262] In certain embodiments of the compound of formula (III), the compound is as follows:

Chemical formula

Chemical formula

[0263] In certain embodiments of the compound of formula (III), the compound is as follows:

Chemical formula

[0264] In certain embodiments of the compound of formula (III), the compound is as follows:

Chemical formula

[0265] In certain embodiments of the compound of formula (III), the compound is as follows:

Chemical formula

[0266] The compounds listed in paragraphs

[0261] and

[0263] [Translator's note: In WO2016 / 081355, they are in

[0261] and

[0263] , and in this specification, they correspond to

[0258] and

[0260] ] are named using Chemistry 4-D Draw Pro, Version 7.01c (Chemlnnovation Software, Inc., San Diego, California).

[0267] In one embodiment, the compound of formula (III) may be prepared using methods known to those skilled in the art, for example, as disclosed in U.S. Patent No. 8,148,414 B2.

[0268] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (IV):

Chemical formula

[0269] In certain embodiments of the compound of formula (IV), each substituent is independently halogen, -OH, -CN, -CF3, -R 14 、 -OR 14 、 or -NR 14 2, where each R 14 is independently hydrogen or C 1-4 alkyl.

[0270] In certain embodiments of the compound of formula (IV), each substituent is independently =O, C 1-4 alkyl, and -COOR 14 , where R 14 is hydrogen or C 1-4 alkyl.

[0271] In certain embodiments of the compound of formula (IV), R 9 is C 1-6 alkyl; in certain embodiments, R 9 is C 1-3 alkyl; and in certain embodiments, R 9 is methyl or ethyl.

[0272] In certain embodiments of the compound of formula (IV), R 9 is methyl.

[0273] In certain embodiments of the compound of formula (IV), R 9 is ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0274] In certain embodiments of the compound of formula (IV), R 9is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl.

[0275] In certain embodiments of the compound of formula (IV), R 10 and R 11 one of which is hydrogen, and R 10 and R 11 the other of which is C 1-6 alkyl. In certain embodiments of the compound of formula (IV), R 10 and R 11 one of which is hydrogen, and R 10 and R 11 the other of which is C 1-4 alkyl.

[0276] In certain embodiments of the compound of formula (IV), R 10 and R 11 one of which is hydrogen, and R 10 and R 11 the other of which is methyl, ethyl, n-propyl, or isopropyl. In certain embodiments of the compound of formula (IV), R 10 and R 11 are each hydrogen.

[0277] In certain embodiments of the compound of formula (IV), R 12 is C 1-6 alkyl; one of R 10 and R 11 is hydrogen, and the other of R 10 and R 11 is C 1-6 alkyl; and R 9 is C 1-6 alkyl.

[0278] In certain embodiments of the compound of formula (IV), R 12 is -OR 13 .

[0279] In certain embodiments of the compound of formula (IV), R 13 is C 1-4It is alkyl, cyclohexyl, or phenyl.

[0280] In certain embodiments of the compound of formula (IV), R 12 is methyl, ethyl, n-propyl, or isopropyl; R 10 and R 11 one of which is hydrogen, and R 10 and R 11 the other is methyl, ethyl, n-propyl, or isopropyl.

[0281] In certain embodiments of the compound of formula (IV), R 12 is substituted C 1-2 alkyl, wherein each substituent is independently -COOH, -NHC(O)CH2NH2, or -NH2.

[0282] In certain embodiments of the compound of formula (IV), R 12 is ethoxy, methylethoxy, isopropyl, phenyl, cyclohexyl, cyclohexyloxy, -CH(NH2)CH2COOH, -CH2CH(NH2)COOH, -CH(NHC(O)CH2NH2)-CH2COOH, or -CH2CH(NHC(O)CH2NH2)-COOH.

[0283] In certain embodiments of the compound of formula (IV), R 9 is methyl or ethyl; R 10 and R 11 one of which is hydrogen, and R 10 and R 11 the other is hydrogen, methyl, ethyl, n-propyl, or isopropyl; and R 12 is C 1-3 alkyl, substituted C 1-2 alkyl, wherein each substituent is -COOH, -NHC(O)CH2NH2, -NH2, or -OR 13 wherein R 13 is C 1-3 alkyl, cyclohexyl, phenyl, or cyclohexyl.

[0284] In certain embodiments of the compound of formula (IV), the compound is as follows: Ethoxycarbonyloxyethyl = methyl (2E) but-2-ene-1,4-dioate; Methyl (methylethoxycarbonyloxy) ethyl (2E) but-2-ene-1,4-dioate; or (Cyclohexyloxycarbonyloxy) ethyl = methyl (2E) but-2-ene-1,4-dioate; or an inclusion compound, solvate, or stereoisomer thereof.

[0285] In certain embodiments of the compound of formula (IV), the compound is as follows: [Chemical formula] Or [Chemical formula] Or an inclusion compound, solvate, or stereoisomer thereof.

[0286] In certain embodiments of the compound of formula (IV), the compound is as follows: Methyl (2-methylpropanoyloxy) ethyl (2E) but-2-ene-1,4-dioate; Methyl = phenylcarbonyloxyethyl (2E) but-2-ene-1,4-dioate; Cyclohexylcarbonyloxybutyl = methyl (2E) but-2-ene-1,4-dioate; [(2E)-3-(Methoxycarbonyl) prop-2-enoyloxy] ethyl = methyl (2E) but-2-ene-1,4-dioate; or Methyl = 2-methyl-1-phenylcarbonyloxypropyl (2E) but-2-ene-1,4-dioate; or an inclusion compound, solvate, or stereoisomer thereof.

[0287] In certain embodiments of the compound of formula (IV), the compound is as follows: [Chemistry] or [Chemistry] or an inclusion complex, solvate, or stereoisomer thereof.

[0288] In certain embodiments of the compound of formula (IV), the compound is as follows: Ethoxycarbonyloxyethyl = methyl (2E) but-2-ene-1,4-dioate; Methyl (methylethoxycarbonyloxy) ethyl (2E) but-2-ene-1,4-dioate; Methyl (2-methylpropanoyloxy) ethyl (2E) but-2-ene-1,4-dioate; Methyl = phenylcarbonyloxyethyl (2E) but-2-ene-1,4-dioate; Cyclohexylcarbonyloxybutyl = methyl (2E) but-2-ene-1,4-dioate; [(2E)-3-(Methoxycarbonyl) prop-2-enoyloxy] ethyl = methyl (2E) but-2-ene-1,4-dioate; (Cyclohexyloxycarbonyloxy) ethyl = methyl (2E) but-2-ene-1,4-dioate; Methyl = 2-methyl-1-phenylcarbonyloxypropyl (2E) but-2-ene-1,4-dioate; or an inclusion complex, solvate, or stereoisomer thereof.

[0289] In certain embodiments of the compound of formula (IV), the compound is as follows: 3-({[(2E)-3-(Methoxycarbonyl) prop-2-enoyloxy] methyl} oxycarbonyl) (3S)-3-aminopropanoic acid, 2,2,2-trifluoroacetic acid; 3-({[(2E)-3-(Methoxycarbonyl) prop-2-enoyloxy] methyl} oxycarbonyl) (2S)-2-aminopropanoic acid, 2,2,2-trifluoroacetic acid; 3-({[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]methyl}oxycarbonyl)(3S)-3-(2-aminoacetylamino)propanoic acid, 2,2,2-trifluoroacetic acid; or 3-{[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]ethoxycarbonyloxy}(2S)-2-aminopropanoic acid, chloride; or an inclusion complex, solvate, or stereoisomer thereof.

[0290] In certain embodiments of the compound of formula (IV), the compound is as follows:

Chem.

Chem.

Chem.

[0291] In certain embodiments of the compound of formula (IV), the compound is as follows:

Chem.

Chem.

Chem.

[0292] In certain embodiments of the compound of formula (IV), the compound is as follows:

Chem.

Chem.

[0293] The compounds listed in paragraphs

[0287] ,

[0289] ,

[0291] , and

[0292] [Translator's note: In WO2016 / 081355, they are in

[0287] ,

[0289] ,

[0291] , and

[0292] , and in this specification, they correspond to

[0284] ,

[0286] ,

[0288] , and

[0289] ] were named using Chemistry 4-D Draw Pro, Version 7.01c (Chemlnnovation Software, Inc., San Diego, California).

[0294] In one embodiment, the compound of formula (IV) may be prepared using methods known to those skilled in the art, for example, as disclosed in U.S. Patent No. 8,148,414 B2.

[0295] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in U.S. Patent Application Publication No. 2014 / 0057918, for example, a compound of formula (V):

Chemical formula

[0296] In certain embodiments of the compound of formula (V), R 15 is methyl.

[0297] In certain embodiments of the compound of formula (V), R 15 is ethyl.

[0298] In certain embodiments of the compound of formula (V), R 15 is 3-6 alkyl.

[0299] In certain embodiments of the compound of formula (V), R 15 is methyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0300] In certain embodiments of the compound of formula (V), R 15 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.

[0301] In certain embodiments of the compound of formula (V), the compound is as follows: methyl = (2-morpholinoethyl) fumarate; methyl = (3-morpholinopropyl) fumarate; methyl = (4-morpholinobutyl) fumarate; methyl = (5-morpholinopentyl) fumarate; or methyl = (6-morpholinohexyl) fumarate; or a pharmaceutically acceptable salt, inclusion complex, or solvate thereof.

[0302] In certain embodiments of the compound of formula (V), the compound is as follows: [Chemical formula] or [Chemical formula] or a pharmaceutically acceptable salt, inclusion complex, or solvate thereof.

[0303] Paragraph

[0304] [Translator's note: In WO2016 / 081355, it is in

[0304] , and in this specification, it corresponds to

[0301] ] The compounds listed are Chemistry 4-D It is named using Draw Pro, Version 7.01c (Chemlnnovation Software, Inc., San Diego, California).

[0304] In one embodiment, the compound of formula (V) may be prepared using methods known to those skilled in the art, for example, as disclosed in US Patent Application Publication No. 2014 / 0057918.

[0305] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (VI):

Chemical formula

Chemical formula

[0306] In certain embodiments of the compound of formula (VI), R 20 is optionally substituted C 1-6 alkyl. In certain embodiments of the compound of formula (VI), R 20 is optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of the compound of formula (VI), R 20 is methyl.

[0307] In certain embodiments of the compound of formula (VI), R 16 is C 1-10 alkyl. In certain embodiments of the compound of formula (VI), R 16 is optionally substituted C 1-6 alkyl. In certain embodiments of the compound of formula (VI), R 16 is optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of the compound of formula (VI), R 16 is optionally substituted C 5-15 aryl. In certain embodiments of the compound of formula (VI), R 16 is optionally substituted C5-C 10 aryl.

[0308] In one embodiment, the monoalkyl fumarate prodrug is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (VI’): [Chemistry] or a pharmaceutically acceptable salt, clathrate, solvate, or stereoisomer thereof, wherein R 16 is C 1-10 alkyl, C 6-10 aryl, hydroxyl, -O-C 1-10 alkyl, or -O-C 6-10 aryl; R 17 、R 18 、and R 19 are each, independently, C 1-10 alkyl, C 6-10 aryl, hydroxyl, -O-C 1-10 alkyl, -O-C 6-10 aryl, or [Chemical formula] wherein R 20 is C 1-6 alkyl; these are each optionally substitutable; and n, p, and q are each, independently, 0 to 4; provided that at least one of R 17 、R 18 、and R 19 is [Chemical formula] In certain embodiments of the compound of formula (VI’), R

[0309] is methyl. 20 In certain embodiments of the compound of formula (VI) or formula (VI’), the compound is: (dimethylsilanediyl)dimethyl = difumarate; methyl = ((trimethoxysilyl)methyl) = fumarate; methyl = ((trihydroxysilyl)methyl) fumarate; or trimethyl(methylsilanetriyl) trifumarate; or a pharmaceutically acceptable salt thereof.

[0310]

[0311] In certain embodiments of the compound of formula (VI) or formula (VI’), the compound is: [Chemical formula] or [Chemical formula] ​ or a pharmaceutically acceptable salt thereof.

[0312] In one embodiment, the compounds of formula (VI) and formula (VI') may be prepared using methods known to those skilled in the art, for example, as disclosed in WO2013 / 119677.

[0313] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug as disclosed in WO2013 / 119677, for example, a compound of formula (VII):

Chemical formula

[0314] In certain embodiments of the compound of formula (VII), R 21 is optionally substituted C 1-6 alkyl. In certain embodiments of the compound of formula (VII), R 21 is optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of the compound of formula (VII), R 21 is methyl.

[0315] In certain embodiments of the compound of formula (VII), R 22 and R 23 are each independently optionally substituted C 1-10 alkyl. In certain embodiments of the compound of formula (VII), R 22 and R 23is each, independently, optionally substituted C 1-6 alkyl. In certain embodiments of the compounds of formula (VII), R 22 and R 23 are each, independently, optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of the compounds of formula (VII), R 22 and R 23 are each, independently, optionally substituted C 5-14 aryl. In certain embodiments of the compounds of formula (VII), R 22 and R 23 are each, independently, optionally substituted substituted C 5-10 aryl.

[0316] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (VII’):

Chemical formula

[0317] In one embodiment, the compounds of formula (VII) and formula (VII’) may be prepared using methods known to those skilled in the art, for example, as disclosed in WO2013 / 119677.

[0318] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (VIII):

Chemical formula

[0319] In certain embodiments of the compound of formula (VIII), R 24 is optionally substituted C1-C6 alkyl. In certain embodiments of the compound of formula (VIII), R 24 is optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of the compound of formula (VIII), R 24 is methyl.

[0320] In certain embodiments of the compound of formula (VIII), R 25 , R 26 , and R 27 are each hydroxyl. In certain embodiments of the compound of formula (VIII), R 25 , R 26 , and R 27 are each, independently, optionally substituted C 1-10 alkyl. In certain embodiments of the compound of formula (VIII), R 25 , R 26 , and R 27 are each, independently, optionally substituted C 1-6 alkyl. In certain embodiments of the compound of formula (VIII), R 25 , R 26 , and R 27are each, independently, methyl, ethyl, or isopropyl, optionally substituted. In certain embodiments of the compounds of formula (VIII), R 25 , R 26 , and R 27 are each, independently, optionally substituted C 5-14 aryl. In certain embodiments of the compounds of formula (VIII), R 25 , R 26 , and R 27 are each, independently, optionally substituted C 5-10 aryl.

[0321] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (VIII’):

Chemical formula

[0322] In one embodiment, the compounds of formula (VIII) and formula (VIII’) may be prepared using methods known to those skilled in the art, for example, as disclosed in WO2013 / 119677.

[0323] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (IX): [Chemical formula] or a pharmaceutically acceptable salt, inclusion complex, solvate, or stereoisomer thereof, wherein R 28 each is, independently, C 1-6 alkyl; and R 29 is C 1-10 alkyl; each of these is optionally substitutable.

[0324] In certain embodiments of the compound of formula (IX), R 28 each is, independently, optionally substituted C 1-6 alkyl. In certain embodiments of the compound of formula (IX), R 28 each is, independently, optionally substituted methyl, ethyl, or isopropyl. In certain embodiments of the compound of formula (IX), R 28 each is methyl.

[0325] In certain embodiments of the compound of formula (IX), R 29 is optionally substituted C 1-6 alkyl. In certain embodiments of the compound of formula (IX), R 29 is optionally substituted methyl, ethyl, or isopropyl.

[0326] In one embodiment, the monoalkyl fumarate prodrug is a prodrug disclosed in WO2013 / 119677, for example, a compound of formula (IX’): [Chemical formula] or a pharmaceutically acceptable salt, inclusion complex, solvate, or stereoisomer thereof, wherein R 28 is C 1-6 alkyl; and R 29 is C1-10 is alkyl.

[0327] In one embodiment, the compounds of formula (IX) and formula (IX’) may be prepared using methods known to those skilled in the art, for example, as disclosed in WO2013 / 119677.

[0328] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in U.S. Patent No. 8,669,281B1, for example, a compound of formula (X):

Chemical formula

[0329] In certain embodiments of the compound of formula (X), R 30 is methyl. In certain embodiments of the compound of formula (X), R 30 is ethyl.

[0330] In certain embodiments of the compound of formula (X), L a is a substituted or unsubstituted C 1-6 alkyl linker. In certain embodiments of the compound of formula (X), L a is a substituted or unsubstituted C 1-3 alkyl linker. In certain embodiments of the compound of formula (X), L a is a substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compound of formula (X), L a is a methyl-substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compound of formula (X), L a is a dimethyl-substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compound of formula (X), L a is a methyl- or dimethyl-substituted C2 alkyl linker. In certain embodiments of the compound of formula (X), L a is an unsubstituted C2 alkyl linker.

[0331] In certain embodiments of the compound of formula (X), R 31 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X), R 31 is unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X), R 31 is unsubstituted C 1-3 alkyl. In certain embodiments of the compound of formula (X), R 31 is unsubstituted C 1-2 alkyl.

[0332] In certain embodiments of the compound of formula (X), R 31 is C(O)OR a substituted C 1-6 alkyl, wherein R a is hydrogen or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X), R 31 is S(O)(O)R b substituted C 1-6 alkyl, wherein R b is unsubstituted C 1-6 alkyl.

[0333] In certain embodiments of the compound of formula (X), R 32 is hydrogen. In certain embodiments of the compound of formula (X), R 32 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X), R 32 is unsubstituted C 1-6 alkyl.

[0334] In certain embodiments of the compound of formula (X), R 31 and R 32Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted heteroaryl containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S, or a substituted or unsubstituted heterocycle containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

[0335] In certain embodiments of the compound of formula (X), R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted heterocycle containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

[0336] In certain embodiments of the compound of formula (X), R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring.

[0337] In certain embodiments of the compound of formula (X), R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted piperidinyl ring.

[0338] In certain embodiments of the compound of formula (X), R 31 and R 32 Together with the nitrogen atom to which they are attached, they form an unsubstituted piperidinyl ring.

[0339] In certain embodiments of the compound of formula (X), R 31 and R 32 Together with the nitrogen atom to which they are attached, they form a halogen-substituted piperidinyl ring. In certain embodiments of the compound of formula (X), R 31 and R32 together with the nitrogen atom to which they are attached form a 4-halogen-substituted piperidinyl ring.

[0340] In certain embodiments of the compound of formula (X), R 31 and R 32 together with the nitrogen atom to which they are attached form an unsubstituted morpholinyl ring.

[0341] In certain embodiments of the compound of formula (X), R 31 and R 32 together with the nitrogen atom to which they are attached form an unsubstituted pyrrolidinyl ring.

[0342] In certain embodiments of the compound of formula (X), R 31 and R 32 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heteroaryl containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

[0343] In certain embodiments of the compound of formula (X), R 31 is substituted or unsubstituted C 6-10 aryl. In certain embodiments of the compound of formula (X), R 31 is unsubstituted C6-C 10 aryl. In certain embodiments of the compound of formula (X), R 31 is unsubstituted phenyl. In certain embodiments of the compound of formula (X), R 31 is unsubstituted benzyl.

[0344] In one embodiment, the compound of formula (X) may be prepared using methods known to those skilled in the art, for example, as disclosed in U.S. Patent No. 8,669,281 B1.

[0345] In one embodiment, the prodrug of monoalkyl fumarate is the prodrug disclosed in U.S. Patent No. 8,669,281B1, for example, a compound of formula (X'): [Chemical formula] or a pharmaceutically acceptable salt, inclusion complex, solvate, or stereoisomer thereof, wherein R 33 is unsubstituted C 1-6 alkyl; L a’ is a substituted or unsubstituted C 1-6 alkyl linker, a substituted or unsubstituted C 3-10 carbocycle, a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted heterocycle containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S, or a substituted or unsubstituted heteroaryl containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S; and R 34 is hydrogen, a substituted or unsubstituted C 1-6 alkyl, a substituted or unsubstituted C 2-6 alkenyl, a substituted or unsubstituted C 2-6 alkynyl, a substituted or unsubstituted C 6-10 aryl, a substituted or unsubstituted C 3-10 carbocycle, a substituted or unsubstituted heterocycle containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S, or a substituted or unsubstituted heteroaryl containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

[0346] In certain embodiments of the compound of formula (X'), R 33 is methyl. In certain embodiments of the compound of formula (X'), R 33 is ethyl.

[0347] In certain embodiments of the compound of formula (X'), L a’is a substituted or unsubstituted C 1-6 alkyl linker. In certain embodiments of the compound of formula (X’), L a’ is a substituted or unsubstituted C 1-3 alkyl linker.

[0348] In certain embodiments of the compound of formula (X’), L a’ is a substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compound of formula (X’), L a’ is a methyl-substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compound of formula (X’), L a’ is a dimethyl-substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compound of formula (X’), L a’ is a methyl- or dimethyl-substituted C2 alkyl linker. In certain embodiments of the compound of formula (X’), L a’ is an unsubstituted C2 alkyl linker.

[0349] In certain embodiments of the compound of formula (X’), R 34 is a substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X’), R 34 is an unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X’), R 34 is methyl. In certain embodiments of the compound of formula (X’), R 34 is an unsubstituted C 1-3 alkyl. In certain embodiments of the compound of formula (X’), R 34 is an unsubstituted C 1-2 alkyl.

[0350] In certain embodiments of the compound of formula (X’), R 34 is C(O)OR a’ substituted C 1-6 alkyl, wherein R a’ is H or unsubstituted C 1-6is alkyl. In certain embodiments of the compound of formula (X’), R 34 is S(O)(O)R b’ substituted C 1-6 alkyl, wherein R b is unsubstituted C 1-6 alkyl.

[0351] In one embodiment, the compound of formula (X’) may be prepared using methods known to those skilled in the art, for example, as disclosed in U.S. Patent No. 8,669,281 B1.

[0352] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in U.S. Patent No. 8,669,281 B1, for example, a compound of formula (X’’):

Chemical formula

[0353] In certain embodiments of the compounds of formula (X''), R 35 is methyl. In certain embodiments of the compounds of formula (X''), R 35 is ethyl.

[0354] In certain embodiments of the compounds of formula (X''), L a’’ is a substituted or unsubstituted C 1-6 alkyl linker. In certain embodiments of the compounds of formula (X''), L a’’ is a substituted or unsubstituted C 1-3 alkyl linker.

[0355] In certain embodiments of the compounds of formula (X''), L a’’ is a substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compounds of formula (X''), L a’’ is a methyl-substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compounds of formula (X''), L a’’is a dimethyl-substituted or unsubstituted C2 alkyl linker. In certain embodiments of the compound of formula (X''), L a’’ is a methyl or dimethyl-substituted C2 alkyl linker. In certain embodiments of the compound of formula (X''), L a’’ is an unsubstituted C2 alkyl linker.

[0356] In certain embodiments of the compound of formula (X''), R 36 is a substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X''), R 36 is an unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X''), R 36 is an unsubstituted C 1-3 alkyl. In certain embodiments of the compound of formula (X''), R 36 is an unsubstituted C 1-2 alkyl.

[0357] In certain embodiments of the compound of formula (X''), R 36 is C(O)OR a’’ substituted C 1-6 alkyl, wherein R a’’ is hydrogen or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X''), R 36 is S(O)(O)R b’’ substituted C 1-6 alkyl, wherein R b’’ is unsubstituted C 1-6 alkyl.

[0358] In certain embodiments of the compound of formula (X''), R 36 and R 37Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted heteroaryl containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S, or a substituted or unsubstituted heterocycle containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

[0359] In certain embodiments of the compound of formula (X''), R 36 and R 37 Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted heterocycle containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

[0360] In certain embodiments of the compound of formula (X''), R 36 and R 37 Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, or morpholinyl ring.

[0361] In certain embodiments of the compound of formula (X''), R 36 and R 37 Together with the nitrogen atom to which they are attached, they form a substituted or unsubstituted piperidinyl ring. In certain embodiments of the compound of formula (X''), R 36 and R 37 Together with the nitrogen atom to which they are attached, they form an unsubstituted piperidinyl ring. In certain embodiments of the compound of formula (X''), R 36 and R 37 Together with the nitrogen atom to which they are attached, they form a halogen-substituted piperidinyl ring. In certain embodiments of the compound of formula (X''), R 36 and R 37 Together with the nitrogen atom to which they are attached, they form a 4-halogen-substituted piperidinyl ring.

[0362] In certain embodiments of the compound of formula (X''), R 36 and R 37 together with the nitrogen atom to which they are attached form an unsubstituted morpholinyl ring.

[0363] In certain embodiments of the compound of formula (X''), R 36 and R 37 together with the nitrogen atom to which they are attached form an unsubstituted pyrrolidinyl ring.

[0364] In certain embodiments of the compound of formula (X''), R 36 and R 37 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heteroaryl containing one or two five- or six-membered rings and 1 to 4 heteroatoms selected from N, O, and S.

[0365] In certain embodiments of the compound of formula (X''), R 36 is a substituted or unsubstituted C 6-10 aryl. In certain embodiments of the compound of formula (X''), R 36 is an unsubstituted C 6-10 aryl. In certain embodiments of the compound of formula (X''), R 36 is an unsubstituted phenyl. In certain embodiments of the compound of formula (X''), R 36 is an unsubstituted benzyl.

[0366] In certain embodiments of the compound of formula (X''), R 37 is hydrogen.

[0367] In certain embodiments of the compound of formula (X''), R 37 is a substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X''), R 37 is an unsubstituted C 1-6 alkyl.

[0368] In certain embodiments of the compound of formula (X''), R 38 is unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (X''), R 38 is unsubstituted C 1-3 alkyl. In certain embodiments of the compound of formula (X''), R 38 is methyl.

[0369] In one embodiment, the compound of formula (X'') may be prepared using methods known to those skilled in the art, for example, as disclosed in U.S. Patent No. 8,669,281 B1.

[0370] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in U.S. Patent No. 8,669,281 B1, for example, a compound of formula (XI):

Chemical formula

[0371] In certain embodiments of the compound of formula (XI), R 39 is methyl. In certain embodiments of the compound of formula (XI), R 39 is ethyl.

[0372] In certain embodiments of the compound of formula (XI), R 40 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (XI), R 40 is unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (XI), R 40 is unsubstituted C 1-3 alkyl. In certain embodiments of the compound of formula (XI), R 40 is unsubstituted C 1-2 alkyl.

[0373] In certain embodiments of the compound of formula (XI), R 40 is C(O)OR b substituted C 1-6 alkyl, wherein R b is hydrogen or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (XI), R 40 is S(O)(O)R b substituted C 1-6 alkyl, wherein R b is unsubstituted C 1-6 alkyl.

[0374] In certain embodiments of the compound of formula (XI), R 40 is a substituted or unsubstituted C 6-10 aryl. In certain embodiments of the compound of formula (XI), R 40 is an unsubstituted C 6-10 aryl. In certain embodiments of the compound of formula (XI), R 40 is an unsubstituted phenyl. In certain embodiments of the compound of formula (XI), R 40 is an unsubstituted benzyl.

[0375] In certain embodiments of the compound of formula (XI), R 41 is hydrogen.

[0376] In certain embodiments of the compound of formula (XI), R 41 is a substituted or unsubstituted C 1-6 alkyl. In certain embodiments of the compound of formula (XI), R 41 is an unsubstituted C 1-6 alkyl.

[0377] In certain embodiments of the compound of formula (XI), R 42 , R 43 , R 44 , and R 45 are each hydrogen.

[0378] In certain embodiments of the compound of formula (XI), R 42 is a substituted or unsubstituted C 1-6 alkyl, and R 43 , R 44 , and R 45 are each hydrogen. In certain embodiments of the compound of formula (XI), R 42 is an unsubstituted C 1-6 alkyl, and R 43 , R 44 , and R 45 are each hydrogen.

[0379] In certain embodiments of the compound of formula (XI), R44 is a substituted or unsubstituted C 1-6 alkyl, and R 42 , R 43 , and R 45 are each hydrogen. In certain embodiments of the compound of formula (XI), R 44 is an unsubstituted C 1-6 alkyl, and R 42 , R 43 , and R 45 are each hydrogen.

[0380] In certain embodiments of the compound of formula (XI), R 42 and R 44 are each independently a substituted or unsubstituted C 1-6 alkyl, and R 43 and R 45 are each hydrogen. In certain embodiments of the compound of formula (XI), R 42 and R 44 are each independently an unsubstituted C 1-6 alkyl, and R 43 and R 45 are each hydrogen.

[0381] In certain embodiments of the compound of formula (XI), R 42 and R 43 are each independently a substituted or unsubstituted C 1-6 alkyl, and R 44 and R 45 are each hydrogen. In certain embodiments of the compound of formula (XI), R 42 and R 43 are each independently an unsubstituted C 1-6 alkyl, and R 44 and R 45 are each hydrogen.

[0382] In certain embodiments of the compound of formula (XI), R 44 and R 45 are each independently a substituted or unsubstituted C 1-6 alkyl, and R42 and R 43 are each hydrogen. In certain embodiments of the compound of formula (XI), R 44 and R 45 are each, independently, unsubstituted C 1-6 alkyl, and R 42 and R 43 are each hydrogen.

[0383] In one embodiment, the compound of formula (XI) may be prepared using methods known to those of skill in the art, for example, as disclosed in U.S. Patent No. 8,669,281 B1.

[0384] In one embodiment, the prodrug of monoalkyl fumarate is a prodrug disclosed in U.S. Patent No. 8,669,281 B1, for example, a compound of formula (XII):

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0385] In certain embodiments of the compounds of formula (XII), R 46 is methyl. In certain embodiments of the compounds of formula (XII), R 46 is ethyl.

[0386] In certain embodiments of the compounds of formula (XII),

Chemical formula

Chemical formula

[0387] In certain embodiments of the compounds of formula (XII),

Chemical formula

Chemical formula

[0388] In certain embodiments of the compounds of formula (XII),

Chemical formula

Chemical formula

Claims

【Claim 1】 The method or composition described in the specification.

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