Combination of BTK inhibitors and fumarate esters for use in the treatment of multiple sclerosis

Abstract

This disclosure relates to compound 1, represented by the following structure, when combined with diloximel fumarate (DRF): This invention provides a method for treating multiple sclerosis (MS) using JPEG2026516049000007.jpg6181 or a pharmaceutically acceptable salt thereof.

Description

Technical Field

[0001] Related Applications This application claims the benefit of the filing date under 35 U.S.C. § 119(e) with respect to U.S. Provisional Application No. 63 / 464,290, filed May 5, 2023, and U.S. Provisional Application No. 63 / 541,968, filed Oct. 2, 2023, the entire contents of which are hereby incorporated by reference herein.

Background Art

[0002] Multiple sclerosis (MS) is a chronic, autoimmune demyelinating disorder of the central nervous system (CNS), characterized by inflammation, demyelination, and axonal injury, as well as loss of oligodendrocytes and neurons. It is the most common demyelinating disorder of the CNS, affecting approximately 2.5 million people worldwide. Relapsing multiple sclerosis (RMS) includes patients with clinically isolated syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS). During the relapsing-remitting phase of the disease, patients experience episodes of neurological dysfunction (relapses) separated by relatively stable periods. Other types of MS include primary progressive multiple sclerosis (PPMS) and non-relapsing SPMS. Patients with radiation-induced separation syndrome (RIS) may develop MS.

[0003] With the approval of many pharmaceuticals, MS care has advanced significantly over the past 25 years, but many MS patients continue to experience progressive disability, and many receive treatments that are burdensome, with limited tolerability, or high risk of serious adverse events (SAEs), or even life-threatening side effects. There remains an important unmet need for tolerable MS treatments, including new options for treating the inflammatory component of MS seen across the spectrum of progressive multiple sclerosis (PMS)-type RMS, as well as effective treatment of disability progression independent of relapse activity.

Summary of the Invention

[0004] This disclosure provides a method for treating multiple sclerosis in subjects requiring treatment, the method comprising administering to the subject an effective amount of compound 1 or a pharmaceutically acceptable salt thereof and an effective amount of fumarate ester (FAE) (e.g., DRF). This disclosure provides a safe and effective dosing regimen of compound 1 and DRF. More specifically, this disclosure provides compound 1 in a total daily oral dose of 200 mg to 1000 mg, or an amount equivalent to 200 mg to 1000 mg of compound 1, or a pharmaceutically acceptable salt thereof, for use in the method of this disclosure.

[0005] In one embodiment, the present disclosure provides a method for treating a subject suffering from MS, the method comprising orally administering an effective amount of compound 1 or a pharmaceutically acceptable salt thereof to the subject in need, and co-administering an effective amount of a fumarate ester (FAE). In one embodiment, the FAE is diloximel fumarate (DRF).

[0006] Compound 1, represented by the following structure: [ka] Or a pharmaceutically acceptable salt thereof may be used in the method of this disclosure.

[0007] In another embodiment, 200 mg to 1000 mg of compound 1 or an amount equivalent to 200 mg to 1000 mg of compound 1, a pharmaceutically acceptable salt thereof, is provided in combination with an effective amount of DRF for oral and daily use in the treatment of subjects suffering from MS. [Modes for carrying out the invention]

[0008] This disclosure provides a combination therapy for the treatment of MS in subjects requiring treatment. The method comprises administering compound 1, which is a BTK inhibitor, to a subject in combination with an effective amount of fumarate ester (FAE), for example, DRF.

[0009] BTK inhibitors Bruton's tyrosine kinase (BTK) is a member of the tyrosine kinase hepatocellular carcinoma (TEC) family of protein tyrosine kinases and is expressed in many hematopoietic cell types known to be dysregulated in MS. Furthermore, the activation of pathogenic B cells is considered a crucial factor in maintaining active inflammation in MS. Recent studies in MS patients have established B cells as a clinically validated target cell type in MS. In addition to B cells, there is a supporting body for the pathological role of myeloid cells (monocytes, macrophages, dendritic cells, mast cells, and granulocytes) in MS. BTK is a key signaling node immediately downstream of the B cell receptor (BCR) in B cells and the Fc receptor (FcR) in myeloid cells. In B cells, BTK mediates B cell activation and effector function (such as cytokine secretion and proliferation, as well as differentiation into memory cells and antibody-producing cells) downstream of BCR activation and is required for BCR-mediated antigen presentation to T cells. In myeloid cells, BTK inhibition blocks FcR-dependent pro-inflammatory activity (including cytokine secretion by mast cells, monocytes, and macrophages, reactive oxygen species generation by neutrophils, and basophil degranulation) triggered by the binding of immune complexes to FcR. Genetic removal of all activated FcγR or FcγRIII has established the role of FcR in pathogenicity in myeloid cells in nonclinical models of MS. The role of FcR in disease pathogenesis is not fully understood, but it includes immune complex-mediated endocytosis and antigen presentation to T cells, as well as the regulation of myeloid cell activation and function. Therefore, by targeting both B cells and myeloid cells, BTK inhibitors have the potential to deliver greater clinical benefits compared to therapies that target B cells only.

[0010] In some embodiments, the BTK inhibitor has the following structural formula: [ka] (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazole-4-yl)amino)pyrimidine-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepine-5-yl)-1H-1,2,3-triazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.

[0011] Fumarate ester (FAE) Fumarate esters are, for example, monomethyl fumarate (MMF) or its prodrugs. The term "MMF" refers to the compound, a pharmaceutically acceptable salt, or monomethyl fumarate in its ionized form. As used herein, a prodrug of MMF is a compound that can be metabolized to MMF in vivo.

[0012] MMF and its prodrugs, such as dimethyl fumarate (DMF) or diroximel fumarate (DRF), are an important class of therapeutic agents for the treatment of MS, primarily exerting immunomodulatory effects on the T cell compartment with minimal effects on the B cell compartment. The oral form of DMF has been approved by the U.S. Food and Drug Administration since 2013 under the brand name Tecfidera® for the treatment of patients with relapsed forms of MS. Tecfidera® is available as hard gelatin delayed-release capsules containing 120 mg or 240 mg of dimethyl fumarate. The starting dose of Tecfidera® is 120 mg orally twice daily. After 7 days, the dose should be increased to a maintenance dose of 240 mg orally twice daily.

[0013] In some embodiments, the fumarate ester used in the method of the present invention is MMF. In other embodiments, the fumarate ester is DMF. In yet another embodiment, a combination of MMF and DMF can be used in the method described herein.

[0014] In some embodiments, the FAE in the methods of this disclosure is DRF. DRF (also known as Vumerity®, BIIB098, and ALKS 8700) is an oral diester fumarate therapeutic approved by the U.S. Food and Drug Administration for patients with relapsing MS. Vumerity® is provided as hard delayed-release capsules for oral administration. Each capsule contains 231 mg of diroximel fumarate. The starting dose of Vumerity® is 231 mg orally twice daily. After 7 days, the dose should be increased to a maintenance dose of 462 mg orally twice daily. Following oral administration, DRF undergoes rapid pre-circulation hydrolysis to produce the major active metabolite MMF (the same major metabolite as DMF), as well as the major inactive metabolite 2-hydroxyethylsuccinimide (HES), and the minor metabolite RDC-8439 (Palte, MJ et al “Improving the Gastrointestinal Toloerability of Fumaric Acid Esters: Early Findings on Gastrointestinal Events with Diroximel Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis from the Phase 3, Open-Label EVOLVE-MS-1 Study” Adv Ther (2019) 36:3154-3165). Oral intake at a dose of 462 mg of DRF provides an MMF exposure comparable to that at a dose of 240 mg of DMF. Therefore, the efficacy and safety profile of the 462 mg dose of DRF is expected to be similar to that of 240 mg of DMF. However, DRF has improved GI tolerability compared to DMF.

[0015] In some embodiments, in the methods described herein (for example, to treat MS, recurrent MS, RRMS, SPMS, PPMS, CIS, RIS, etc.), the BTK inhibitor is compound 1 or a pharmaceutically acceptable salt thereof, and the FAE is DRF.

[0016] Treatment method The present disclosure provides a method of treating a subject (e.g., a human patient) suffering from MS by administering to the subject a combination of Compound 1 and a fumaric acid ester (e.g., dimethyl fumarate (DRF)).

[0017] In some embodiments, the MS is relapsing MS.

[0018] In some embodiments, the MS is relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS).

[0019] In some embodiments, the MS is primary progressive MS (PPMS).

[0020] As used herein, "relapsing MS" includes clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease.

[0021] In some embodiments, the method can be used to treat MS selected from relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), non-relapsing SPMS, primary progressive MS (PPMS), clinically isolated syndrome (CIS), and radiologically isolated syndrome (RIS).

[0022] CIS is the first symptom of neurological symptoms caused by inflammation and demyelination in the central nervous system. The manifestation of this symptom must, by definition, last for at least 24 hours and is characteristic of multiple sclerosis. However, since a person who has experienced CIS may or may not develop MS, they do not yet meet the diagnostic criteria for MS. If CIS is accompanied by lesions similar to those seen in MS on brain MRI (magnetic resonance imaging), the neurological symptoms are likely to appear a second time and be diagnosed as relapsing-remitting MS. If the brain MRI examination does not show MS-like lesions in CIS, the likelihood that the person will develop MS is much lower.

[0023] RRMS is the most common disease course of MS, characterized by clearly defined attacks of new or increasing neurological symptoms. After these attacks (also called relapses or exacerbations), a period of partial or complete recovery (remission) follows. During the remission period, all symptoms may disappear, or some symptoms may continue and become permanent. However, no obvious progression of the disease is seen during the remission period. RRMS can further be characterized as active (with relapses and / or evidence of new MRI activity over a specific period) or inactive, as well as worsening (an increase in disability after a relapse is confirmed) or non-worsening.

[0024] SPMS follows an initial relapsing-remitting course. Among those diagnosed with RRMS, some will eventually transition to a secondary progressive course, with progressive worsening of neurological function (accumulation of disability) over time. SPMS can further be characterized as active (with relapses and / or evidence of new MRI activity during a specified period) or inactive, as well as progressive (evidence of accumulation of disability over time, regardless of the presence or absence of relapses or new MRI activity) or non-progressive.

[0025] PPMS is characterized by worsening of neurological function (accumulation of disability) from the onset of symptoms without early relapses or remissions. PPMS can further be characterized as active (occasionally with relapses and / or evidence of new MRI activity over a specific period) or inactive, as well as progressive (evidence of accumulation of disability over time, regardless of the presence or absence of relapses or new MRI activity) or non-progressive.

[0026] Patients diagnosed with RIS do not exhibit any obvious symptoms of MS, but show brain abnormalities similar to those seen in MS patients (e.g., observed on magnetic resonance imaging (MRI)). RIS is often diagnosed during brain scans for unrelated conditions such as headache, migraine, head injury, or stroke. While there is a strong correlation between RIS and MS (RIS often represents the earliest detectable preclinical stage of the disease), RIS patients may not develop MS.

[0027] In the disclosed methods, compound 1 and FAE are administered in combination or used as a combination therapy. Combination therapy means the administration of two or more therapeutic agents to a single subject and is intended to include a treatment plan in which the agents are administered by the same or different routes of administration or at the same or different times. These include simultaneous administration in separate compositions, simultaneous administration in the same composition, and administration in separate compositions at different times. In the present disclosure, compound 1 and FAE (e.g., DRF) may be administered by the same or different routes of administration or at the same or different times. In some embodiments, compound 1 and FAE (e.g., DRF) are administered simultaneously. In some embodiments, compound 1 inhibitor and FAE (e.g., DRF) are administered sequentially. In some embodiments, compound 1 inhibitor is administered before FAE (e.g., DRF). In some embodiments, compound 1 inhibitor is administered after FAE (e.g., DRF).

[0028] As used herein, the term “pharmaceutically acceptable salt” refers to a pharmaceutically acceptable salt that, within the bounds of appropriate medical judgment, is suitable for use in contact with human and lower animal tissues, and that provides a reasonable benefit-risk ratio without excessive toxicity, irritation, or allergic reactions. Pharmacologically acceptable salts are well known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci., 1977, 66, 1-19.

[0029] As used herein, the terms “subject” and “patient” may be used synonymously and refer to mammals in need of treatment, such as humans, companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0030] As used herein, the terms “to treat” or “treatment” mean obtaining a desired pharmacological and / or physiological effect. The effect may be therapeutic, including the partial or substantial achievement of one or more of the following results: partial or complete reduction of the degree of a disease, disorder, or syndrome; relief or improvement of clinical symptoms or signs associated with the disorder; or delay, inhibit, or reduce the likelihood of progression of a disease, disorder, or syndrome.

[0031] The “effective dose” of Compound 1 is the amount sufficient, when combined with an FAE, to provide a therapeutic benefit in the treatment of the disease or disorder described herein, or to delay or minimize one or more symptoms associated with the disease or disorder. The “effective dose” of an FAE described herein is the amount sufficient, when combined with Compound 1, to provide a therapeutic benefit in the treatment of the disorder or disease described herein, or to delay or minimize one or more symptoms associated with the disorder or disorder. The terms “therapeutic effective dose” and “effective dose” are used synonymously. The term “effective dose” may include an amount that improves the overall therapy, reduces or avoids the symptoms, signs or causes of a pathological condition, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, the effective dose is the amount sufficient to produce a therapeutic effect in the treatment of MS described herein. In some embodiments, the effective dose of Compound 1 that may be used in the combination therapy described herein is the same amount as when Compound 1 is used as a monotherapy. In some embodiments, the effective dose of an FAE that may be used in the combination therapy described herein is the same amount as when the FAE is used as a monotherapy. In some embodiments, the effective amount of compound 1 used in the combination therapy described herein is less than the amount used when compound 1 is used as a monotherapy. In some embodiments, the effective amount of FAE used in the combination therapy described herein is less than the amount used when FAE is used as a monotherapy.

[0032] This disclosure provides a method for treating human subjects with multiple sclerosis (MS), wherein the subject receives a total daily dose of compound 1: 200 mg to 1000 mg. [ka] Alternatively, the treatment may include orally administering a pharmaceutically acceptable salt of compound 1 in an amount equivalent to the total daily dose of 200 mg to 1000 mg, administered concurrently with an effective dose of fumarate ester (FAE).

[0033] Compound 1 disclosed herein can be used in the form of a free base or as a salt. Typical salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulfonate. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66:1-19).

[0034] In some embodiments, in the therapeutic methods disclosed herein, compound 1 is administered as a free base. In some embodiments, in the therapeutic methods disclosed herein, a pharmaceutically acceptable salt of compound 1 is administered.

[0035] If the stereochemical configuration of compound 1 at a chiral center is represented by its chemical name (e.g., if the configuration is indicated by a chemical name with "R" or "S") or structure (e.g., if the configuration is indicated by a "wedge" bond), then the enrichment of the indicated configuration with respect to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. The "enrichment of the indicated configuration with respect to the opposite configuration" is expressed in mole percent and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center(s) by the total number of all compounds in the mixture having the same or opposite stereochemical configurations.

[0036] Pharmaceutical composition The pharmaceutical compositions of this disclosure (also referred to herein as “Disclosed Pharmaceutical Compositions”) comprise one or more pharmaceutically acceptable carriers or diluents, and (i) Compound 1 or a pharmaceutically acceptable salt thereof, or (ii) FAE, for example, DRF.

[0037] "Pharmacopoeia-acceptable carriers" and "pharmacopoeia-acceptable diluents" refer to substances that can be included in the pharmaceutical compositions of this disclosure without causing any significantly harmful toxic effects to the subject, and which assist in the formulation and / or administration of activators to a subject and / or absorption by the subject. Non-limiting examples of pharmacopoeia-acceptable carriers and / or diluents include NaCl, Ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings, alcohols, oils, gelatin, carbohydrates, e.g., lactose, amylose or starch, hydroxymethylcellulose, fatty acid esters, polyvinylpyrrolidine, and colorants. Such preparations may be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts to affect osmotic pressure, buffers, colorants, and / or aromatics, which do not react harmfully with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutically acceptable excipients are suitable for use with the disclosed compound or its pharmaceutically acceptable salts.

[0038] The pharmaceutical compositions of this disclosure optionally include one or more pharmaceutically acceptable carriers and / or diluents, such as lactose, starch, cellulose, and dextrose. Other excipients, such as flavoring agents, sweeteners, and preservatives, such as methyl, ethyl, propyl, and butylparabens, may also be included. A more complete list of suitable excipients is found in *Handbook of Pharmaceutical Excipients* (5th Ed., Pharmaceutical Press (2005)). Those skilled in the art will know how to prepare formulations suitable for various types of administration routes. Conventional procedures and components for selecting and preparing suitable formulations are found, for example, in *Remington's Pharmaceutical Sciences* (2003-20th edition) and *The United States Pharmacopeia: The National Formulary* (USP 24 NF19), published in 1999. Carriers, diluents, and / or excipients are “acceptable” in the sense that they are compatible with the other components of the pharmaceutical composition and are not harmful to its recipient.

[0039] Method of administration and dosage form The precise amount of compound administered to provide an "effective dose" to a subject will depend on the type and severity of MS, as well as the subject's characteristics, such as overall health status, age, sex, weight, and drug tolerance. A person skilled in the art will be able to determine the appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, for example, in combination with FAE (e.g., DRF), the "effective dose" of any additional therapeutic agent(s) will depend on the type of drug used. Appropriate doses of approved therapeutic agents are known and can be adjusted by a person skilled in the art depending on the subject's condition, the type of condition(s) being treated, and the amount of compound(s) used according to dosages reported in the literature and recommended in, for example, Physician's Desk Reference (57th Ed., 2003).

[0040] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 ranging from 300 mg to 900 mg.

[0041] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 ranging from 400 mg to 800 mg.

[0042] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 ranging from 500 mg to 700 mg.

[0043] In some embodiments, subjects requiring it are administered compound 1 in a total daily dose of 200 mg to 400 mg, 300 mg to 500 mg, 400 mg to 600 mg, 500 mg to 700 mg, 600 mg to 800 mg, 700 mg to 900 mg, 800 mg to 1000 mg, 450 mg to 550 mg, or 650 mg to 750 mg.

[0044] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 200 mg.

[0045] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 300 mg.

[0046] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 400 mg.

[0047] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 500 mg.

[0048] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 600 mg.

[0049] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 700 mg.

[0050] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 800 mg.

[0051] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 900 mg.

[0052] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 1000 mg.

[0053] In some embodiments, the subjects requiring it are 200mg, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 375mg, 400mg, 425mg, 450mg, 460mg, 470mg, 480mg, 490mg, 500mg, 510mg, 520mg, 530mg, 540mg, 550mg, 560mg, 570mg, 580mg, 590mg, 600mg, 61 Compound 1 is administered in a total daily dose of 0 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 825 mg, 850 mg, 900 mg, 925 mg, 950 mg, 975 mg, or 1000 mg.

[0054] In some embodiments, subjects requiring it are orally administered compound 1 once daily (QD) in the above-mentioned amount.

[0055] In some embodiments, subjects requiring it are orally administered compound 1 twice daily (BID) in the above-mentioned amounts.

[0056] In some embodiments, subjects requiring it are administered 100 mg to 500 mg of compound 1 twice daily (BID). The total daily dose is 200 mg to 1000 mg of compound 1.

[0057] In some embodiments, subjects requiring it are administered 150 mg to 450 mg of compound 1 twice daily (BID). The total daily dose is 300 mg to 900 mg of compound 1.

[0058] In some embodiments, subjects requiring it are administered 200 mg to 400 mg of compound 1 twice daily (BID). The total daily dose is 400 mg to 800 mg of compound 1.

[0059] In some embodiments, subjects requiring it are administered 250 mg to 350 mg of compound 1 twice daily (BID). The total daily dose is 500 mg to 700 mg of compound 1.

[0060] In some embodiments, subjects requiring it are administered compound 1 twice daily (BID) in amounts of 100 mg to 200 mg, 150 mg to 250 mg, 200 mg to 300 mg, 250 mg to 350 mg, 300 mg to 400 mg, 350 mg to 450 mg, 400 mg to 500 mg, 225 mg to 275 mg, or 325 mg to 375 mg.

[0061] In some embodiments, subjects requiring it are administered 200 mg of compound 1 twice daily (BID).

[0062] In some embodiments, subjects requiring it are administered 250 mg of compound 1 twice daily (BID).

[0063] In some embodiments, subjects requiring it are administered 275 mg of compound 1 twice daily (BID).

[0064] In some embodiments, subjects requiring it are administered 300 mg of compound 1 twice daily (BID).

[0065] In some embodiments, subjects requiring it are administered 325 mg of compound 1 twice daily (BID).

[0066] In some embodiments, subjects requiring it are administered 350 mg of compound 1 twice daily (BID).

[0067] In some embodiments, subjects requiring it are administered 375 mg of compound 1 twice daily (BID).

[0068] In some embodiments, subjects requiring it are administered 400 mg of compound 1 twice daily (BID).

[0069] In some embodiments, subjects requiring it are administered 450 mg of compound 1 twice daily (BID).

[0070] In some embodiments, subjects requiring it are administered 500 mg of compound 1 twice daily (BID).

[0071] In some embodiments, subjects requiring it are administered compound 1 in amounts of 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, or 500 mg twice daily (BID).

[0072] In some embodiments, subjects requiring it are administered compound 1 with food (e.g., a normal meal). In some embodiments, subjects requiring it are administered compound 1 with a moderate-fat diet. In some embodiments, the moderate-fat diet has a total calorie content of 500-800 kcal. In some embodiments, the moderate-fat diet has 14-55 g of fat and / or 25-50% by weight of the meal is fat and / or the total calorie content of the fat in the meal is 125-500 kcal. In some embodiments, subjects requiring it are administered compound 1 after a meal (e.g., a normal meal, moderate-fat diet, etc.). In one embodiment, subjects requiring it are administered compound 1 immediately after a meal (e.g., a normal meal, moderate-fat diet, etc.), for example, less than 4 hours, less than 2 hours, less than 1 hour, or less than 30 minutes after the meal (e.g., a normal meal, moderate-fat diet, etc.). In some embodiments, subjects requiring it are administered compound 1 30-60 minutes after a meal (e.g., a normal meal, moderate-fat diet, etc.).

[0073] In some embodiments, subjects requiring this are administered compound 1 while fasting.

[0074] In some embodiments, the subject requiring it is administered compound 1 in the amount described in any one of the embodiments above (for example, any one of paragraphs

[0039] to

[0070] ) in combination with an effective amount of fumarate ester (FAE). In one embodiment, the FAE is diloximel fumarate (DRF).

[0075] In some embodiments, subjects requiring it are administered compound 1 in the amount described in any one of the embodiments above, in combination with 231 mg of DRF, twice daily (BID).

[0076] In some embodiments, subjects requiring it are administered compound 1 in the amount described in any one of the embodiments above, in combination with 350 mg of DRF, twice daily (BID).

[0077] In some embodiments, subjects requiring it are administered compound 1 in the amount described in any one of the embodiments above, in combination with 462 mg of DRF, twice daily (BID).

[0078] In some embodiments, subjects requiring it are administered compound 1 in the amounts described in any one of the embodiments above, in combination with 231 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 462 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, or 600 mg of DRF twice daily (BID).

[0079] In some embodiments, subjects requiring it are administered compound 1 in the amount described in any one of the embodiments above, twice daily (BID) for the first 7 days in combination with 231 mg of DRF, and thereafter twice daily (BID) in combination with 350 mg of DRF.

[0080] In some embodiments, subjects requiring it are administered compound 1 in the amount described in any one of the embodiments above, twice daily (BID) for the first 7 days in combination with 231 mg of DRF, and thereafter twice daily (BID) in combination with 462 mg of DRF.

[0081] In some embodiments, the first and second doses in the BID drug regimen described above are spaced 6 to 15 hours, 8 to 12 hours, 10 to 12 hours, or 15 hours, 14 hours, 13 hours, 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, or 6 hours apart.

[0082] In some embodiments, the methods of this disclosure use tablets of an immediate-release formulation of compound 1. In some embodiments, the tablets contain 50 mg, 150 mg, or 250 mg of compound 1. In some embodiments, the immediate-release formulation of compound 1 comprises one or more excipients selected from silicified microcrystalline cellulose, sodium starch glycolate, sodium stearyl fumarate, and colloidal silicon dioxide. In some embodiments, the immediate-release tablets comprise a film coating containing titanium dioxide, hypromellose, macrogol, yellow iron oxide, and ferric oxide. [Examples]

[0083] Test design This is a multicenter, randomized, blinded, active-controlled phase 2 trial to sequentially evaluate the safety and efficacy of compound 1 in combination with DRF in participants suffering from RMS. The trial design is shown below. [Table 1]

[0084] This study includes a 4-week screening period, a 16-week double-blind active-controlled treatment period, a 32-week blinded active-controlled treatment period, and a 2-week post-treatment safety follow-up period. Participants whose absolute lymphocyte count (ALC) is below the lower limit of normal (LLN) at the 2-week safety follow-up visit will be re-examined and confirmed at 2 weeks. For these participants, the follow-up will be extended at 8-week intervals until their ALC exceeds LLN, or for a maximum of 6 months, or until another disease-modifying therapy is initiated, whichever comes first, and their lymphocyte counts will be monitored.

[0085] Analysis of the primary, secondary, and selected exploratory endpoints of the compound 1 monotherapy study will be conducted. The Independent Data Monitoring Committee (IDMC) will review the safety and laboratory data obtained from the analysis of the compound 1 monotherapy study and recommend whether or not to initiate compound 1 in combination with DRF. If unfavorable safety findings are obtained, the IDMC may recommend pausing or discontinuing the cohort or study, or modifying the study design. Details regarding the IDMC's data review are provided in the IDMC Charter. Selected sponsor team members will participate in an open-label primary analysis of compound 1 monotherapy data at week 16 to decide whether or not to proceed with compound 1 in combination with DRF based on the overall benefit-risk profile and to select the dosage of compound 1 to be used in combination with DRF.

[0086] In combination therapy with compound 1 and DRF, participants in the RMS will be randomized to one of three treatment groups: a combination of the selected compound 1 dose and the standard dose of DRF (462 mg BID), a combination of the selected compound 1 dose and a low dose of DRF (350 mg BID), and DRF monotherapy at the standard dose (462 mg BID). A primary analysis comparing compound 1 / DRF combination therapy with DRF monotherapy will be conducted after all participants have completed their 16-week visit with combination therapy.

[0087] The final analysis of 48-week data from compound 1 monotherapy and compound 1 in combination with DRF will enable long-term safety and efficacy evaluation of compound 1 monotherapy and compound 1 in combination with DRF. To maintain blinding, data review at week 16 (compound 1 monotherapy and combination with DRF) and members of the study management team not involved with the study site will remain blinded for the entire duration of the study. Details regarding the methods for maintaining blinding of the study will be provided in a separate deblinding plan.

[0088] Participants will visit the study site for safety, MRI, and clinical efficacy assessments from day 28 to day 1 (MRI assessment must be completed at least 7 calendar days prior to baseline [day 1] and within 14 calendar days prior) and at weeks 4, 8, 12, 16, 24, and 48. Additional specific safety assessments will be conducted at weeks 1, 2, 6, 36, and 50. The primary efficacy endpoint for combination therapy with compound 1 and DRF is the cumulative number of new T1 GdE lesions at weeks 8, 12, and 16. Secondary endpoints are the effect of the combination therapy on MRI measurements of CNS inflammation and the safety of the combination therapy.

[0089] If a relapse of MS is suspected during the study, the participant must return to the study site for an unscheduled visit and be evaluated within 72 hours of the event's onset to determine if a relapse has occurred. Treatment for acute relapse events may proceed at the discretion of the treating neurologist, only after the studying neurologist has completed the necessary examinations. Treatment for relapse in this study is intravenous administration of methylprednisolone (IVMP) at a dose of ≤1000 mg / day for up to 5 days, with or without tapering of oral prednisone (up to 15 days). Any changes to this treatment must be discussed first with the investigator or designated participant. If the initiation of treatment for relapse with high-dose corticosteroids falls within 7 days of the next scheduled visit, all attempts should be made to obtain an MRI before administering the first dose of high-dose corticosteroids. If the visit occurs outside of scheduled visit hours, it should be recorded as unscheduled. An MRI taken during an unscheduled visit prior to steroid treatment must be at least 21 days after the previous MRI. However, if an unscheduled MRI visit occurs less than 21 days after the previous MRI, the use of Gd should be strongly avoided unless the principal investigator deems it clinically necessary. In this scenario, the next regular MRI should also be obtained.

[0090] Test locations: Approximately 80 locations are planned worldwide.

[0091] Test population: This test will be administered to participants who meet the following criteria: At the time of informed consent, the age range is 18-55 years old (including both ends). Less than 20 years since the onset of MS symptoms Diagnosed with MS according to McDonald's criteria of 2010 or 2017 [Polman2011; Thompson2018] Applicants must have an EDSS score of 0-5.0 at the time of screening. Before the baseline (day 1), at least one of the following must occur: Two or more clinical relapses in the past 24 months (but not within 30 days prior to baseline [Day 1]) AND at least one relapse in the last 12 months prior to randomization. One or more clinical relapses within the past 24 months (but not within 30 days prior to baseline [day 1]) and one or more new brain MRI lesions (Gd-positive and / or new or expanding T2 hyperintensity lesions) within 12 months prior to randomization. This criterion can be met using baseline MRI (local MRI interpretation is permitted). For new or expanding T2 hyperintensity lesions, reference scans cannot be performed more than 12 months prior to randomization. One or more GdE lesions on brain MRI within 6 months prior to randomization.

[0092] Planned number of participants: Approximately 275 participants will be randomized.

[0093] Treatment Group: Participants are randomized to a treatment group. Randomization is stratified by intensive PK cohort (Yes / No) and region (Eastern Europe vs. Other). For stratification purposes, Eastern Europe includes participants from countries such as Poland and the Czech Republic.

[0094] Combination therapy with compound 1 and DRF: Compound 1 selective dose and DRF standard dose (462 mg) BID (N=50) Compound 1 selective dose and DRF low dose (350 mg) BID (N=50)

[0095] DRF monotherapy: Standard dose (462mg) BID (N=50)

[0096] Placebo tablets and placebo capsules (which visually match Compound 1 tablets and DRF capsules, respectively) are administered, and blinding of the treatment group assignment is maintained by misrepresenting both the type and dose level of the investigational drug administered.

[0097] Sample size determination: The planned sample size is 275 participants. With a dropout rate of 12%, 275 participants are expected to be enrolled in this study. Of these, 150 will be randomized to a trial of compound 1 in combination with DRF.

[0098] The sample size of 50 participants per group (44 evaluable) was designed to detect an 80% reduction from the mean number (standard deviation) of cumulative new T1 GdE lesions across MRI scans at weeks 8, 12, and 16 at the standard dose of DRF monotherapy, with approximately 90% power and a 10% type 1 error rate.

[0099] A sample size of 50 participants per treatment group (44 evaluable) allows for an event rate of 3.6% and an 80% or higher probability of observing at least one AE. Intensity PK will be collected from up to 30 participants (approximately 10 participants each in the compound 1 monotherapy, compound 1 and DRF combination therapy, and DRF monotherapy groups).

[0100] Visit Schedule: Participants will make up to 12 scheduled visits during the trial. The trial evaluations conducted at each visit will be recorded in the activity schedule.

[0101] Participants in the monotherapy trial of Compound 1 are not eligible to participate in the combination therapy trial of Compound 1 and DRF. The number of hospital visits is calculated based on day 1 (the day of the first dose).

[0102] Trial participation period: The trial period for participants is approximately 54 weeks and includes the following: 4-week screening period 16-week double-blind, active-controlled treatment period 32-week blinded active-controlled treatment period Two-week post-treatment safety follow-up period

Claims

1. A method for treating a human subject suffering from multiple sclerosis (MS), wherein the method involves administering compound 1 to the subject in a total daily dose of 200 mg to 1000 mg: 【Chemistry 1】 Alternatively, the method comprises orally administering an amount of a pharmaceutically acceptable salt equivalent to a total daily dose of 200 mg to 1000 mg of compound 1, wherein the subject is administered simultaneously with an effective amount of fumarate ester (FAE).

2. The method according to claim 1, wherein the MS is a recurrent type of MS.

3. The method according to claim 1, wherein the MS is relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS).

4. The method according to claim 1, wherein the MS is primary progressive mass sterilization (PPMS).

5. The method according to any one of claims 1 to 4, wherein the subject is administered a total daily dose of compound 1 of 300 mg to 900 mg.

6. The method according to any one of claims 1 to 4, wherein the subject is administered a total daily dose of compound 1 of 400 mg to 800 mg.

7. The method according to any one of claims 1 to 4, wherein the subject is administered a total daily dose of compound 1 of 500 mg to 700 mg.

8. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 200 mg.

9. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 300 mg.

10. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 400 mg.

11. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 500 mg.

12. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 600 mg.

13. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 700 mg.

14. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 800 mg.

15. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 900 mg.

16. The method according to any one of claims 1 to 4, comprising administering compound 1 to the subject in a total daily dose of 1000 mg.

17. The method according to any one of claims 1 to 16, wherein compound 1 is administered to the subject once a day.

18. The method according to any one of claims 1 to 16, wherein compound 1 is administered to the subject twice a day.

19. The method according to claim 18, wherein 100 mg to 500 mg of compound 1 is administered to the subject twice a day.

20. The method according to claim 18, wherein 150 mg to 450 mg of compound 1 is administered to the subject twice a day.

21. The method according to claim 18, wherein 200 mg to 400 mg of compound 1 is administered to the subject twice a day.

22. The method according to claim 18, wherein 250 mg to 350 mg of compound 1 is administered to the subject twice a day.

23. The method according to claim 18, wherein 200 mg of compound 1 is administered to the subject twice a day.

24. The method according to claim 18, wherein 250 mg of compound 1 is administered to the subject twice a day.

25. The method according to claim 18, wherein 275 mg of compound 1 is administered to the subject twice a day.

26. The method according to claim 18, wherein 300 mg of compound 1 is administered to the subject twice a day.

27. The method according to claim 18, wherein 325 mg of compound 1 is administered to the subject twice a day.

28. The method according to claim 18, wherein 350 mg of compound 1 is administered to the subject twice a day.

29. The method according to claim 18, wherein 375 mg of compound 1 is administered to the subject twice a day.

30. The method according to claim 18, wherein 400 mg of compound 1 is administered to the subject twice a day.

31. The method according to claim 18, wherein 450 mg of compound 1 is administered to the subject twice a day.

32. The method according to claim 18, wherein 500 mg of compound 1 is administered to the subject twice a day.

33. The method according to any one of claims 1 to 32, wherein compound 1 is administered to the subject after a normal meal.

34. The method according to any one of claims 1 to 33, wherein the FAE is diloximel fumarate (DRF).

35. The method according to any one of claims 1 to 33, wherein 231 mg of DRF is administered to the subject twice a day.

36. The method according to any one of claims 1 to 33, wherein 350 mg of DRF is administered to the subject twice a day.

37. The method according to any one of claims 1 to 33, wherein 462 mg of DRF is administered to the subject twice a day.

38. The method according to any one of claims 1 to 33, wherein 231 mg of DRF is administered to the subject twice daily for the first seven days, and thereafter 350 mg of DRF is administered to the subject twice daily.

39. The method according to any one of claims 1 to 33, wherein 231 mg of DRF is administered to the subject twice daily for the first seven days, and thereafter 462 mg of DRF is administered to the subject twice daily.

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