BTK inhibitors for treating multiple sclerosis

Abstract

This disclosure relates to a compound represented by the following structure (1): A method for treating multiple sclerosis (MS) is provided using JPEG2026516050000009.jpg4890 or a pharmaceutically acceptable salt thereof.

Description

[Background technology]

[0001] Related applications This application asserts the benefit of the filing date under Section 119(e) of the United States Patent Act with respect to U.S. Provisional Application No. 63 / 464,288 filed on 5 May 2023 and U.S. Provisional Application No. 63 / 541,965 filed on 2 October 2023, the entirety of which is incorporated herein by reference.

[0002] Multiple sclerosis (MS) is a chronic, autoimmune, demyelinating disorder of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal damage, 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-remitting multiple sclerosis (RMS) includes patients with clinical isolation syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and active secondary progressive multiple sclerosis (SPMS). During the relapse-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 radioisotope separation syndrome (RIS) may develop MS.

[0003] While MS treatment has advanced significantly over the past 25 years with the approval of numerous medications, many MS patients continue to experience persistent disability progression, often receiving treatments that are tolerable, require cumbersome monitoring, or carry the risk of severe adverse events (SAEs), or even life-threatening side effects. A significant unmet need remains for well-tolerated MS treatments, including highly effective new options for treating the inflammatory component of MS found across the spectrum of progressive multiple sclerosis (PMS), as well as for effective treatment of disability progression independent of relapsing activity. [Overview of the project]

[0004] This disclosure provides a method for treating multiple sclerosis in subjects requiring treatment, the method comprising administering to a subject an effective amount of compound 1 or a pharmaceutically acceptable salt thereof. This disclosure provides a safe and effective dosing regimen of compound 1. 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, for use in the method of this disclosure.

[0005] In one embodiment, the 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 a subject in need.

[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, or a pharmaceutically acceptable salt thereof, is provided for oral and daily use in the treatment of subjects suffering from MS. [Brief explanation of the drawing]

[0008] [Figure 1] The mean plasma concentration-time profiles of BIIB091 when administered as an IR tablet in different regimens are shown. [Figure 2] This shows the pre-medication plasma BIIB091 concentration after oral administration of multiple doses of 250 mg IR tablets via BID along with MF food. [Figure 3] 250 mg of BIIB091 IR tablets (BID) administered for 7 days showed a 69% inhibition of CD19+ in all B cells (data up to day 9). [Modes for carrying out the invention]

[0009] This disclosure provides a therapy for the treatment of MS in subjects requiring treatment. The method comprises administering compound 1, which is a BTK inhibitor, to the subject. In some embodiments, compound 1 is used as a monotherapy for the treatment of MS.

[0010] 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.

[0011] In some embodiments, the BTK inhibitor is (R)-1-(tert-butyl)-N-(8-(2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)-2-(oxetan-3-yl)-2,3,4,5-tetrahydro-1H-benzo[c]azepin-5-yl)-1H-1,2,3-triazole-4-carboxamide represented by the following structural formula:

Chemical formula

[0012] In some embodiments, in the methods described herein (e.g., for treating MS, relapsing MS, RRMS, SPMS, PPMS, CIS, RIS, etc.), the BTK inhibitor is Compound 1 or a pharmaceutically acceptable salt thereof.

[0013] Treatment method The present disclosure provides a method for treating a subject (e.g., a human patient) suffering from MS by administering Compound 1 to the subject.

[0014] In some embodiments, the MS is relapsing MS.

[0015] In some embodiments, the MS is relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS).

[0016] In some embodiments, the MS is primary progressive MS (PPMS).

[0017] As used herein, "relapsing MS" includes clinically isolated syndrome (CIS), relapsing-remitting disease (RRMS), and active secondary progressive disease.

[0018] In some embodiments, the method can be used to treat multiple sclerosis (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).

[0019] CIS is the first onset of neurological symptoms caused by inflammation and demyelination in the central nervous system. By definition, the manifestation of this symptom must last for at least 24 hours and is characteristic of multiple sclerosis. However, since a person who experiences 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), there is a high probability that neurological symptoms will appear a second time and be diagnosed as relapsing-remitting MS. If no MS-like lesions are associated with CIS on brain MRI examination, the likelihood that the person will develop MS is much lower.

[0020] RRMS is the most common disease course of MS and is 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 not worsening.

[0021] SPMS follows an initial relapsing-remitting course. Some individuals diagnosed with RRMS eventually progress to a secondary progressive course, experiencing a progressive deterioration of neurological function (accumulation of impairment) over time. SPMS can further be characterized as either active (with evidence of relapse and / or new MRI activity during a specified period) or inactive, and as progressive (with evidence of accumulation of impairment over time, regardless of relapse or new MRI activity) or not progressive.

[0022] PPMS is characterized by a progression of neurological function (accumulation of impairment) from the onset of symptoms without early relapse or remission. PPMS can be further characterized as active (with occasional relapses and / or evidence of new MRI activity over a specific period) or inactive, and as progressive (with evidence of accumulation of impairment over time, regardless of relapse or new MRI activity) or non-progressive.

[0023] 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.

[0024] 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.

[0025] 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.

[0026] As used herein, the terms “to treat” or “treatment” mean to obtain 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.

[0027] The “effective dose” of Compound 1 is an amount sufficient to provide a therapeutic benefit to the treatment of any of the diseases or disorders described herein, or to delay or minimize one or more symptoms associated with the disorder or disorder, and is an amount sufficient to provide a therapeutic benefit to the treatment of any of the diseases or disorders described herein, or to delay or minimize one or more symptoms associated with the disorder or disorder, when used in combination with Compound 1. 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 an amount sufficient to produce a therapeutic effect in the treatment of MS as described herein.

[0028] 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] This includes orally administering a pharmaceutically acceptable salt thereof in an amount equivalent to the total daily dose of 200 mg to 1000 mg of compound 1.

[0029] 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).

[0030] 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.

[0031] 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.

[0032] Pharmaceutical composition The pharmaceutical compositions of this disclosure (also referred to herein as the “Disclosed Pharmaceutical Compositions”) comprise one or more pharmaceutically acceptable carriers or diluents and compound 1 or a pharmaceutically acceptable salt thereof.

[0033] "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.

[0034] 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.

[0035] 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 anti-MS agents, 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 1 used according to the dosage reported in the literature and recommended in, for example, the Physician's Desk Reference (57th Ed., 2003).

[0036] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 ranging from 300 mg to 900 mg.

[0037] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 ranging from 400 mg to 800 mg.

[0038] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 ranging from 500 mg to 700 mg.

[0039] In some embodiments, the subjects requiring it are those with a dosage of 200mg-400mg, 300mg-500mg, 400mg-600mg, 500mg-700mg, 600mg- Compound 1 is administered in a total daily dose of 800 mg, 700 mg to 900 mg, 800 mg to 1000 mg, 450 mg to 550 mg, or 650 mg to 750 mg.

[0040] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 200 mg.

[0041] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 300 mg.

[0042] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 400 mg.

[0043] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 500 mg.

[0044] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 600 mg.

[0045] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 700 mg.

[0046] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 800 mg.

[0047] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 900 mg.

[0048] In some embodiments, subjects requiring it are administered a total daily dose of compound 1 of 1000 mg.

[0049] 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.

[0050] In some embodiments, subjects requiring it are orally administered compound 1 once daily (QD) in the above-mentioned amount.

[0051] In some embodiments, subjects requiring it are orally administered compound 1 twice daily (BID) in the above-mentioned amounts.

[0052] 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.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] In some embodiments, the subjects requiring it are those with doses of 100mg-200mg, 150mg-250mg, 200mg-300mg, 250mg-350mg, and 300mg- Compound 1 is administered twice daily (BID) in amounts of 400 mg, 350 mg to 450 mg, 400 mg to 500 mg, 225 mg to 275 mg, or 325 mg to 375 mg.

[0057] In some embodiments, subjects requiring it are administered 200 mg of compound 1 twice daily (BID).

[0058] In some embodiments, subjects requiring it are administered 250 mg of compound 1 twice daily (BID).

[0059] In some embodiments, subjects requiring it are administered 275 mg of compound 1 twice daily (BID).

[0060] In some embodiments, subjects requiring it are administered 300 mg of compound 1 twice daily (BID).

[0061] In some embodiments, subjects requiring it are administered 325 mg of compound 1 twice daily (BID).

[0062] In some embodiments, subjects requiring it are administered 350 mg of compound 1 twice daily (BID).

[0063] In some embodiments, subjects requiring it are administered 375 mg of compound 1 twice daily (BID).

[0064] In some embodiments, subjects requiring it are administered 400 mg of compound 1 twice daily (BID).

[0065] In some embodiments, subjects requiring it are administered 450 mg of compound 1 twice daily (BID).

[0066] In some embodiments, subjects requiring it are administered 500 mg of compound 1 twice daily (BID).

[0067] 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).

[0068] In some embodiments, subjects requiring it are administered compound 1 with food (e.g., a normal meal, a moderate-fat meal, a high-fat meal, etc.). In some embodiments, subjects requiring it are administered compound 1 with a moderate-fat meal. In some embodiments, the moderate-fat meal has a total calorie content of 500 to 800 kcal. In some embodiments, the moderate-fat meal has 14 to 55 g of fat, and / or 25% to 50% by weight of the meal is fat, and / or the total calorie content of the fat in the meal is 125 to 500 kcal. In some embodiments, subjects requiring it are administered compound 1 after a meal (e.g., a normal meal, a moderate-fat meal, etc.). In one embodiment, subjects requiring it are administered compound 1 immediately after a meal (e.g., a normal meal, a moderate-fat meal, etc.), for example, less than 4 hours, less than 2 hours, less than 1 hour, or less than 30 minutes after a meal (e.g., a normal meal, a moderate-fat meal, etc.). In some embodiments, subjects requiring it are administered compound 1 30 to 60 minutes after a meal (e.g., a normal meal, a moderate-fat meal, etc.).

[0069] In some embodiments, subjects requiring this are administered compound 1 while fasting.

[0070] In some embodiments, the methods of this disclosure use tablets of an immediate-release (IR) 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.

[0071] In some embodiments, in the methods described herein, the subject is administered compound 1 in the absence of a cytochrome P450 3A4 (CYP3A4) inhibitor.

[0072] "Administering in the absence of a CYP3A4 inhibitor" means that the subject was not taking a CYP3A4 inhibitor, or had discontinued taking a CYP3A4 inhibitor before treatment with compound 1 or a pharmaceutically acceptable salt thereof was initiated, or had discontinued taking a CYP3A4 inhibitor at the time treatment with compound 1 or a pharmaceutically acceptable salt thereof was initiated. If the subject is taking a CYP3A4 inhibitor, it is desirable that administration of the CYP3A4 inhibitor be terminated 1, 2, 3, 4, 5, or 6 days before the initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof; or at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more before the initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof; or at least 1, 2, or 3 months before the initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof.

[0073] CYP3A4 inhibitors are substances that reduce the activity of CYP3A4. In some embodiments, CYP3A4 inhibitors are potent inhibitors of CYP3A4, such as clarithromycin, indinavir, nefazodone, sacchinavir, subxon, telithromycin, erythromycin, diltiazem, itraconazole, ketoconazole, ritonavir, and goldenseal. Moderate-strength inhibitors include aprepitant, erythromycin, fluconazole, grapefruit, verapamil, and diltiazem. In some embodiments, CYP3A4 inhibitors are weak inhibitors of CYP3A4, such as cimetidine. Other exemplary CYP3A4 inhibitors include, but are not limited to, amiodarone, voseprevir, chloramphenicol, ciprofloxacin, delavyridine, diethyl-dithiocarbamate, fluvoxamine, gestodene, imatinib, mibefradil, mifepristone, norfloxacin, norfluoxetine, starfruit, telaprevir, and voriconazole. In some embodiments, the CYP3A4 inhibitor is itraconazole.

[0074] In some embodiments, in the method described herein, the subject is administered compound 1 in the absence of a proton pump inhibitor (PPI). In some embodiments, in the method described herein, the subject is administered compound 1 in the absence of a proton pump inhibitor (PPI) while the subject is fasting. In some embodiments, in the method described herein, the subject is administered compound 1 and a proton pump inhibitor (PPI) together with a meal (e.g., a normal meal, a moderate-fat meal, a high-fat meal, etc.).

[0075] "Administering in the absence of PPIs" means that the subject was not taking PPIs, or had discontinued taking PPIs before treatment with compound 1 or a pharmaceutically acceptable salt thereof was initiated, or had discontinued taking PPIs at the time treatment with compound 1 or a pharmaceutically acceptable salt thereof was initiated. If the subject is taking PPIs, it is desirable that PPI administration be terminated 1, 2, 3, 4, 5, or 6 days before the initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof; or at least 1, 2, 3, 4, 5, 6, 7, or 8 weeks or more before the initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof; or at least 1, 2, or 3 months before the initiation of treatment with compound 1 or a pharmaceutically acceptable salt thereof.

[0076] PPIs are a class of drugs that cause a significant and long-term reduction in gastric acid production by irreversibly inhibiting the gastric H+ / K+ ATPase proton pump. Exemplary PPIs include, but are not limited to, omeprazole, lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole, and iraprazole. In some embodiments, the PPI is rabeprazole. [Examples]

[0077] Example 1. Phase 2 Clinical Trial Test design This is a multicenter, randomized, blinded, active-controlled, phase 2 trial to evaluate the safety and efficacy of compound 1 in participants with RMS. The primary objective of this trial is to investigate the safety and tolerability of BIIB091 monotherapy in participants with RMS, and the primary endpoints of the trial are the incidence of adverse events (AEs) and single-agent inflammatory encephalograms (SAEs). A secondary objective of this trial is to evaluate the effect of BIIB091 monotherapy on MRI measurements of active CNS inflammation.

[0078] 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.

[0079] Participants with active RMS will be randomized to one of three treatment groups: high-dose monotherapy with compound 1 (350 mg BID), low-dose monotherapy with compound 1 (250 mg BID), or standard-dose monotherapy with DRF (462 mg BID). Analysis of the primary, secondary, and selected exploratory endpoints of the compound 1 monotherapy trial will be conducted. An independent data monitoring committee (IDMC) will review the safety and laboratory data obtained from the compound 1 monotherapy analysis. If unfavorable safety findings are obtained, the IDMC may recommend temporary suspension or termination of the cohort or trial, or modification of the trial design. Further details regarding the IDMC's data review are provided in the IDMC Charter.

[0080] A final analysis of 48 weeks of data from monotherapy with compound 1 will enable an evaluation of the long-term safety and efficacy of compound 1 monotherapy. To maintain blinding, data review at week 16 and members of the trial management team not involved in 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.

[0081] 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 and no later than 14 calendar days prior to baseline [day 1]) 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.

[0082] 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.

[0083] Test locations: Approximately 80 locations are planned worldwide.

[0084] 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.

[0085] Planned number of participants: Approximately 275 participants will be randomized.

[0086] Treatment Group: Participants are randomized to a treatment group. Randomization is stratified by intensive PK cohort (Yes / No) and region (Eastern Europe vs. Others). For stratification purposes, Eastern Europe includes participants from countries such as Poland and the Czech Republic.

[0087] Monotherapy with compound 1: High dose (350mg) BID (N=50) Low dose (250mg) BID (N=50)

[0088] DRF monotherapy: Standard dose (462mg) BID (N=50)

[0089] Sample size determination: The planned sample size is 275 participants. Given a dropout rate of 12%, 275 participants are expected to be enrolled in this study. Of these, 150 will be randomized to a separate compound 1 combination therapy trial.

[0090] 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 occurrence of an AE. Aggregate PK will be collected from up to 25 participants (approximately 10 in each BIIB091 group and approximately 5 in the DRF group).

[0091] 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.

[0092] The number of hospital visits is calculated based on the first day (the day of the first dose).

[0093] 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

[0094] Example 2. Pharmacokinetic studies for the optimization of formulations and treatment regimens. In single-center, open-label trials, pharmacokinetic (PK) variability is reduced, and drug exposure (C) is minimized. max ) while limiting steady state C trough Several formulations and treatment regimens were investigated to achieve a level of >221 ng / mL. This study consisted of three parts.

[0095] Part 1 IR tablets (50 mg) were tested in 19 healthy subjects at different dose levels (150, 250, and 350 mg), and in fed (medium-fat and high-fat) and fasted states, and as once-daily divided doses (12-hour intervals). Subjects were treated with BIIB091 for up to 4 periods. To facilitate comparison between different regimens, subjects were randomized into two groups (Group 1 and Group 2) on Day 1 before dosing in Periods 1, 3, and 4. Period 2 was used as a reference period, and all subjects were administered BIIB091 IR DiC (drug in capsule). [Chemical formula]

[0096] The IR tablet (150 mg) had higher exposures (129% Cmax and 138% AUCinf) and lower variability (CV%) in the range of 17.1% - 30.8% for Cmax and AUCinf compared to 43.4% - 78.1% of the DiC 150 mg reference. For the two doses of IR tablets of 250 mg (fasted) and 350 mg (with MF) administered at 12-hour intervals, the geometric mean C 24 (CV%) was 282 ng / mL (44.7%) and 411 ng / mL (31.1%), respectively, both exceeding the target C trough . When dosed with HF diet, T max was delayed and C max decreased, but the total exposure was similar. When dosed with medium-fat (MF) diet, the delay in T max was shorter compared to high-fat (HF), but the maximum C max and AUC inf were similar. All regimens of BIIB091 tested were generally safe and considered to have good tolerability. Figure 1 shows the plasma concentration of BIIB091 over time.

[0097] Part 2 A new cohort of 12 healthy males and females (non-pregnant and non-lactating) was enrolled and administered medication. The subjects were randomized into two groups of six subjects each, receiving either regimen sequence MNO over three study periods (Group 1) or regimen sequence MNP over three study periods (Group 2). Both groups received medication while fasting during periods 1 and 2. Specifically, BIIB091 alone was administered while fasting during period 1, and BIIB091 was administered with the CYP3A4 inhibitor itraconazole while fasting during period 2. For the PPI evaluation in period 3, BIIB091 was administered to subjects in either a fasted or fed state, contemporaneously with rabeprazole, to assess pharmacokinetics under each of these conditions. [Table 1-1] [Table 1-2]

[0098] These data indicated that BIIB091 is a moderate CYP3A4 substrate. Concomitant administration of CYP3A4 inhibitors increased exposure to BIIB091. Concomitant administration of PPIs reduced the bioavailability of BIIB091 in a fasted state, but when PPIs and BIIB091 were taken with food, the bioavailability of BIIB091 increased compared to a fasted state.

[0099] Part 3

[0100] 250 mg of BIIB091 was administered twice daily (BID) with a moderate-fat meal for 7 days in a new cohort of 10 healthy subjects. After 7 days of BID administration of BIIB091, accumulation appeared to be moderate, and C max and AUC tau The accumulation ratios were 1.49 and 1.75, respectively. Geometric mean C tauThe (CV%) was 407 ng / mL (48.3%), which exceeded the target of >221 ng / mL, and the target was met in 9 out of 10 subjects. Complete inhibition of CD69 upregulation against ex vivo stimulated B cells (mean >90% from baseline before administration on day 1) was observed from 1 hour to 8 hours post-administration (range 96.5–99.2%) on days 1 and 7. See Figure 2. Mean CD69 inhibition decreased slightly to 86.8% and 85.4% at 12 hours post-administration on days 1 and 7, respectively. CD69 inhibition returned to baseline 24 hours after the final dose. IR tablets 250 mg administered via BID for 7 days in a fed state were considered safe and well-tolerated.

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】 The method comprising orally administering a pharmaceutically acceptable salt thereof in an amount equivalent to a total daily dose of 200 mg to 1000 mg of compound 1.

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 as monotherapy.

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

35. The method according to any one of claims 1 to 34, wherein compound 1 is administered to the subject in the absence of a CYP3A4 inhibitor.

36. The method according to claim 35, wherein the CYP3A4 inhibitor is itraconazole.

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