Method for treating multiple sclerosis

Abstract

The present invention relates to methods of treating multiple sclerosis by oral administration of at least 20 mg / day, preferably 50-100 mg / day, of obrutinib to a subject in need thereof. The method is effective for treating relapse-remission type multiple sclerosis for ten times.

Description

Field of the Invention

[0001] The present invention relates to a method of orally administering 20 - 100 mg / day of orelabrutinib to a patient in need thereof for the treatment of multiple sclerosis. Background of the Invention

[0003] Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS). Multiple sclerosis affects 2.1 million people globally each year and nearly 1 million people in the United States, and is also considered a major cause of the global economic health burden. Genetic and environmental factors play important roles in the pathogenesis of multiple sclerosis by activating the immune response and causing an inflammatory reaction. MS patients may have different clinical courses. In most patients, the disease presents as relapsing - remitting multiple sclerosis (RRMS). It is the most common type of multiple sclerosis, accounting for approximately 85% of all cases.

[0004] Multiple sclerosis is an autoimmune - active disease directed against central nervous system antigens. Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system, which is clinically characterized by relapses and remissions and usually leads to progressive physical impairment. The cause of MS is unknown; however, pathological, genetic, and immunological features have been identified, indicating that the disease has an autoimmune basis. Although the antigen targets in MS are thought to be confined within the CNS, there may be systemic immunoregulatory defects. T cells reactive to myelin basic protein (MBP) have been detected in the blood of MS patients. Circulating blood cells in MS patients are also activated to enhance cytokine synthesis. Increased induced cytokine synthesis by peripheral monocytes has been measured several weeks before a recurrent MS attack. Thus, the overproduction of tumor necrosis factor (TNF), interleukin - 1 (IL - 1), and interferon by circulating blood cells may serve as peripheral triggers or markers for inducing CNS demyelinating inflammation.

[0005] The activities and interactions of B cells, T cells, and myeloid cells are involved in the immunopathological features of multiple sclerosis. Antigen - activated B cells exert effector functions through antigen presentation and the production of cytokines and antibodies. Macrophages and microglial cells, which are abundant in MS lesions, also contribute to tissue damage.

[0006] Currently, there is no cure for multiple sclerosis, but the disease course can be modified by disease - modifying therapies with different efficacies, unique safety profiles, and tolerances.

[0007] There remains a significant unmet medical need for treating MS to reduce the relapse frequency and improve radiological lesions.

[0008] Brief Description of the Drawings

[0009] Figure 1A Shows the clinical scores of EAE mice administered a single oral dose of 30 mg / kg of orelabrutinib (QD) or vehicle control (PO, QD) daily on the specified days. Figure 1B Shows the relative percentage change in body weight of EAE mice administered 30 mg / kg of orelabrutinib (PO, QD) or vehicle control (PO, QD) daily on the specified days.

[0010] Figure 2 Shows the study design of the clinical trial (Example 2) to evaluate the safety and efficacy of oral orelabrutinib in the treatment of patients with multiple sclerosis.

[0011] Figure 3 Shows the cumulative mean number of new Gd+T1 brain lesions adjusted at the visits up to week 24 (post hoc analysis, N = 115). Detailed implementation mode

[0012] The inventors found that orelabrutinib at a dose of at least 20 mg / day, preferably 50 - 100 mg / day, can effectively treat multiple sclerosis.

[0013] Orelabrutinib is a chemically synthesized small molecule. The chemical name is 2-(4-phenoxyphenyl)-6-[1-(prop-2-enoyl)piperidin-4-yl]pyridine-3-carboxamide, with a molecular weight of 427.50. The CAS number is 1655504-04-3. The chemical structure of orelabrutinib is shown below.

[0014]

[0015] The present invention provides methods and pharmaceutical compositions for treating subjects suffering from multiple sclerosis and for maintaining and / or increasing the myelin content in subjects suffering from multiple sclerosis. The method comprises administering to a subject suffering from multiple sclerosis an oral dose of 50 - 100 mg / day of orelabrutinib.

[0016] The present invention can be used to treat four main clinical types of MS: 1) relapsing-remitting MS ("RR-MS"), which is characterized by well-defined relapses with complete recovery or with sequelae and residual deficits at the time of recovery; the period between disease relapses characterized by the absence of disease progression; 2) secondary progressive MS ("SP-MS"), which is characterized by an initial relapsing-remitting course followed by progression, with or without occasional relapses, minor remissions and plateaus; 3) primary progressive MS ("PP-MS"), which is characterized by disease progression from onset, with occasional pauses and allowing for temporary minor improvements; and 4) progressive-relapsing MS ("PR-MS"), which is characterized by a progressive disease onset with distinct acute relapses, with or without complete recovery; the relapse intervals characterized by continuous progression.

[0017] In one embodiment, orelabrutinib slows or prevents neurodegeneration, including demyelination and neuronal death.

[0018] Pharmaceutical composition

[0019] The present invention provides a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and the active compound orelabrutinib. The amount of the active compound in the pharmaceutical composition is generally about 0.1-5% in injection preparations, about 1-90% in tablet preparations, and 1-100% in capsule preparations.

[0020] In one embodiment, the pharmaceutical composition can be in dosage forms such as tablets, capsules, granules, fine granules, powders, syrups, suppositories, injectable solutions, patches, etc. For example, the active compound can be prepared in Ora- (aqueous oral suspension, including water, microcrystalline cellulose, carboxymethyl cellulose, xanthan gum, carrageenan, calcium sulfate and trisodium phosphate). The above pharmaceutical composition can be prepared by conventional methods. The pharmaceutically acceptable carrier is not the active ingredient and can be selected by those skilled in the art using conventional standards.

[0021] Pharmaceutically acceptable carriers include, but are not limited to, non-aqueous solutions, suspensions, emulsions, microemulsions, micellar solutions, and gels. Pharmaceutically acceptable carriers may also include, but are not limited to, the following components: saline and aqueous electrolyte solutions; ionic and non-ionic osmotic agents such as sodium chloride, potassium chloride, glycerol, and glucose; pH regulators and buffers such as hydroxides, phosphates, citrates, acetates, borates; and triethanolamine; antioxidants such as bisulfites, sulfites, metabisulfites, thiosulfites, ascorbic acid, acetylcysteine, cysteine, glutathione, butylated hydroxyanisole, butylated hydroxytoluene, tocopherol, and ascorbyl palmitate; surfactants such as lecithin, phospholipids including, but not limited to, phosphatidylcholine, phosphatidylethanolamine, and phosphatidylinositol; poloxamers and poloxamines; polysorbates such as polysorbate 80, polysorbate 60, and polysorbate 20; polyethers such as polyethylene glycol and polypropylene glycol; polyvinyl alcohols such as polyvinyl alcohol and povidone; cellulose derivatives such as microcrystalline cellulose, methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and hydroxypropyl methyl cellulose and their salts; petroleum derivatives such as mineral oil and white petrolatum; lanolin, peanut oil, palm oil, soybean oil and other fats; glycerol mono-, di-, and triesters; polymers of acrylic acid such as carboxy polymethylene gels and hydrophobically modified crosslinked acrylate copolymers; polysaccharides such as dextran and glycosaminoglycans such as sodium hyaluronate; xanthan gum and carrageenan. Such pharmaceutically acceptable carriers can be preserved using well-known preservatives to prevent bacterial contamination, which include, but are not limited to, benzalkonium chloride, ethylenediaminetetraacetic acid and its salts, benzethonium chloride, chlorhexidine, chlorobutanol, methylparaben, thimerosal, and phenethyl alcohol, or can be formulated as single- or multi-use non-preservative formulations.

[0022] For example, tablets or capsules of an active compound may contain other excipients that are not biologically active and do not react with the active compound. Excipients for tablets or capsules may include fillers, binders, lubricants and glidants, disintegrants, wetting agents, and release rate regulators. Binders promote the adhesion of formulation particles and are important for tablet formulations. Examples of excipients for tablets or capsules include, but are not limited to, carboxymethyl cellulose, cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, karaya gum, starch, tragacanth, gelatin, magnesium stearate, titanium dioxide, poly(acrylic acid), and polyvinylpyrrolidone. For example, tablets may contain inactive ingredients such as colloidal silica, crospovidone, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, sodium starch glycolate, and / or titanium dioxide. Capsule formulations may contain inactive ingredients such as gelatin, magnesium stearate, and / or titanium dioxide.

[0023] Method of Use

[0024] The present invention relates to a method for treating multiple sclerosis. Obutinib is administered in the form of a pharmaceutical composition, which comprises a pharmaceutically active ingredient and a pharmaceutically acceptable formulation. The first step in implementing this method is to first screen subjects suffering from multiple sclerosis, and then administer to the subjects an effective dose of obutinib for treatment. The "effective dose" herein refers to the amount of drug that can improve the pathological condition or relieve the symptoms of the disease in the treatment of the disease.

[0025] In one embodiment, the method can treat relapsing-remitting MS, secondary progressive MS, primary progressive MS, and progressive-relapsing MS.

[0026] In one embodiment, the method includes the patient taking obutinib orally for at least one month at a dose of approximately 50-100 mg per day. The "approximately" as expressed herein means ±5% of the stated value.

[0027] In one embodiment, the daily dose of obutinib taken by the patient is 50-80 mg.

[0028] In one embodiment, the daily dose of obutinib taken by the patient is a single dose of 50-80 mg.

[0029] In one embodiment, the daily dose of obutinib taken by the patient is a single dose of 80 mg.

[0030] In one embodiment, the treatment period for the patient is three months to two years

[0031] In one embodiment, a subject suffering from multiple sclerosis, such as relapsing-remitting multiple sclerosis, after taking an effective dose of obutinib for a period of time, can achieve one or more of the following changes compared to a subject receiving a placebo: (a) a reduced relapse frequency; (b) a reduced likelihood of relapse in the subject; (c) a reduced annual relapse rate in the subject; (d) a reduced risk of disability in the subject; (e) a reduced number of newly developed or newly enlarged T2 lesions; (f) a reduced number of new non-enhancing T1 lesions in the subject; (g) a reduced number of gadolinium (Gd + ) lesions in the subject.

[0032] In another embodiment, a subject suffering from relapsing-remitting multiple sclerosis, after taking an effective dose of obutinib, can achieve one or more of the following changes compared to a subject receiving a placebo after a period of time: (a) a reduction in the annual relapse rate of at least 30%; (b) a reduction in the risk of disability onset in the subject of at least 30%; (c) a reduction in the number of newly developed or newly enlarged T2 lesions in the subject of at least 65%.

[0033] The present invention also relates to the use of orelabrutinib in the method for treating MS, wherein the subject is orally administered at a dose of 50-100 mg per day for at least one month.

[0034] Furthermore, the present invention also relates to the use of 50-100 mg of orelabrutinib for the preparation of a medicament for treating MS, wherein the subject is orally administered at a dose of 50-100 mg per day for at least one month.

[0035] The pharmaceutical composition of the present invention can be administered topically and systemically. Topical administration is mainly topical application. Systemic administration includes oral administration, injection (such as intravenous injection, intramuscular injection, subcutaneous or rectal injection) and other systemic administration routes. In systemic administration, the active ingredient of the drug first reaches the plasma and then acts on the target tissue. Oral administration is the preferred administration route of the present invention. The dose of the pharmaceutical composition may vary depending on the patient's condition and individual response, and therefore, it may also be used in combination with other therapeutic drugs.

[0036] Generally, the effective oral dose of orelabrutinib for adult subjects is about 50-100 mg per day. The daily dose can be taken once or divided into 2, 3, 4 or 6 portions for taking. For example, the dosage can be 50 mg once a day, or 50 mg twice a day, or 80 mg once a day.

[0037] In one embodiment, the pharmaceutical composition is administered to the subject by subcutaneous injection.

[0038] The subject can receive any of the above administration methods, and the treatment period of orelabrutinib can also fluctuate within a certain range, such as ranging from one week to any period of the remaining life of the subject. For example, the administration time of orelabrutinib can be ≥1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 or 50 weeks, or ≥1, 2, 3, 4, 5, 6, 7, 8, 9, 11 or 12 months, or ≥1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40 or 50 years.

[0039] Those skilled in the art can recognize that there are multiple drug delivery mechanisms that can be used in the present invention

[0040] The present invention is applicable to treating mammals, such as humans, horses and dogs, and is particularly applicable to humans.

[0041] The following examples further illustrate the present invention. These examples are intended to illustrate the present invention and should not be construed as limiting it.

[0042] Example

[0043] Example 1 In vivo study of oral administration of orelabrutinib in a mouse model of multiple sclerosis

[0044] Multiple sclerosis is a chronic inflammatory demyelinating disease of the central nervous system. Experimental autoimmune encephalomyelitis (EAE) is very important for studying the neuroinflammatory pathway and has become one of the most commonly used animal models similar to human multiple sclerosis. In this study, the synthetic polypeptide MOG 35-55 -induced EAE mouse model was constructed to evaluate the in vivo efficacy of obutinib.

[0045] A 100 μL emulsion composed of 0.75 mg / mL MOG35-55 and 4 mg / mL CFA was subcutaneously injected into two different sites on each posterior rib of each C57BL / 6 mouse. On the day of immunization and two days later, 300 ng of pertussis toxin in 100 μL of PBS was intraperitoneally injected. The mice were randomly divided into the following 2 groups: vehicle and obutinib 30 mg / kg / day. Each group had 10 animals. On the day of immunization, the animals were administered the vehicle or the test compound QD via PO gavage for 21 days.

[0046] EAE induced by MOG35-55 peptide in mice was evaluated on day 9 after immunization. The severity of EAE disease in control vehicle-treated mice continued to increase from 0.4 to 2.0, reached a peak of 2.0 on day 15 after slowly decreasing to 1.5 on day 21. The degree of weight loss was negatively correlated with the clinical score. On day 15 after immunization, the weight loss was as high as 10%. In contrast, oral obutinib at 30 mg / kg / day significantly improved the severity of EAE, reduced the clinical score and weight loss. The average score of obutinib-treated mice was 0.9 on day 15 and then continued to decrease to 0.6 on day 21 (p<0.05). At the same time, obutinib reduced the weight loss associated with EAE( Figure 1A , 1B).

[0047] In summary, the oral dose of obutinib significantly improved the severity of EAE, with a 50% reduction in the EAE score and weight loss at 30 mg / kg / day. Obutinib can effectively alleviate the disease progression in the mouse EAE model, which may provide support for the development of obutinib for the treatment of human MS.

[0048] Example 2 Clinical study of oral obutinib in patients with multiple sclerosis

[0049] This is a randomized, double-blind, placebo-controlled phase 2 study of obutinib in patients with relapsing-remitting multiple sclerosis (RRMS), which consists of 2 parts: the core phase and the open-label extension (OLE). The core phase has been completed and the OLE part is ongoing.

[0050] The completed core period consisted of a 4-week screening period and a 24-week treatment period. Patients with RRMS were randomly assigned in a 1:1:1:1 ratio to one of 4 treatment groups: placebo, orelabrutinib 50 mg once daily (QD), orelabrutinib 50 mg twice daily (BID), or orelabrutinib 80 mg QD. At week 13, patients in the placebo group were switched to orelabrutinib 50 mg QD.

[0051] The ongoing OLE part was a single-treatment-group study to recruit patients who completed the week 24 visit in the core period for continued treatment and to collect additional long-term safety and efficacy data. The OLE part consisted of a 1-day entry visit (the day of the week 24 visit in the core period) and a treatment period of up to 96 weeks. After completing the OLE or early discontinuation, patients would have safety follow-up approximately 4 weeks after their final dose during the OLE period. During the OLE period, eligible patients received orelabrutinib 50 mg QD.

[0052] Major inclusion criteria:

[0053] 1) Male or female patients aged 18 to 55 years (inclusive).

[0054] 2) Diagnosed with relapsing-remitting multiple sclerosis (RRMS) based on the McDonald criteria (2017 revised version) (Thompson et al., 2018).

[0055] 3) Neurologically stable for at least 30 days before screening and baseline.

[0056] 4) At least 1 documented relapse within 2 years before screening, including:

[0057] a. 1 relapse within 1 year before randomization, or

[0058] b. At least 1 Gd+T1 lesion detected by MRI within 6 months before randomization.

[0059] 5) Disability Status (EDSS) score of 0 to 5.5 (including the cut-off) at screening and baseline (day 1)

[0060] a. For patients with an EDSS score of 0 to 2 (including the cut-off) at screening and baseline (day 1), the inclusion criterion was disease duration (since symptom onset) ≤ 10 years.

[0061] 6) Women of childbearing potential must agree to use barrier contraception and another highly effective contraceptive method (based on ICH M3[R2]) simultaneously within 4 weeks before randomization, during the trial, and for 90 days after the last use of the investigational medicinal product (IMP).

[0062] Major exclusion criteria:

[0063] Patients meeting any of the following criteria will be excluded from this study:

[0064] Disease status

[0065] 1) Patients diagnosed with progressive MS according to the McDonald criteria (2017 revised version), including primary progressive MS and secondary progressive MS.

[0066] 2) Patients with an EDSS score ≤ 2 at screening and baseline (day 1) and a disease duration > 10 years.

[0067] 3) Patients with other immune diseases other than MS, or any other condition requiring oral, intravenous (IV), intramuscular, or intra-articular corticosteroid injection. However, well-controlled type 2 diabetes or thyroid diseases will not be excluded.

[0068] 4) Patients with a history of past or current other neurological diseases similar to MS, including but not limited to neuromyelitis optica, transverse myelitis, simultaneous bilateral optic neuritis, Lyme disease, neurosarcoidosis, and cerebrovascular diseases.

[0069] 5) Patients with a history of past or current progressive multifocal leukoencephalopathy (PML).

[0070] 6) Patients with active, clinically significant viral, bacterial, or fungal infections, or major infections requiring hospitalization or parenteral anti-infective drug treatment within 4 weeks before screening, or completion of oral anti-infective drug treatment within 2 weeks before screening or during the screening period, or a history of recurrent infections (i.e., 3 or more infections of the same type within 12 months). However, vaginal candidiasis, onychomycosis, and genital or oral herpes simplex virus that are judged by the investigator to be adequately controlled will not be excluded.

[0071] 7) Patients

[0072] · with a history of past or current active tuberculosis (TB), or

[0073] · receiving treatment for latent tuberculosis infection (LTBI), or

[0074] · having untreated LTBI, determined based on a positive TB skin test result (induration ≥ 5 mm) with purified protein derivative within 3 months before screening, or

[0075] · during the screening period - positive TB test

[0076] Patients with a documented history of completed appropriate treatment for LTBI will not be excluded and do not require testing;

[0077] Indeterminate - The TB test result can be retested once. If the retest result is positive or indeterminate, it is considered positive.

[0078] Patients who have been in contact with family members suffering from active pulmonary tuberculosis will also be excluded.

[0079] 8) Suffering from Gilbert syndrome or chronic liver disease.

[0080] 9) Suffering from hemophilia, having a history of life-threatening severe bleeding, and / or suffering from a coagulation disorder.

[0081] 10) Having undergone splenectomy or any major surgical operation within 2 months before screening.

[0082] 11) Having had a myocardial infarction or cerebrovascular disease within 6 months before screening, or currently suffering from active angina pectoris, having had congestive heart failure with a New York Heart Association (NYHA) functional class of III or IV in the past or currently, uncontrolled epilepsy, or long-term untreated hypertension (systolic blood pressure ≥ 160 mmHg and / or diastolic blood pressure ≥ 100 mmHg).

[0083] 12) Having had suicidal tendencies within 6 months before screening, or answering "yes" to item 4 or 5 of the Columbia - Suicide Severity Rating Scale (C - SSRS) during the screening period.

[0084] 13) Having had severe depression within 6 months before screening (clinically stable mild depression will not be excluded).

[0085] 14) Patients with a history of tumors. However, patients with adequately treated basal cell carcinoma or squamous cell carcinoma of the skin (never exceeding 3 lesions) or carcinoma in situ of the cervix / cervical intraepithelial neoplasia will not be excluded, unless the cure time exceeds 5 years.

[0086] 15) Breastfeeding / lactating or pregnant women.

[0087] 16) Having electrocardiogram (ECG) abnormalities during the screening period that, in the investigator's judgment, may affect participation in the study.

[0088] 17) Having other abnormalities that, in the investigator's judgment, have clinical significance.

[0089] Previous / concomitant treatment

[0090] 18) Injection (such as intravenous injection, intramuscular injection, intra - articular injection) or oral administration of glucocorticoids, or adrenocorticotropic hormone (such as Acthar gel) within 4 weeks before randomization. Inhaled or topical corticosteroids are permitted.

[0091] 19) Having received treatment with β - interferon or glatiramer acetate within 4 weeks before randomization.

[0092] 20) Received dimethyl fumarate, difluprednate fumarate or other fumarate esters within the previous 4 weeks randomly.

[0093] 21) Received teriflunomide within the previous 4 weeks randomly (if an accelerated elimination procedure (AEP) was carried out), or received teriflunomide within the previous 14 weeks randomly (if AEP was not completed before randomization).

[0094] 22) Received natalizumab within the previous 3 months randomly. Please note that patients who have used natalizumab within the previous 6 months need to undergo MRI examination for progressive multifocal leukoencephalopathy (PML) before screening.

[0095] 23) Received S1P inhibitors within the previous 24 weeks randomly (such as, fingolimod, siponimod, ozanimod, ponesimod).

[0096] 24) Received immunoglobulin (Ig) or plasma exchange therapy within the previous 12 weeks randomly.

[0097] 25) Have received rituximab, ofatumumab or ocrelizumab in the past or currently, except for the following situations:

[0098] · The patient has received rituximab, ofatumumab or ocrelizumab only once, and the reason for drug withdrawal is not treatment failure, and the time of the last drug use is at least 48 weeks before randomization.

[0099] 26) Have received daclizumab, any B cell depletion therapy, BTK inhibitor, mitoxantrone, or lymphocyte depletion therapy (such as, alemtuzumab, CD4 antibody, cladribine, cyclophosphamide, azathioprine, total body irradiation, bone marrow transplantation, or other similar therapies not listed) in the past or currently.

[0100] 27) Patients who have had a stable dose of extended-release fampridine or fampridine concomitant therapy for 3 months before randomization will not be excluded.

[0101] 28) The use of medical marijuana for the treatment of MS symptoms will be excluded, unless it complies with MS treatment guidelines and local regulations. Cannabinoids without THC are allowed to be used, and the dose, dosage form and administration route should be recorded as concomitant medications.

[0102] 29) Receiving anticoagulant or antiplatelet therapy, except for the following situations:

[0103] · Lower daily dose of aspirin (81 mg) for protecting the cardiovascular system.

[0104] · Stopped taking fish oil supplements 4 weeks before randomization.

[0105] 30) Regular use of NSAIDs (except as needed). Regular use of aspirin for the purpose of protecting the cardiovascular system will not be excluded.

[0106] 31) Use of a strong to moderate CYP3A inducer within 3 weeks before randomization, or use of a strong to moderate CYP3A inhibitor within 1 week before randomization, or treatment with both a strong to moderate CYP3A inducer and inhibitor during the study.

[0107] Previous / current clinical research experience

[0108] 32) Participated in a clinical trial and received the investigational medicinal product (IMP) within 6 months before screening or within 5 half-lives of the IMP (whichever is longer).

[0109] Diagnostic assessment

[0110] 33) Meet any of the following criteria:

[0111] a. History of human immunodeficiency virus (HIV) or positive test result during screening.

[0112] b. History of hepatitis C virus (HCV) or positive antibody test result during screening.

[0113] c. Positive hepatitis B surface antigen (HbsAg) and / or positive hepatitis B core antibody test result.

[0114] 34) Estimated glomerular filtration rate (eGFR) < 30 mL / min / 1.73 m2, calculated by the central laboratory with correction for 4 variables of diet in the RenalDisease equation. Patients who may develop kidney disease (such as acute kidney injury) after taking gadolinium-based contrast agents will also be excluded.

[0115] 35) ALT, AST, amylase or lipase > 2x ULN, total bilirubin > 1.5x ULN, or other clinically significant abnormal findings.

[0116] 36) Severe cytopenia, including neutrophil count < 1,500 / mm3, platelet count < 75,000 / mm3, absolute lymphocyte count < 1,000 / mm3, or white blood cell count < 3,500 / mm3. 37)

[0117] International normalized ratio (INR) ≥ 1.5, or activated partial thromboplastin time (APTT) ≥ 1.5x ULN.

[0118] 38) B cell CD19 count below the normal range during screening.

[0119] Other exclusion criteria

[0120] 39) Patients who are allergic to, contraindicated for, or intolerant to orelabrutinib or its excipients (including orelabrutinib tablets and placebo tablets).

[0121] 40) Patients who cannot undergo MRI scans, including MRI scan contraindications such as known gadolinium contrast agent allergy or other contraindications, claustrophobia, presence of a pacemaker, cochlear implant, ferromagnetic device or clip, intracranial vascular clip, insulin pump, or nerve stimulator on the body.

[0122] 41) Vaccination with live virus vaccines or attenuated live virus vaccines within 1 month before screening.

[0123] 42) The average daily alcohol consumption within 6 months before screening reaches the following criteria: for men, the average weekly alcohol consumption > 14 units, or for women, the average weekly alcohol consumption > 7 units. One unit is equivalent to 8 g of alcohol: half a pint (about 240 ml) of beer, 1 glass (125 ml) of wine, or 1 (25 ml) shot of spirits.

[0124] Dosage and administration schedule:

[0125] The trial design is as Figure 2 shown. Eligible RRMS patients will be randomly assigned in a 1:1:1:1 ratio to receive placebo or orelabrutinib (50 mg QD, 80 mg QD, and 50 mg BID), and the specific administration schedule is as follows:

[0126] · Group 1: Placebo (Week 1 - Week 12) / 50 mg QD orelabrutinib (Week 13 - Week 24);

[0127] · Group 2: 50 mg QD orelabrutinib (Week 1 - Week 24);

[0128] · Group 3: 80 mg QD orelabrutinib (Week 1 - Week 24);

[0129] · Group 4: 50 mg BID orelabrutinib (Week 1 - Week 24).

[0130] After taking placebo for 12 weeks, patients in Group 1 will switch from taking placebo to taking 50 mg QD orelabrutinib. In the case of good safety and tolerance, they will subsequently enter an independent open-label extension period (OLE) to ensure continuous medication for patients.

[0131] Patients will start taking placebo or orelabrutinib orally on the first day of the treatment cycle. Patients will return to the research center on the 8th day after the start of the study and on the first day of every 4 weeks after the start of treatment to receive safety and efficacy evaluations.

[0132] Treatment duration:

[0133] This study included a 4-week screening period, a 24-week treatment period, and a 4-week follow-up period.

[0134] Primary study objective:

[0135] To evaluate the efficacy of orelabrutinib compared with placebo in relapsing-remitting multiple sclerosis during a 12-week treatment period, using the cumulative number of new gadolinium-enhanced (GdE) T1 magnetic resonance (MRI) brain lesions as the evaluation index.

[0136] Primary study endpoint:

[0137] The cumulative number of new GdE T1 brain lesions of orelabrutinib compared with placebo at 12 weeks

[0138] Secondary study objectives:

[0139] To evaluate the efficacy of orelabrutinib compared with placebo through clinical symptoms and imaging indexes.

[0140] To evaluate the safety and tolerability of orelabrutinib.

[0141] Secondary study endpoints:

[0142] To evaluate the efficacy and safety of orelabrutinib compared with placebo:

[0143] The cumulative number of new Gd+T1 brain lesions up to week 24 compared with placebo.

[0144] The total number of GdE T1 lesions at weeks 12, 16, 20, and 24.

[0145] The total number of new or enlarged T2 lesions at weeks 12, 16, 20, and 24.

[0146] The annualized relapse rate (ARR) judged according to the protocol-defined relapse criteria at weeks 12 and 24.

[0147] The proportion of patients without relapse at weeks 12 and 24. The change in EDSS relative to baseline at weeks 12 and 24.

[0148] The change in the volume of GdE T1 lesions relative to baseline at weeks 12 and 24

[0149] The change in the volume of T2 lesions relative to baseline at weeks 12 and 24

[0150] To evaluate safety (according to NCI-CTCAE 5.0); vital signs; electrocardiogram (ECG) and laboratory result abnormalities according to the nature, severity, and incidence of adverse events (AEs).

[0151] Research group of the invention content ·

[0152] Intention-to-treat (ITT) population.

[0153] 158 patients were randomly assigned: 40 in the placebo group, 37 in the 50 mg QD group, 41 in the 50 mg BID group, and 40 in the 80 mg QD group.

[0154] Three force majeure events during the study resulted in the loss of MRI data at the 4th, 8th, or 12th week time points: the war and crisis in Ukraine, the outbreak of the COVID-19 pandemic, and a partial clinical hold by the FDA.

[0155] Post hoc analysis set (PHS) population. 115 patients remained after excluding those who missed any of the 3 MRI data points within the first 12 weeks: 27 in the placebo group, 30 in the 50 mg QD group, 29 in the 50 mg BID group, and 29 in the 80 mg QD group.

[0156] 132 patients completed 12 weeks of treatment, and 127 patients completed 24 weeks of treatment.

[0157] Primary endpoint

[0158] Cumulative number of new Gd+T1 brain lesions up to week 12

[0159] In the ITT (intention-to-treat) population, for the orelabrutinib treatment groups of 50 mg QD, 50 mg BID, and 80 mg QD, the percentage reduction in lesions relative to placebo at week 12 was 73.3%, 78.8%, and 80.5% respectively, and all reached statistical significance.

[0160] In the PHS (post hoc analysis) population, for the orelabrutinib treatment groups of 50 mg QD, 50 mg BID, and 80 mg QD, the percentage reduction in lesions relative to placebo at week 12 was 73.8%, 81.0%, and 90.4% respectively, and all reached statistical significance.

[0161] Table 1 shows the cumulative number of new Gd+T1 brain lesions at week 12 by analysis population. (PHS population, N = 115) The adjusted mean cumulative number, percentage reduction (orelabrutinib vs placebo) associated with p-values was estimated from a Poisson regression model with a Pearson scale parameter, a log link function, and offset to the log number of scans at week 12. The baseline number of Gd+T1 brain lesions was included as a continuous covariate in the model.

[0162] Table 1

[0163]

[0164] The primary endpoint was achieved for all active treatment groups, with the 80 mg QD group showing the highest reduction of 90.4% in new Gd+T1 brain lesions at Week 12.

[0165] Primary secondary endpoints

[0166] · Cumulative number of new Gd+T1 lesions up to Week 24

[0167] Control of new T1 lesions was achieved in all olitinib groups after 4 weeks of treatment, and the effect persisted up to 24 weeks. In the PHS population, compared with placebo, all three original active treatment groups of 50 mg QD, 50 mg BID, and 80 mg QD still showed significant cumulative lesion reductions of 67.4%, 83.3%, and 92.3% respectively from Week 4 to Week 24, although the placebo group switched to 50 mg QD treatment after Week 12. The 80 mg QD dose remained the best dose for lesion control throughout the 24 weeks.

[0168] All olitinib groups achieved control of new T1 lesions after 4 weeks of treatment, and this effect persisted up to 24 weeks. Olitinib at 80 mg QD maintained the best dose level for T1 lesion control throughout the 24 weeks. Although the placebo group switched to 50 mg QD treatment after Week 12, compared with the placebo / 50 mg QD switch group, all three original active treatment groups still showed significant cumulative lesion reductions from Week 4 to Week 24 ( Figure 3 and Table 1). Figure 3 The mean cumulative number of new Gd+T1 brain lesions adjusted by visit up to Week 24 is shown (PHS, n = 115). The adjusted mean cumulative number was estimated from a Poisson regression model with a Pearson scale parameter, a log link function, and offset by the logarithm of the number of scans up to that visit. The baseline number of Gd+T1 brain lesions was included as a continuous covariate in the model.

[0169] Table 2 shows the cumulative number of new Gd+T1 lesions from Week 4 to Week 24. (PHS population, n = 115).

[0170] Table 2

[0171]

[0172]

[0173] · Annualized relapse rate (ARR) up to Week 24

[0174] At week 12, compared with the placebo group, the ARRs in all orelabrutinib groups decreased and continued to decrease through week 24. In the PHS population, compared with 0.14 in the placebo / 50 mg QD conversion arm, low ARRs of 0.05, 0.12, and 0.06 were achieved at week 24 in the 50 mg QD, 50 mg BID, and 80 mg QD groups, respectively.

[0175] Efficacy Summary

[0176] Compared with placebo, in all orelabrutinib treatment groups of 50 mg QD, 50 mg BID, and 80 mg QD, there was a statistically significant decrease in the cumulative number of new Gd+T1 lesions at week 12. The 80 mg QD group showed the highest decrease of 90.4%. Efficacy appears to be dose-dependent, increasing in the order of 50 mg QD, 50 mg BID, and 80 mg QD, indicating a potential Cmax-driven efficacy correlation.

[0177] In all groups initially treated with orelabrutinib, control of new T1 lesions persisted for up to 24 weeks. Orelabrutinib at 80 mg QD maintained the best dose level of Gd+T1 lesion control throughout 24 weeks, with the highest lesion decrease of 92.3% at week 24. Although the placebo group switched to 50 mg QD treatment after week 12, compared with the placebo / 50 mg QD group, all 3 original active treatment groups still showed a significant cumulative lesion decrease from week 4 to week 24. In addition, the annual relapse rate in all active treatment groups decreased at week 24.

[0178] The invention and the manner and process of making and using it are now described in full, clear, concise, and exact terms, so that a person skilled in the art can make and use the invention. It should be understood that the preferred embodiments of the invention are described above, and modifications can be made within the scope of the claims of the invention. To clearly indicate and claim the invention, the following claims summarize this specification.

Claims

1. A method for treating multiple sclerosis (MS), the method comprising the following steps: Subjects in need are orally administered ibrutinib at a dose of 50-100 mg / day for at least one month.

2. The method according to claim 1, wherein the subject is treated with ibrutinib at a dose of 50-80 mg / day.

3. The method according to claim 1, wherein the subject is treated with ibrutinib at a dose of 50-80 mg / day as a single dose.

4. The method according to claim 1, wherein the subject is treated with ibrutinib at a dose of 80 mg / day as a single dose.

5. The method according to any one of claims 1-4, wherein the subject is treated for 3 months to 2 years.

6. The method according to claim 1, for treating relapsing-remitting MS, secondary-progressive MS, primary progressive MS, and progressive-relapsing MS.

7. The method according to claim 6, for treating relapsing-remitting MS.

8. Use of ibrutinib for the treatment of multiple sclerosis, wherein it is orally administered to subjects in need at a dose of 50-100 mg / day for at least 1 month.

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