Methods of treating Sjogren's syndrome using Bruton's tyrosine kinase inhibitors

Abstract

The present disclosure relates to methods for treating Sjogren's syndrome disease using compounds of formula (I) or pharmaceutically acceptable salts thereof. Also disclosed herein are compounds of formula (I) or pharmaceutically acceptable salts thereof for treating Sjogren's syndrome patients, as well as medicaments, dosing regimens, pharmaceutical formulations, dosage forms and kits for use in the disclosed uses and methods.

Description

[Technical Field]

[0001] The present disclosure relates to methods for treating Sjogren's syndrome using Bruton's tyrosine kinase (BTK) inhibitors. [Background technology]

[0002] Sjögren's syndrome (SjS) is a systemic autoimmune disease of unknown cause characterized by lymphatic infiltration and progressive destruction of exocrine glands (Brito-Zeron P., et al., (2016) Treating the Underlying Pathophysiology of Primary Sjögren's Syndrome: Recent Advances and Future Prospects. Drugs p.1601-1623).

[0003] Although the disease primarily affects the lacrimal and salivary glands, the inflammatory process can target any organ, with approximately 15% of patients exhibiting severe extraglandular findings (Baldini C., et al. (2014) Primary Sjogren's syndrome as a multiorgan disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology (Oxford) p. 839-44). Clinical symptoms are most commonly characterized by salivary and lacrimal gland exocrinopathy, primarily manifested by oral and ocular dryness. However, symptoms can be highly heterogeneous, ranging beyond dryness to include musculoskeletal pain and fatigue affecting nearly all patients, and in a more limited subset, severe extraglandular disease and systemic complications (characterized by periepithelial lymphocytic infiltration and immune complex deposition). The underlying mechanism of Sjögren's syndrome is the destruction of the exocrine epithelium as a result of autoreactive B and T cells (Brito-Zeron P., et al., (2016) Treating the Underlying Pathophysiology of Primary Sjögren's Syndrome: Recent Advances and Future Prospects. Drugs pp. 1601-1623). The high prevalence of autoantibodies, especially those against Ro / SSA, even at very early stages suggests that autoreactive B cells contribute to the pathogenesis of Sjögren's syndrome (Nocturne G., et al., (2018) B cells in the pathogenesis of primary Sjögren's syndrome. Nat Rev Rheumatol pp. 133-145).

[0004] As a result of B-cell pathology, there is also an increased risk for malignant transformation, with 5% of Sjögren's syndrome patients having a 10-fold increased lifetime risk of B-cell lymphoma (Baldini C., et al., (2014) Primary Sjögren's syndrome as a multi-organ disease: impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients. Rheumatology (Oxford) p. 839-44). The estimated prevalence of Sjögren's syndrome is 0.3-1 per 1,000 people (Qin B., et al. (2015) Epidemiology of primary Sjögren's syndrome: a systematic review and meta-analysis. Ann. Rheum. Dis. p. 1983-9), making it the second most common systemic autoimmune disease after rheumatoid arthritis. The disease primarily affects women, with a female-to-male ratio of 9:1, and can occur at any age. The primary impact of Sjögren's syndrome is its severe impact on quality of life and productivity, often driven by the disabling fatigue associated with the disease (Mariette X., et al. (2018) Primary Sjögren's Syndrome. N. Engl. J. Med. pp. 931-939). There are also numerous potentially severe systemic complications involving multiple organ systems, occurring in 20-40% of patients, including arthritis, cutaneous vasculitis, peripheral neuropathy, glomerulonephritis, interstitial nephritis, biliary cholangitis, and bronchiolitis obliterans (Seror R., et al. (2014) Outcome measures for primary Sjögren's syndrome: a comprehensive review. J. Autoimmune. pp. 51-56).

[0005] The clinical features of Sjögren's syndrome can be divided into medically evaluable findings and symptomatic findings in patients. Currently, no single assessment tool can capture the disease activity of both of these clinical manifestations of Sjögren's syndrome. Therefore, the European League Against Rheumatism (EULAR) Sjögren's Syndrome (SS) Patient-Reported Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI) are widely accepted and validated for measuring the symptomatic and systemic findings of Sjögren's syndrome (Sjögren's syndrome) (Franceschini F., et al., (2017), BMC Medicine, 15:69).

[0006] Regarding the current treatment status, there are no internationally approved systemic therapies available for SjS. As far as dry mouth and dry eyes are concerned, treatment for SjS patients is limited to symptomatic care. Steroids and typical DMARDs are largely ineffective, and there are no effective pharmaceutical interventions for the severe fatigue that interferes with daily life. The lack of effective treatment options emphasizes the need to evaluate newer therapeutic approaches for this extremely debilitating disease. Because the pattern of B-cell autoreactivity shares some similarities with systemic lupus and rheumatoid arthritis, B-cell ablative therapy using the anti-CD20 monoclonal antibody (mAb) rituximab has recently been evaluated for both glandular and extraglandular manifestations of SjS and for lymphoma management, with variable success rates. However, this approach is not currently an approved treatment for SjS. The ineffectiveness of rituximab may be related to incomplete B-cell depletion in affected tissues (Brito-Zeron P et al (2016) Treating the Underlying Pathophysiology of Primary Sjögren Syndrome: Recent Advances and Future Prospects. Drugs p. 1601-1623).

[0007] Despite the availability of treatments for SjS, there remains a significant medical need for new therapeutic options for SjS subjects. Summary of the Invention [Means for solving the problem]

[0008] It is an object of the present invention to provide a novel method of treating Sjogren's syndrome disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[0009] Accordingly, disclosed herein is a method of treating Sjögren's syndrome (SjS), comprising administering to a subject in need thereof a daily dose of about 0.5 mg to about 600 mg, preferably a daily dose of about 10 mg to about 200 mg, or more preferably a dose of about 10 mg to about 100 mg, of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[0010] Also disclosed is N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide; or a pharmaceutically acceptable salt thereof, for use in the treatment of SjS, wherein the N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 0.5 mg to about 600 mg, preferably a daily dose of about 10 mg to about 200 mg, and most preferably a daily dose of about 10 mg to about 100 mg. [Brief explanation of the drawings]

[0011] [Figure 1] Blood concentration-time course of Compound (I) after single ascending doses of 0.5 mg to 600 mg. [Figure 2] Blood concentration-time course of Compound (I) after multiple ascending doses of 10 mg to 400 mg, qd. [Figure 3] Blood concentration-time course of Compound (I) following multiple ascending doses of 100 mg bid and 200 mg bid. [Figure 4] Food effect as observed after a single oral dose of 60 mg of a compound of formula (I). [Figure 5] Figure 16. Mean (SD) percent BTK occupancy in peripheral blood following a single dose of a compound of formula (I). [Figure 6] Median percent inhibition of basophil activation versus total daily dose of compound of formula (I) on day 12 of repeated ascending administration of compound of formula (I). [Figure 7] Reduction in wheal size on skin prick testing with repeated ascending doses. DETAILED DESCRIPTION OF THE INVENTION

[0012] Bruton's tyrosine kinase (BTK) is a cytoplasmic tyrosine kinase and a member of the TEC kinase family. BTK is expressed in cells of both the adaptive and innate immune systems, including B cells, macrophages, basophils, mast cells, and platelets. BTK is essential for signaling through the Fc epsilon receptor (FcεR1 for IgE) and activated Fc gamma receptor (FcγR for IgG) as well as the B cell antigen receptor (BCR). BTK inhibition has been shown to be an effective strategy for treating B cell malignancies. The covalent BTK inhibitors ibrutinib (Imbruvica®), acalabrutinib (Calquence®), and zanubrutinib (Brukinsa®) are approved for the treatment of certain B-cell malignancies (Thompson PA, et al, (2018) Bruton's tyrosine kinase inhibitors: first and second generation agents for patients with chronic lymphocytic leukemia (CLL). Expert Opin Investig Drugs p. 31-42).BTK inhibition has shown promising efficacy against B cell autoimmunity in preclinical and clinical trials (Tan SL., et al., (2013) Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives. Pharmacol. Ther. pp. 294-309; Whang JA, et al. (2014) Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov. Today pp. 1200-4; Satterthwaite AB (2017) Bruton's tyrosine kinase, a component of B cell signaling pathways, has multiple roles in the pathogenesis of lupus. Front Immunol p. 1986; Rip J., et al., (2018) The role of Bruton's tyrosine kinase in immune cell signaling and systemic Autoimmunity.Crit.Rev.Immunol.p.17-62).Therefore, inhibition of BTK is an attractive therapeutic approach for treating various autoimmune and chronic inflammatory diseases, including rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, chronic urticaria, atopic dermatitis, asthma, and primary Sjögren's syndrome (Tan SL, Liao C, Lucas MC, et al. (2013) Targeting the SYK-BTK axis for the treatment of immunological and hematological disorders: recent progress and therapeutic perspectives. Pharmacol. Ther. p. 294-309; Whang JA, Chang BY (2014) Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov. Today p. 1200-4).

[0013] Furthermore, BTK levels have been shown to be elevated in circulating B cells in a significant percentage of SjS patients, who are accompanied by high serum rheumatoid factor (RF) levels (Corneth OBJ et al. (2017) Enhanced Bruton's Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease. p. 1313-1324).

[0014] N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is a BTK inhibitor, referred to herein as the compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof.

[0015] This compound was described in International Publication No. 2015 / 079417, filed June 4, 2015 (Attorney docket number PAT056021-WO-PCT). This compound is a selective, potent, irreversible covalent inhibitor of Bruton's tyrosine kinase (BTK) and may be used to treat BTK-mediated diseases or disorders.

[0016] Accordingly, the inventors have now devised a dosing regimen for treating SjS patients with the compound N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof.

[0017] Definition: For the purposes of interpreting this specification, the following definitions will apply and terms used in the singular will, where appropriate, also include the plural and vice versa.

[0018] As used herein, the phrase "pharmaceutically acceptable" refers to those compounds, substances, compositions and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0019] Any formula given herein is also intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure shown by the formula given herein except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present disclosure include, for example, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F and 36 These include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, such as Cl. Thus, the present disclosure provides, for example,3 H and 14 a radioactive isotope of C, or 2 H and 13 It should be understood to include compounds incorporating one or more of any of the foregoing isotopes, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds may be used in metabolic studies ( 14 C), reaction rate tests (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or in radiation treatment of patients. 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, for example, by substituting an appropriate isotopically labeled reagent for a previously utilized non-labeled reagent.

[0020] The term "pharmaceutical combination," as used herein, refers to a product resulting from the use or mixing or combining of two or more active ingredients. It should be understood that pharmaceutical combination, as used herein, includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and one or more combination partners are administered to a patient simultaneously as a single entity or dosage form. In such cases, the term refers to a fixed-dose combination in a single unit dosage form (e.g., a capsule, tablet, or sachet). The terms "non-fixed combination" and "unit-in-one" both refer to active ingredients, e.g., a compound of the present disclosure and one or more combination partners and / or one or more co-agents, administered independently or simultaneously to a patient as separate entities, either simultaneously, at the same time, or sequentially without specific time limitations, such administration providing therapeutically effective levels of the two compounds in the patient's body, particularly such time intervals that allow the combination partners to exhibit a cooperative, e.g., additive, or synergistic, effect. The term "non-fixed combination" also applies to cocktail therapy, e.g., the administration of three or more active ingredients. Thus, the term "non-fixed combination" specifically defines an administration, use, composition, or formulation in the sense that the compounds described herein can be administered independently of each other, i.e., simultaneously or at different times. It should be understood that the term "non-fixed combination" also encompasses the use of a single agent together with one or more fixed combination products, each in a separate formulation containing a distinct amount of the active ingredient. It should be further understood that the combination products described herein, as well as the term "non-fixed combination," encompass active ingredients (including the compounds described herein), in which the combination partners are administered as completely separate pharmaceutical dosage forms or pharmaceutical formulations that are also sold independently of each other. Instructions for use of non-fixed combinations are or may be provided on packaging, e.g., in leaflets, or other information provided to physicians and / or medical staff.The independent formulations or components of this formulation, product or composition can then be administered simultaneously or chronologically staggered, i.e., each individual component of the set can be administered at different times and / or at equal or different time intervals relative to any of the components of the set. In particular, the time intervals for administration are selected so that the combined use of the components produces a greater / higher effect on the disease being treated than the effect obtained by using only the compound of formula (I); thus, the compounds used in the drug combinations described herein are jointly active. The ratio of the total amount of the compound of formula I and the second drug to be administered as a drug combination can be varied or adjusted to better address the needs of a specific patient subpopulation or the needs of a single patient to be treated, which may depend, for example, on the patient's age, sex, weight, etc.

[0021] The terms "co-administration" or "administration in combination" and the like, as used herein, are meant to encompass the administration of one or more compounds described herein together with selected combination partners to a single subject (e.g., patient or subject) in need thereof, and are intended to include therapeutic regimens in which the compounds are not necessarily administered by the same route of administration and / or at the same time.

[0022] The term "pharmaceutical composition" is defined herein to refer to a mixture (e.g., a solution or emulsion) containing at least one active ingredient or therapeutic agent to be administered to a warm-blooded animal, e.g., a mammal or a human, to prevent or treat a particular disease or condition affecting the warm-blooded animal.

[0023] The term "therapeutically effective amount" of a compound of the present disclosure (i.e., a compound of Formula (I) or a pharmaceutically acceptable salt thereof) refers to the amount of a compound of the present disclosure that elicits a biological or medical response in a subject (subject patient), such as reducing or inhibiting enzyme or protein activity or ameliorating symptoms, alleviating a condition, slowing or delaying disease progression, or preventing a disease. The therapeutically effective dosage of a compound, pharmaceutical composition, or combination thereof depends on the species, weight, age, sex, and individual condition of the patient, the disorder or disease being treated, or its severity. A skilled physician, clinician, or veterinarian can readily determine the effective amount of each of the active ingredients required to prevent, treat, or inhibit the progression of a disorder or disease.

[0024] The frequency of dosing can vary depending on the compound used and the particular condition to be treated or prevented. Generally, use of the minimum dosage sufficient to provide effective treatment is preferred. Patients may generally be monitored for therapeutic effectiveness using assays appropriate for the condition being treated or prevented, which will be apparent to those skilled in the art.

[0025] As used herein, the term "carrier" or "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial, antifungal), isotonicity agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, and the like, and combinations thereof, as known to those skilled in the art (e.g., Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0026] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject also refers to, for example, primates (e.g., humans, male and female), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In certain embodiments, the subject is a primate. In preferred embodiments, the subject is a human. The term "subject" is used interchangeably with "patient" when referring to a human.

[0027] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0028] As used herein, the phrase "patient population" is used to mean a group of patients.

[0029] The term "comprising" encompasses "including" as well as "consisting," e.g., a composition "comprising" X may consist exclusively of X or may include some additional material (e.g., X+Y).

[0030] The term "about" in connection with a numerical value x means, for example, + / - 10%. When used before a range or list of numerical values, the term "about" applies to each numerical value in turn, e.g., the phrase "about 1 to 5" should be interpreted as "about 1 to about 5", or the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc."

[0031] The term "treatment" or "treat" is defined herein as the application or administration of a compound according to the present disclosure (a compound of Formula (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound) to a subject, or an isolated tissue or cell line derived from a subject, having a particular disease (e.g., SjS), symptoms associated with a disease (e.g., SjS), or a predisposition to developing a disease (e.g., SjS) (if applicable), for the purpose of curing (if applicable), delaying onset of the disease, reducing the severity of, alleviating, ameliorating one or more symptoms of, ameliorating the disease, reducing or ameliorating any associated symptoms of the disease, or reducing or ameliorating the predisposition to developing the disease. The term "treatment" or "treat" includes treating patients suspected of having a disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes the suppression of clinical recurrence.

[0032] As used herein, "selecting" and "selected" in reference to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (or resulting from) the particular patient having predetermined criteria. Similarly, "selectively treating" refers to providing treatment to a patient with a particular disease, where the patient is specifically selected from a larger group of patients based on (or resulting from) the particular patient having predetermined criteria. Similarly, "selectively administering" refers to administering a drug to a patient specifically selected from a larger group of patients based on (or resulting from) the particular patient having predetermined criteria. "Selecting," "selectively treating," and "selectively administering" refer to providing a patient with personalized therapy based on the patient's individual treatment history (e.g., previous therapeutic interventions, e.g., previous treatment with a biological agent), biological factors (e.g., particular genetic markers), and / or symptoms (e.g., failure to meet specific diagnostic criteria), rather than providing a standard treatment regimen based solely on the patient's membership in a larger group. As used herein, in reference to treatment methods, selecting refers to the intentional selection of a patient to receive treatment based on the patient having certain criteria, rather than the incidental treatment of a patient having certain criteria. Thus, selective treatment / administration differs from standard treatment / administration in that it delivers specific drugs to patients with specific diseases, regardless of their individual medical history, disease manifestations, and / or biology. In some embodiments, patients are selected for treatment based on having SjS.

[0033] Embodiments of the present invention Sjogren's Syndrome and Efficacy of Treatment According to the Present Invention The disclosed BTK inhibitors, i.e., compounds of Formula (I) or pharmaceutically acceptable salts thereof, can be used in vitro, ex vivo, or incorporated into pharmaceutical compositions and administered in vivo to treat SjS patients (e.g., human patients).

[0034] The effectiveness of Sjogren's treatment can be assessed using various known methods and tools for measuring the status of Sjogren's syndrome and / or the clinical response of Sjogren's syndrome, some examples of which include the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI), the Physician Global Assessment Scale (PhGA), the EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue), and EQ5D.

[0035] Effectiveness Clinical efficacy measures for the primary and secondary objectives are outlined below.

[0036] EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) The ESSDAI is a validated disease outcome measure for Sjögren's syndrome and is applied to study subjects (Seror R, et al (2015) Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66). The instrument contains 12 organ-specific domains that contribute to disease activity. For each domain, characteristics of disease activity are scored at 3 or 4 levels according to their severity. These scores are then summed across the 12 domains in a weighted manner to provide a total score. The domains (weights) are as follows: constitution (3), lymphadenopathy (4), glandular symptoms (2), joints (2), skin (3), lungs (5), kidneys (5), muscles (6), PNS (5), CNS (5), hematology (2), and biological findings (1). The maximum possible score is 123.

[0037] In our study, to calculate the ESSDAI, all 12 organ domains must be assessed individually at all planned time points (from the screening visit to the end of the study). Domain assessments are entered into a table (provided by the central vendor) and the software calculates the ESSDAI score.

[0038] For evaluations not listed in the protocol as essential tests but that may be required to estimate the ESSDAI, including X-ray, high-resolution computed tomography (HRCT), pulmonary function tests (DLCO, FVC), estimated glomerular filtration rate (eGFR), electromyography (EMG), muscle (or any other) biopsy, the investigator will, at his discretion, evaluate these based on the patient's signs and symptoms to provide a correct ESSDAI reading. The definitions and weights of the EULAR Sjögren's Syndrome Disease Index (ESSDAI), domains and items are summarized in Table 1:

[0039] [Table 1]

[0040] [Table 2]

[0041] [Table 3]

[0042] [Table 4]

[0043] Physician Global Assessment Scale (PhGA) A Physician's Global Assessment Scale is used by the treating physician to assess the patient's disease activity using a 100mm VAS ranging from "no disease activity" (0) to "maximum disease activity" (100).

[0044] To promote objectivity, physicians should not be aware of a particular patient's reported outcome assessment when making their own assessment of that patient, and therefore must make this assessment before looking at the patient's global assessment of the global disease activity score.

[0045] EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI) The ESSPRI is an established disease outcome measure for Sjögren's syndrome (Seror R, et al (2011) EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjögren's syndrome. Ann. Rheum. Dis. p. 968-72). It consists of three domains: dryness, pain, and fatigue. Subjects can rate the severity of their symptoms on a single 0-10 numeric scale for each of the three domains. The ESSPRI score is defined as the average of the scores from the three scales: (dryness + pain + fatigue) / 3.

[0046] FACIT-Fatigue The Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during their usual daily activities over the past week. Fatigue levels are rated on a 5-point Likert scale (0 = not at all, 1 = slightly, 2 = somewhat, 3 = quite a lot, 4 = extremely) (Webster K, et al. (2003) The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. Health Qual Life Outcomes p. 79).

[0047] EQ5D The EQ-5D is a standardized instrument measuring health-related quality of life. The EQ-5D consists of a descriptive system and an EQ VAS scale.

[0048] This descriptive system includes five dimensions: mobility, self-care, usual activities, pain / discomfort, and anxiety / depression. It can be used as a quantitative measure of health outcomes that reflects the patient's own judgment. Scores on these five dimensions can be presented as a health profile or converted into a single aggregated index number (utility) that reflects a more favorable health profile compared to other health profiles.

[0049] The EQ VAS records the patient's self-assessed health status on a vertical visual analogue scale, with 0 representing the "worst imaginable health state" and 100 representing the "best imaginable health state."

[0050] Appropriateness of efficacy evaluation The efficacy measures in this study were primarily based on the ESSDAI (EULAR SS Disease Activity Index), which measures organ-specific disease criteria, and the ESSPRI (European League Against Rheumatism [EULAR] Sjögren Syndrome [SS] Patient Reported Index), which measures the patient's subjective impact of disease. Both instruments are widely accepted and validated gold-standard measures of systemic and symptomatic findings in Sjögren Syndrome (Sjögren Syndrome), respectively. The ESSDAI is a systemic disease activity index that categorizes disease activity into three to four levels across 12 differently weighted domains: biological findings, hematological, joint, glandular, skin, constitutional, lymphadenopathy, kidney, lung, PNS, CNS, and muscle. Composite weighted scores provide accurate assessments of disease activity with good sensitivity to change when validated in multiple cohort studies (Seror R et al. (2015) Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66). The ESSPRI tool, on the other hand, is a patient-reported composite score of symptoms of dryness, extremity pain, and fatigue rated on a 0-10 visual analog scale during the preceding 2 weeks (Seror R et al. (2011) EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI): development of a consensus patient index for primary Sjögren's syndrome. Ann. Rheum. Dis. p. 968-72). Patient-reported scores are less sensitive to changes in disease activity, but the ESSPRI has been reported to have significantly better sensitivity among available tools.A recent prospective study reported a low correlation between the systematic score and the patient score, suggesting that the two indices assess complementary components of disease activity, thus emphasizing the importance of assessing both parameters to arrive at a correct assessment of disease activity and its changes (Seror R et al (2015) Validation of EULAR primary Sjögren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66).

[0051] Pharmaceutical Composition The BTK inhibitor, i.e., the compound of Formula (I) or a pharmaceutically acceptable salt thereof, can be used as a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. In addition to the compound of Formula (I), such compositions may contain carriers, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The characteristics of the carrier depend on the route of administration. The pharmaceutical compositions used in the disclosed methods may also contain additional therapeutic agents for the treatment of specific targeted disorders. For example, the pharmaceutical composition may also include an anti-inflammatory or anti-itch agent. Such additional factors and / or agents may be included in the pharmaceutical composition to produce a synergistic effect with the compound of Formula (I) or to minimize side effects caused by the compound of Formula (I). In a preferred embodiment, the pharmaceutical composition for use in the disclosed methods contains the compound of Formula (I) in a dose of 10 mg, 20 mg, 25 mg, 50 mg, or about 100 mg.

[0052] Suitable compositions for oral administration comprise an effective amount of a compound of the present invention in the form of tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use are prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives to provide a pharmaceutically accurate and palatable preparation. Tablets may contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients suitable for the manufacture of tablets. These excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc. The tablets may be uncoated or may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate may be used. Formulations for oral use may be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0053] Pharmaceutical compositions for use in the disclosed methods can be prepared in a conventional manner. In one embodiment, the pharmaceutical composition is provided for oral administration. For example, the pharmaceutical composition is a tablet or gelatin capsule containing the active ingredient together with: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; also for tablets, c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or e) Absorbents, colorants, flavors and sweeteners. Tablets can be either film coated or enteric coated according to methods known in the art.

[0054] combination: In practicing some of the disclosed methods of treatment or use, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a patient, e.g., a mammal (e.g., a human). While it is understood that the disclosed methods provide for the treatment of Sjogren's patients using a compound of formula (I) or a pharmaceutically acceptable salt thereof, this treatment is not necessarily a monotherapy. Indeed, if a patient is selected for treatment with a compound of formula (I), the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered according to the disclosed methods either alone or in combination with other agents and therapies for treating Sjogren's patients, for example, in combination with at least one additional Sjogren's agent. When co-administered with one or more additional SjS agents, the compound of formula (I) or a pharmaceutically acceptable salt thereof can be administered either simultaneously or sequentially with the other agents. If administered sequentially, the attending physician will determine the appropriate sequence of administering the compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with other agents and appropriate dosages for simultaneous delivery.

[0055] Various therapeutic agents may be beneficially combined with the disclosed compounds of Formula (I) or pharmaceutically acceptable salts thereof during the treatment of SjS, including steroids (corticosteroids such as prednisone or equivalents); DMARDs such as hydroxychloroquine (Plaquenil), methotrexate (Trexall), sulfasalazine (Azulfidine), minocycline (Minocin), or leflunomide (Arava); or B-cell depleting drugs such as rituximab.

[0056] Those skilled in the art will be able to determine appropriate dosages of the SjS agents described above for co-delivery with the disclosed compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0057] Kits of the Invention The present disclosure also encompasses kits for treating SjS. Such kits include a BTK inhibitor, such as N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutical composition thereof. Additionally, such kits may include instructions for use.

[0058] In one embodiment, the kit comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of Formula (I) or a pharmaceutically acceptable salt thereof. In one embodiment, the kit comprises a means for separately retaining the compositions, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, and the like.

[0059] The kits of the present disclosure can be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to each other. To aid in compliance, the kits of the present disclosure typically include directions for administration.

[0060] In the combination therapy of the present invention, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the other SjS agent (as defined herein) may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the other SjS agent may be combined together in the combination therapy: (i) prior to release of the combination product to the physician (e.g., in the case of a kit containing the compound of formula (I) or a pharmaceutically acceptable salt thereof and the other SjS agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) in the patient, for example, during sequential administration of the compound of formula (I) or a pharmaceutically acceptable salt thereof and the other SjS agent.

[0061] Further embodiments The compounds of formula (I) or a pharmaceutically acceptable salt thereof are conveniently administered to a patient (preferably orally) in a dosage of from about 10 mg to about 200 mg per day.

[0062] The compounds of formula (I) or a pharmaceutically acceptable salt thereof are conveniently administered to a patient (preferably orally) in a daily dosage of between about 10 mg and about 200 mg per day.

[0063] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 10 mg to about 100 mg.

[0064] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 100 mg.

[0065] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 50 mg.

[0066] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 35 mg.

[0067] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25 mg.

[0068] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 20 mg.

[0069] In one embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 10 mg, about 35 mg, about 50 mg, or about 100 mg.

[0070] In another embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 10 mg, about 25 mg, about 50 mg, or about 100 mg.

[0071] It will be appreciated that dose escalation may be required for certain patients, e.g., Sjogren's patients who demonstrate an inadequate response (e.g., as measured by any of the Sjogren's scoring systems disclosed herein). It will also be appreciated that dose reduction may be required for certain patients, e.g., Sjogren's patients who experience adverse events or adverse reactions to treatment with the compound of Formula (I) or a pharmaceutically acceptable salt thereof. Thus, the dosage of the compound of Formula (I) or a pharmaceutically acceptable salt thereof may be less than about 10 mg, about 20 mg, about 25 mg, about 50 mg, or about 100 mg.

[0072] The timing of administration is generally measured from the date of first administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof (also known as the "baseline"). The timing of administration is generally measured from the date of first administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof (also known as the "baseline").

[0073] However, healthcare providers often use different naming conventions to identify dosing schedules. For clarity, as disclosed herein, the first day of administration will be referred to as day 1. However, it will be understood by those skilled in the art that this naming convention is used merely for consistency and should not be construed as limiting, i.e., a daily administration is the provision of a daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and that a physician may refer to a particular day as "day 0" or "day 1."

[0074] Disclosed herein is a method of treating Sjögren's syndrome (SjS), comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a dose of about 10 mg to about 200 mg.

[0075] Also disclosed herein is a method of treating Sjögren's syndrome (SjS), comprising administering to a patient in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof, in a daily dose of about 10 mg to about 200 mg.

[0076] Also disclosed herein is a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in treating SjS, wherein the daily dose of the compound is from about 10 mg to about 200 mg.

[0077] In one embodiment of the disclosed methods, uses and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 10 mg to about 100 mg.

[0078] In another embodiment of the disclosed methods, uses, and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 100 mg, or about 200 mg.

[0079] In another embodiment of the disclosed methods, uses and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 100 mg.

[0080] In another embodiment of the disclosed methods, uses and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 50 mg.

[0081] In another embodiment of the disclosed methods, uses and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 35 mg.

[0082] In another embodiment of the disclosed methods, uses and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 25 mg.

[0083] In another embodiment of the disclosed methods, uses and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in a daily dose of about 20 mg.

[0084] In another embodiment of the disclosed methods, uses, and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered once daily at a dose of about 10 mg, about 35 mg, about 50 mg, or about 100 mg.

[0085] In another embodiment of the disclosed methods, uses, and kits, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 10 mg, about 25 mg, about 50 mg, or about 100 mg.

[0086] In another embodiment of the disclosed methods, uses, and kits, the patient has moderate to severe SjS. Patients with moderate to severe SjS are defined as those with an ESSDAI score (based on weighted scores as shown in Table 1) of ≥ 5 (i.e., at least 5) from eight defined domains (biology, hematology, joints, skin, glandular, lymphadenopathy, renal, constitutional) and an ESSPRI score of at least 5 prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0087] In another embodiment of the disclosed methods, uses and kits, the patient is an adult.

[0088] In another embodiment of the disclosed methods, uses, and kits, the patient achieves a change from baseline in at least one patient- and / or physician-reported outcome (i.e., ESSPRI, FACIT-F, EQ-5D, PhGA) by week 12 or by week 24 of treatment.

[0089] In another embodiment of the disclosed methods, uses and kits, the patient achieves a change from baseline in ESSPRI score by week 12 or by week 24 of treatment.

[0090] In another embodiment of the disclosed methods, uses and kits, the patient achieves a reduction in ESSPRI score by week 12 or by week 24 of treatment.

[0091] In another embodiment of the disclosed methods, uses and kits, the patient achieves a reduction in ESSPRI score of at least 1 point, preferably at least 2 points, by week 12 or by week 24 of treatment.

[0092] In another embodiment of the disclosed methods, uses, and kits, the patient achieves a reduction in ESSPRI score by week 12 or by week 24 of treatment. In another embodiment of the disclosed methods, uses, and kits, the patient achieves at least a 15%, at least a 25%, at least a 35%, at least a 50%, or at least a 60% reduction in ESSPRI score by week 12 or by week 24 of treatment. The reduction in ESSPRI score is calculated as follows:

number

[0093] In another embodiment of the disclosed methods, uses and kits, the patient achieves a reduction in ESSDAI score by week 12 or by week 24 of treatment.

[0094] In yet another embodiment of the disclosed methods, uses and kits, the patient achieves a reduction in ESSDAI score of at least 3 points by week 12 or by week 24 of treatment.

[0095] In another embodiment of the disclosed methods, uses and kits, the patient achieves a change from baseline in ESSDAI score by week 12 or by week 24 of treatment.

[0096] In preferred embodiments of the disclosed methods, uses, and kits, the patient is an adult. In some embodiments of the disclosed methods, uses, and kits, the patient is an adolescent.

[0097] Further enumerated embodiments 1. A method of treating Sjögren's syndrome (SjS), comprising administering to a subject in need thereof a daily dose of about 10 mg to about 200 mg of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof. 2. The method of embodiment 1, wherein the daily dose of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is from about 10 mg to about 100 mg. 3. The method of embodiment 1, wherein the daily dose of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is about 100 mg. 4. The method of embodiment 1, wherein the daily dose of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is about 50 mg. 5. The method of embodiment 1, wherein the daily dose of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is about 35 mg. 5. The method of embodiment 1, wherein the daily dose of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is about 25 mg. 7. The method of embodiment 1, wherein the daily dose of N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is about 20 mg. 8. The method of embodiment 1, wherein N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is administered once a day at a dose of about 10 mg, about 35 mg, about 50 mg, or about 100 mg. 9. The method of embodiment 1, wherein N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is administered twice daily at a dose of about 10 mg, about 25 mg, about 50 mg, or about 100 mg. 10. The method of any one of embodiments 1 to 9 above, wherein the subject has moderate to severe SjS. 11. The method of any one of embodiments 1-10, wherein the subject is selected according to at least one of the following criteria: a) prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, the subject has an ESSPRI score of ≧5; b) Prior to treatment with a compound of formula (I) or a pharmaceutically acceptable salt thereof, the subject has an ESSDAI based on a weighted score of ≥ 5 from eight defined areas selected from biological findings, blood, joints, skin, glandular symptoms, lymphadenopathy, kidney, and constitution. 12. The method of any one of embodiments 1 to 11, wherein the patient is an adult. 13. The method of any one of embodiments 1-12, wherein the subject achieves at least one of the following by week 12 or by week 24 of treatment: a) A decrease in ESSPRI score; and / or b) Decrease in ESSDAI score. 14. The method of any one of embodiments 1 to 13, wherein the subject achieves a sustained response as measured by ESSPRI or ESSDAI 5 weeks after completing treatment. 15. The method of any one of embodiments 1 to 14, wherein N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof is disposed in a pharmaceutical formulation, and the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier. 16. N-(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidin-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutically acceptable salt thereof max 16. The method of any one of embodiments 1 to 15, wherein the time is about 0.5 to 3 hours.

[0098] The accompanying description above sets forth details of one or more embodiments of the present disclosure. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will be apparent from the description and claims. In this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. All patents and publications cited herein are incorporated by reference. The following examples are provided to more fully illustrate preferred embodiments of the present disclosure. These examples should in no way be construed as limiting the scope of the disclosed subject matter, as defined by the appended claims.

[0099] Abbreviation AE Adverse Event Area under the AUC curve AUCinf: Area under the plasma (or serum or blood) concentration-time curve from time 0 to infinity (mass x time / volume) AUClast: Area under the plasma (or serum or blood) concentration-time curve from time 0 to the final quantifiable concentration (mass x time / volume) AUCtau: Area under the plasma (or serum or blood) concentration-time curve from time 0 to the end of the administration interval (mass x time / volume) BCR B cell receptor Bid or bid twice a day (Latin: “bis in die”) BMI body mass index BTK Bruton's tyrosine kinase CBC complete blood count cm centimeters CL / F: Apparent systemic (or total body) clearance (mass / volume) from plasma (or serum or blood) after administration CNS central nervous system CV coefficient of variation DMARDs Disease-modifying antirheumatic drugs ECG electrocardiogram eGFR Estimated glomerular filtration rate ELISA enzyme-linked immunosorbent assay EMG electromyography EQ-5D EuroQual 5 dimensions (standard instrument for measuring health-related quality of life) ESSDAI EULAR Sjogren's Syndrome Disease Activity Index ESSPRI EULAR Sjogren's Syndrome Patient Reported Index EULAR European League against Rheumatism FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue FIH First in Human h time HRCT High-resolution computed tomography iv intravenous IA interim analysis INR International Normalized Ratio kg kilogram LC-MS / MS Liquid Chromatography / Mass Spectrometry-Mass Spectrometry mAb monoclonal antibody MCP-Mod Multiple Comparison Procedures - Modeling MMRM Mixed Effects Model Repeated Measures MRT average residence time NOACs (novel oral anticoagulants) NSAIDs (nonsteroidal anti-inflammatory drugs) PD Pharmacodynamics PhGA Physician Global Assessment Scale PK Pharmacokinetics PNS Peripheral Nervous System PT Prothrombin Time PTT Partial Thromboplastin Time Qd or qd once a day (Latin: "quaque die") QTcF QT interval corrected by Fridericia's formula Racc Drug accumulation coefficient SAE serious adverse event SjS Sjögren's syndrome SOM Site Operations Manual SPT Skin Prick Test SS Safety Set TEC tyrosine-protein kinase Apparent volume of distribution (volume) during the terminal elimination phase after Vz / F administration [Example]

[0100] Example 1: Preclinical studies Example 1a: BTK Occupancy and Preclinical PK / PD Relationship The in vivo PD efficacy of irreversible BTK inhibitors, such as Compound (I), is determined by the extent and duration of covalent BTK occupancy by the inhibitor. BTK occupancy after treatment with a compound of Formula (I) (also referred to as Compound (I)) was measured by ex vivo immunoassay. Because Compound (I) and the probe bind BTK mutually exclusively, the fraction of unoccupied BTK protein was assayed after in vitro incubation with a covalently biotinylated BTK probe. Relative protein levels of unoccupied BTK and total BTK were determined in lysates of selected tissues, and the level of unoccupied BTK was normalized to the total BTK protein level in the same sample.

[0101] In female rats, a single oral dose of 3 mg / kg of Compound (I) resulted in complete splenic BTK occupancy, with 76%-81% occupancy at a 1 mg / kg dose, whereas only a partial occupancy of 30% was achieved after a single dose of 0.3 mg / kg. BTK occupancy in the blood reached levels consistent with that observed in the spleen. Experimental data revealed that at low oral doses of 1-3 mg / kg, short, transient systemic exposure of Compound (I) was sufficient to achieve complete BTK occupancy in some tissues. After a 1 mg / kg dose, Compound (I) blood exposure reached 49.1 nM at 0.5 hours and 5.6 nM at 5 hours after administration. This very low and transient systemic exposure is consistent with a typical PK / PD model for irreversible inhibitors.

[0102] The duration of BTK occupancy was examined in rats and mice after a single oral dose of Compound (I) in the spleen, blood, lymph nodes, and lungs. In rats, BTK occupancy demonstrated a long blood half-life of approximately 87 hours. The estimated BTK occupancy half-life in rat spleens was significantly shorter than that in blood, at only approximately 5 hours. The different turnover rates may reflect the fact that BTK-expressing B cells and monocytes in peripheral blood are quiescent and metabolically relatively inactive compared to the spleen. It has previously been reported that BTK occupancy persists longer in blood (Advani et al. 2013, J Clin Onc;31(1):88-94). All other tissues analyzed (lungs and lymph nodes) demonstrated similar BTK turnover and occupancy half-lives to those in the spleen.

[0103] Because the levels of BTK-expressing cells in the skin were too low to measure occupancy, we assessed the duration of the PD effect in the skin after a single dose in the reverse passive Arthus (RPA) model of mast cell FcγRIII-mediated inflammation. In this model, inhibition of skin swelling was maximal when Compound (I) was administered 2 hours before eliciting the Arthus reaction. This effect gradually diminished and reached baseline when the Arthus reaction was elicited 45 hours or later after Compound (I) administration. This suggests that BTK occupancy in the skin follows a similar time course as in the spleen, lungs, and lymph nodes.

[0104] In these preclinical pharmacology studies, BTK occupancy and the individual pharmacological readouts showed strong correlations. Therefore, BTK occupancy is a suitable PD biomarker for use in clinical trials and was therefore used in a Phase 1 clinical trial.

[0105] Example 2: Phase 1 Clinical Trial A first-in-human study was conducted to evaluate the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single and repeated doses of Compound (I) administered orally both once daily (qd) and twice daily (bid) in healthy volunteers and those with atopic predisposition, to support further clinical development of Compound (I) in autoimmune diseases. The study also investigated the effect of food intake.

[0106] In the first-in-human study, up to approximately 168 healthy volunteers (HVs) were included, of which 64 (Parts 2 and 4) had asymptomatic atopic dermatitis. Part 1 was a 10-cohort, double-blind (subject and investigator blinded, sponsor unblinded), placebo-controlled, single ascending dose (SAD) titration study (N=80). Part 2 was a double-blind (subject and investigator blinded, sponsor unblinded), placebo-controlled, multiple ascending dose (MAD) (13 doses over 12 days) titration study in 6 cohorts of asymptomatic, atopic, healthy volunteers (N=48) using once-daily dosing. Part 3 was a single-dose, open-label, crossover food-effect study in 12HV. Part 4 was a double-blind (subject and investigator blinded, sponsor unblinded), placebo-controlled, multiple-dose (25 doses over 12 days) study (N=16) using twice-daily dosing in two cohorts of asymptomatic, atopic, healthy volunteers.

[0107] The SAD part (Part 1) consisted of 10 dose levels, and the MAD parts (Parts 2 and 4) consisted of 8 dose levels (6 cohorts using single daily dosing in Part 2 and 2 cohorts using twice-daily dosing in Part 4). Eight subjects were randomized into each cohort to receive either Compound (I) or matching placebo in a 6:2 (active:placebo) ratio in the SAD and MAD parts. Within the SAD part, if no safety signals had previously emerged from the SAD part, doses up to 4 times the estimated pharmacologically active dose (PAD) were to be evaluated before the MAD part of the study began. The total daily dose of Compound (I) used in Part 2 (MAD qd regimen) and Part 4 (multiple-dose bid regimen) did not exceed the maximum SAD dose level investigated. Furthermore, the total daily dose in Part 4 did not exceed the total daily dose in Part 2.

[0108] In Part 1 (SAD), sentinel dosing consisted of the first dose at each dose level: the first two subjects were dosed on Day 1 (one active drug, one placebo). After a 48-hour observation period, the remaining six subjects in this cohort were dosed (five active drug, one placebo).

[0109] Standard safety monitoring was used throughout all study parts, including dedicated assessment of potential cutaneous bruising events. All vital signs, physical examination and subject medical history, ECG, adverse events and safety laboratory parameters (blood chemistry, hematology, and urinalysis) up to 96 hours after the last dose, and PK data (if available) from the previous dose group up to 48 hours after the last dose were to be blindly reviewed for each cohort prior to dose escalation. A summary safety report of reported adverse events, safety laboratory parameters, QTc, and cardiac rate was provided after completion of each dose level.

[0110] In Parts 1, 2, and 4, each subject participated in a 28-day screening period (Days -29 to -2), a baseline period, a treatment period, and a follow-up period that included an assessment at the end of the study.

[0111] In Part 1, subjects were admitted to the study site on Day -2 or Day -1 for baseline safety assessments and to confirm eligibility. Eligible subjects received a single dose of Compound (I) or placebo under fasting conditions on Day 1. Eligible subjects remained from Day -1 until the morning of Day 5 (96 hours after the last drug administration).

[0112] In Parts 2 and 4, subjects were admitted on Day -2 or Day -1 for baseline safety assessments and to confirm eligibility. Eligible subjects received their first dose of Compound (I) under fasting conditions on Day 1 and continued to receive study medication under fasting conditions up to and including Day 12. Subjects remained from Day -2 or -1 until the morning of Day 16, 96 hours after the last dose of Compound (I) was administered. Study medication was administered once daily and twice daily in Parts 2 and 4, respectively (details can be found in the Assessment Schedule).

[0113] Part 3 was an open-label, randomized, two-arm crossover, single-dose study to evaluate the effect of food. In Part 3, each subject participated in a 28-day screening period (Days -29 to -2), two baseline (Day -1), and two treatment periods, each consisting of a single-dose administration on Day 1 followed by safety and PK assessments through Day 5. Treatment Period 2 consisted of a follow-up visit and end-of-study assessments on Days 22 and 40, respectively. The two treatment periods were separated by a washout period of at least 18 days (+ / - 1 day).

[0114] [Table 5]

[0115] [Table 6]

[0116] [Table 7]

[0117] Inclusion Criteria: 1. Healthy male and female subjects, aged 18-65 years (inclusive) at screening, in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests. Healthy subjects had atopic predisposition to be eligible for these specific study parts and participated in Part 2 or Part 4. Atopic healthy volunteers had to have a positive skin prick test to known allergens at screening (atopic predisposition), but were clinically asymptomatic and did not require any systemic medication. 2. Subjects were required to weigh at least 50 kg and have a body mass index (BMI) in the range of 18–30 kg / m² (inclusive). BMI = weight (kg) / [height (m)] 2 . 3. At screening and initial baseline, vital signs (temperature, systolic and diastolic blood pressure, and pulse rate) were assessed in a sitting position after the subject had rested for at least 3 minutes, and also (if necessary) after 3 minutes in an upright position. Sitting vital signs were required to be within the following ranges (inclusive): ·Oral body temperature 35.0~37.5℃ Systolic blood pressure 90-139mmHg Diastolic blood pressure 50-89mmHg Pulse rate: 50-90 bpm

[0118] Exclusion criteria 1. History of hypersensitivity to any of the study drugs or to drugs of a similar chemical class. 2. Clinically significant ECG abnormalities at screening and / or pre-procedure or a history of any of the following ECG abnormalities: ·PR interval>200msec ·QRS complex>120msec QTcF>450msec (male) QTcF>460msec (female) 3. Hemoglobin level <12.0 g / dL at screening or initial baseline. 4. Platelet count outside the normal range (150x10) at screening or initial baseline 9 / L or less or 450x10 9 (exceeding ). 5. Any clinically significant abnormality in any of the standard coagulation tests, including prothrombin time (PT), partial thromboplastin time (PTT), or international normalized ratio (INR), at screening and / or baseline. 6. History or presence of thrombotic or thromboembolic events or increased risk for thrombotic or thromboembolic events.

[0119] Treatment to be performed Part 1 (SAD) Subjects were assigned to one of the following ten cohorts: Within each cohort, eight subjects were randomly assigned to either Compound (I) or matching placebo in an overall 6:2 ratio; the first subcohort was randomly assigned in a 1:1 ratio, with one subject receiving Compound (I) and one receiving matching placebo; the remaining six subjects per cohort were randomized in a 5:1 ratio after a 48-hour observation period for the first two subjects. Cohort 1: Single oral administration of 0.5 mg of Compound (I) or matching placebo Cohort 2: Single oral administration of 1.5 mg of Compound (I) or matching placebo Cohort 3: Single oral administration of 5 mg of Compound (I) or matching placebo Cohort 4: Single oral administration of 15 mg of Compound (I) or matching placebo Cohort 5: A single oral dose of 30 mg of Compound (I) or matching placebo Cohort 6: Single oral administration of 60 mg of Compound (I) or matching placebo Cohort 7: Single oral administration of 100 mg of Compound (I) or matching placebo Cohort 8: Single oral administration of 200 mg of Compound (I) or matching placebo Cohort 9: Single oral administration of 400 mg of Compound (I) or matching placebo Cohort 10: A single oral dose of 600 mg of Compound (I) or matching placebo

[0120] Part 2 (MAD, qd regimen) Subjects were assigned to one of six cohorts: Within each cohort, eight subjects were randomly assigned in a 6:2 ratio to either Compound (I) or matching placebo. Cohort 1: Repeated oral administration of 10 mg of Compound (I) or matching placebo Cohort 2: Repeated oral administration of 25 mg of Compound (I) or matching placebo Cohort 3: Repeated oral administration of 50 mg of Compound (I) or matching placebo Cohort 4: Repeated oral administration of 100 mg of Compound (I) or matching placebo Cohort 5: Repeated oral administration of 400 mg of Compound (I) or matching placebo Cohort 6: Repeated oral administration of 600 mg or less of Compound (I) or matching placebo

[0121] Part 3 (Dietary Effects) Subjects were randomly assigned to one of two treatment sequences in a 1:1 ratio.

[0122] [Table 8]

[0123] Part 4 (MAD, bid regimen) Subjects were assigned to one of the following cohorts: Within each cohort, 8 subjects were randomly assigned to either Compound (I) or matching placebo in a 6:2 ratio. Cohort 1: Repeated oral administration of 100 mg of Compound (I) or matching placebo in a bid regimen Cohort 2: Repeated oral administration of 200 mg of Compound (I) or matching placebo in a bid regimen

[0124] Pharmacokinetic data Biological analysis methods Blood pharmacokinetic samples were obtained and evaluated in all subjects at all dose levels. Samples from placebo subjects were not analyzed. Samples for PK evaluation were collected from subjects at designated time points throughout the study. Compound (I) concentrations were measured in blood by a validated LC-MS / MS method.

[0125] Pharmacokinetics of single ascending doses of 0.5 mg to 600 mg: The mean blood concentration-time course of Compound (I) after a single ascending dose is shown in Figure 1. Compound (I) was rapidly absorbed over time, reaching Cmax at approximately 1 to 1.5 hours across all doses. The absorption phase was characterized by a single, distinct absorption peak in most subjects. Drug pharmacokinetics showed a biexponential decline. Most of the drug was eliminated during the initial distribution phase, suggesting that substantial drug clearance may occur before systemic tissue equilibration. The apparent terminal elimination phase was not reached until 12 hours after administration and was measurable only in subjects receiving doses of 100 mg or higher. Measurable terminal half-lives ranged from 4 hours (100 mg) to 18 hours (600 mg), resulting in mean residence times (MRT) in the circulation of 1 to 5 hours (MRT ≈ T1 / 2 / ln2). The distribution phase showed a major dose-dependent T1 / 2 of approximately 1 hour. The calculated geometric mean oral blood clearance (CL / F) after single-dose administration ranged from 250 to 506 L / h across the SAD cohort, with an estimated value of approximately 383 L / h across all cohorts.

[0126] Repeated oral dose pharmacokinetics The mean blood concentration-time course of Compound (I) after repeated dose escalation from 10 mg to 400 mg is shown in FIG. The apparent geometric mean clearance at steady state after oral administration (CLss / F, Day 12 MAD, qd) ranged from 246 L / h to 414 L / h across cohorts. In general, lower clearance was observed at steady state compared to Day 1, but this difference nearly disappeared at doses of 100 mg and above (Table 2-1 (Day 1) and Table 2-2 (Day 12)). The reason for this behavior is likely covalent target (BTK) binding, which contributes to the initial clearance of Compound (I). This effect is most pronounced on Day 1, as residual target occupancy at trough levels on successive days reduces the contribution of target binding to clearance (CLss / F). Naturally, this difference diminishes with increasing dose, given that target occupancy at trough levels is nearly complete. Consequently, drug exposure (AUC, Cmax) was found to be higher on day 12 compared to day 1, as exemplified by the (within-subject) drug accumulation coefficient (Racc), which ranged from 5 (low dose) to 1.2 (high dose) and was generally higher for AUC than for Cmax, confirming that an effect on systemic clearance may be involved.

[0127] [Table 9]

[0128] [Table 10]

[0129] In general, blood concentrations 24 hours after the final dose were usually below 1 ng / ml, except in a few subjects receiving 100 mg or more, suggesting that Compound (I) was almost completely washed out within two consecutive doses, and also suggesting that a steady state was reached within several doses.

[0130] Because BTK turnover is higher in tissues, bid administration was also investigated. Figure 3 shows the mean plasma concentration-time profiles obtained after repeated ascending doses of 100 mg and 200 mg twice daily. Consistent with results from other cohorts, rapid absorption was observed after the bid regimen, with Tmax approximately 1 h postdose. The observed accumulation coefficients (Racc) reached 1.5 (100 mg) and 2.0 (200 mg) for AUC and approximately 1.65 (both doses) for Cmax. A dose-proportional increase in AUCtau was observed on day 12, while only a small increase (1.33-fold) was seen in Cmax. In conclusion, bid administration of Compound (I) offers an option to address faster target resynthesis in tissues during the dosing interval without compromising the overall PK profile and without the need for high-dose qd treatment.

[0131] Dietary Effects: Part 3 Results: PK data from the food effect cohort, summarized in Tables 2-3 below, showed a slower absorption rate, as suggested by a 1.25-fold lower Cmax, and more complete overall absorption, as indicated by a 1.4-fold higher AUC. Most importantly, mean Tmax shifted from 1 hour (fasted) to >3 hours (fed) (Figure 4).

[0132] [Table 11]

[0133] Pharmacodynamics Pharmacodynamic (PD) characteristics were investigated by assessing target occupancy and distal pathway inhibition. Measurement of BTK occupancy in human whole blood (derived as the ratio of free to total BTK) provides a direct marker of therapeutic target engagement.

[0134] Across preclinical models for compounds of Formula (I), relationships between BTK occupancy, dose, systemic compound exposure, and efficacy in multiple in vivo pathways and disease readouts have been established (e.g., Example 1).

[0135] Compound (I) is an irreversible inhibitor of BTK, and the extent and duration of BTK occupancy were determined. In two separate assays, the PD effect of Compound (I) was assessed by measuring both free (unbound) and total BTK in whole blood by enzyme-linked immunosorbent assay (ELISA) on the Meso Scale Diagnostics (MSD) platform.

[0136] The relationship between dose and pharmacodynamics was characterized by measuring BTK occupancy in human blood (derived as the ratio of free to total BTK), a direct marker of therapeutic target engagement. BTK occupancy was determined for single ascending doses ranging from 0.5 to 400 mg, for repeated ascending doses qd ranging from 10 mg to 400 mg, and for repeated ascending doses of 100 mg and 200 mg bid.

[0137] Compounds of Formula (I) demonstrated a clear dose-dependent increase in both the extent and duration of peripheral blood BTK occupancy. Peak target occupancy was generally observed as early as 0.5 h post-dose, indicating a rapid onset of peak drug exposure without associated hysteresis of drug effect. As concluded from their ability to covalently bind to BTK, target occupancy was well-retained beyond its disposition from the systemic circulation, indicating a non-equilibrium PK-PD relationship. Therefore, it is concluded that the duration of BTK occupancy is governed by the rate of de novo synthesis of BTK.

[0138] Unlike lower dose cohorts (0.5-1.5 mg), single doses of 15 mg Compound (I) or higher established peak target occupancy approaching 100% in nearly all subjects, remaining >80% at 24 h. While there was significant inter-subject variability in responses at 15 mg, doses of 30 mg and higher resulted in sustained (>24 h) and nearly complete (>90%) occupancy in all subjects, demonstrating a significant reduction in inter-subject variability. The time to recovery of the BTK protein pool to pre-dose levels was approximately 10 days, corresponding to a median turnover T1 / 2 of approximately 48 h (Figure 5).

[0139] After repeated administration of Compound (I), 10 mg of Compound (I) qd already achieved >96% BTK occupancy in the blood before the 12th day of administration.

[0140] Furthermore, ex vivo inhibition of basophil activation (monitored by surface expression of CD63 and CD203c) was used as a terminal mechanistic biomarker to examine the downstream PD effects of Compound (I). To determine the PD effect of Compound (I) on basophil activation, whole blood was stimulated ex vivo with anti-IgE. Degranulation was assessed by flow cytometry using the percentage of CD63+ and CD203+ basophils.

[0141] After single escalating doses of Compound (I), data show dose-dependent inhibition of FcεR1-mediated basophil activation. Ex vivo blood basophil activation, as measured by CD63, was almost completely inhibited (>89%) at the 60 mg dose and reached nearly 100% inhibition at higher doses 24 hours after administration. Meanwhile, maximal inhibition of CD203c (approximately 50% inhibition) 24 hours after a single dose of Compound (I) was only achieved with 200 mg of Compound (I).

[0142] On day 12, already 8 hours after qd or bid administration of the MAD of compound of Formula (I), the lowest tested dose of Compound (I) (10 mg qd) resulted in >90% inhibition of CD63 upregulation, with trough-level inhibition of CD63 being >90% at Compound (I) doses ≥ 50 mg qd (Figure 6). Maximum trough-level inhibition of CD203c activation on day 12 was consistently higher than after a single dose of Compound (I) and was only achieved with 100 mg and 200 mg bid doses of Compound (I).

[0143] The ability of Compound (I) to inhibit defined allergen responses was assessed by skin prick testing (SPT) in healthy atopic subjects in the MAD study portion of the first-in-human trial. SPTs were performed pre-dose (screening, baseline, and pre-dose on Day 1), at different time points after the first dose (Day 1), and 11 days after once-daily dosing (Day 12).

[0144] Similar to the inhibition of ex vivo basophil activation, a dose-dependent effect on wheal diameter was discernible in the repeated dose-escalation cohorts, as indicated by a reduction in mean post-dose wheal size compared to baseline (Figure 7). The effect began to plateau around 100 mg of Compound (I) qd.

[0145] Rationale / Conclusions for Dose Selection Healthy volunteers were exposed to Compound (I) in Phase 1 clinical trials at doses ranging from 0.5 mg to 600 mg, either given as a single dose or once or twice daily for up to 18 days. Compound (I) was well tolerated, and there were no serious or severe adverse events associated with taking Compound (I). In clinical trials, observed adverse events (AEs) did not appear to be dose-dependent, most were single events, and were usually mild in nature. Therefore, clinical safety information supports the dose selected for this Phase 2b study. The dose levels of the present invention were derived from the following analyses: BTK occupancy, inhibition of basophil activation (monitored by CD63 and CD203c upregulation) in healthy volunteers; and effect on skin prick testing (SPT)—a surrogate for mast cell and basophil inhibition in the skin—in asymptomatic, atopic, healthy volunteers.

[0146] In this above-mentioned clinical trial, administration of 10 mg of Compound (I) qd resulted in nearly complete BTK occupancy in the blood, a >90% reduction in CD63 upregulation (8 hours after administration of Compound (I) at steady state), and minimal inhibition of wheal size in the SPT. Thus, 10 mg of Compound (I) qd corresponds to the onset of biological activity. At 100 mg of Compound (I), the mean reduction in wheal size in the SPT began to plateau. Thus, 100 mg of this compound corresponds to the maximal effect of Compound (I). The moderate dose of 35 mg of Compound (I) qd is well suited to accurately represent the dose-response curve of Compound (I) qd.

[0147] Compounds of Formula (I) inhibit BTK by covalent binding. While BTK occupancy in the blood is >24 hours (h), rapid BTK turnover in tissues (e.g., approximately 5 hours in the rodent spleen) may require bid administration of Compound (I) to reach maximum efficacy. Doses of 10 mg, 25 mg, and 100 mg bid of Compound (I), respectively, adequately represent the dose-response curve of Compound (I) when given twice daily.

[0148] Human safety For the analysis of adverse effects, placebo subjects from all SAD and MAD cohorts (2 per cohort) and separated by SAD and MAD parts were pooled into one placebo group (n=20 for SAD and n=16 for MAD) and compared with each single Compound (I) dose group (n=6 each) and the total Compound (I) group (n=60 for SAD and n=48 for MAD). For both the SAD and MAD populations, no significant differences in demographic data were evident between the placebo and active groups. Safety assessment of the FIH study in healthy volunteers did not reveal any significant safety concerns at doses up to 600 mg.

[0149] Example 3: Efficacy and Safety Data in Subjects with Moderate to Severe SjS To further develop the compound for the treatment of this disease, a Phase 2 trial with the compound of Formula (I) will be conducted in subjects with moderate to severe SjS, designed to establish the safety and efficacy and characterize the dose response of the compound of Formula (I).

[0150] [Table 12]

[0151] [Table 13]

[0152] [Table 14]

[0153] Study design This is an adaptive, phase 2, randomized, double-blind, placebo-controlled, multicenter, integrated dose-ranging study to evaluate the safety and efficacy of repeated doses of Compound (I) in patients with moderate to severe Sjögren's syndrome (SjS). In this study, moderate to severe SjS is defined as Sjögren's syndrome according to the ACR / EULAR criteria and an ESSDAI of at least 5 (8 out of 12 domains) and an ESSPRI of at least 5. If study subjects are receiving certain concomitant treatments for their underlying disease and still meet the inclusion criteria, they will remain on this treatment if it remains stable until the end of the study.

[0154] The study consists of two parts. In Part 1 of this study, two different dosing regimens will be tested to determine the single dose with the highest biological activity (100 mg of the compound of Formula (I) or a pharmaceutically acceptable salt thereof): once daily (qd) or twice daily (bid) and compared with a placebo group. A total of approximately 72 study subjects will be equally randomized into these three treatment groups, with an expected sample size of 24 subjects per group. In Part 2, the selected dosing regimen (qd or bid) will be extended to lower doses to evaluate the safety and dose-response of this dosing regimen between the lowest (10 mg of the compound of Formula (I)) and highest (100 mg of the compound of Formula (I)) doses that will be determined. This will result in four treatment groups: placebo plus three dose levels (100 mg bid / qd, 25 mg bid, or 35 mg qd, and 10 mg bid / qd) of the compound of Formula (I). A total of approximately 180 subjects are expected to be equally randomized into these four treatment groups, resulting in a sample size of 45 subjects per group.

[0155] Each individual study subject will undergo an initial screening period of up to 6 weeks, a treatment duration of 24 weeks, and a follow-up period of 30 days after the last dose of study treatment and a visit before the end of the study. The total duration for each subject in this study, including screening, will be up to 35 weeks.

[0156] For the entire duration of the treatment period (24 weeks), subjects will receive a compound of formula (I) or placebo twice daily, regardless of the dosing regimen selected, ensuring that blinding is maintained throughout the study.

[0157] Safety assessments include physical examination, ECG, vital signs, standard clinical laboratory evaluations (hematology, biochemistry, and urinalysis), and monitoring for adverse events and serious adverse events.

[0158] screening After signing informed consent, subjects will be assessed for the ESSDAI and ESSPRI and will complete safety and other assessments to assess eligibility. For logistical reasons, assessments will occur on different days during the 6-week screening period if deemed appropriate by the investigator. Subjects who fail screening may be re-screened for one additional opportunity. Once subjects are confirmed eligible for the study, they will also be given guidance on how to use the wearable device (if they choose to use it), which will be provided to them.

[0159] Baseline Eligible subjects will return for a baseline visit on Day 1. Subjects may stay overnight at the study site for logistical reasons, but this will not be considered a hospital stay. Eligibility will be confirmed prior to randomization, and required baseline assessments will be completed prior to dosing on Day 1. If preferred by the study site for scheduling purposes, some baseline assessments will be conducted the evening before Day 1.

[0160] Test treatment The investigational drug will be provided in appropriately blinded, labeled bottles containing capsules containing either 10 mg, 25 mg, or 50 mg of active substance (compound of formula (I)) or matching placebo. Each dose (two capsules) should be swallowed with water and taken on an empty stomach. A dosing interval of approximately 12 hours (10 to 14 hours) should be maintained between the morning and evening doses. Detailed requirements for storage and administration of the study drug, as well as instructions to be followed for subjects to count, dispense, and take the study drug, will be outlined in the SOM.

[0161] treatment group In Part 1, on Day 1, subjects are assigned in a 1:1:1 ratio to one of the following three treatment groups: Compound of formula (I), 100 mg bid 100 mg qd of the compound of formula (I) ·placebo

[0162] The dosing schedule and dose range for Part 2 will be based on data from the IA. In Part 2, subjects will be assigned on Day 1 in a 1:1:1:1 ratio to one of the following four treatment arms: Compound of formula (I), 100 mg bid or qd Compound of formula (I), 35 mg qd or 25 mg bid Compound of formula (I), 10 mg bid or qd ·placebo

[0163] Subjects will take two capsules at each dose. All subjects in both parts will receive morning and evening doses (two capsules each).

[0164] Subjects will receive their morning dose of a compound of Formula (I) or placebo at the study site on days 1, 29 (Week 4), 57 (Week 8), 85 (Week 12), 113 (Week 16), 141 (Week 20), and 169 (Week 24). Other morning doses and all evening doses will be administered by the participating subject, typically at home. All subjects will receive their individual supply of a compound of Formula (I) or placebo capsules every four weeks during their scheduled visit to the study site.

[0165] Subjects will be randomized into individual treatment groups for each study part. Randomization will be stratified by baseline ESSDAI (weighted score < or ≥ 10), except in Japan. Separate blocks of randomization numbers will be created for participating Japanese and other national subjects to ensure equal distribution of Japanese subjects across all treatment groups in this study. Subjects will receive their morning dose of a compound of Formula (I) or placebo at the investigational site on Day 1 (Week 1), Day 29 (Week 4), Day 57 (Week 8), Day 85 (Week 12), Day 113 (Week 16), Day 141 (Week 20), and Day 169 (Week 24). Subjects will then be provided with study medication and may return home to continue their daily dosing regimen (self-administration). Post-dose safety and PK assessments will also be performed on subjects at the Week 4 and Week 24 visits. Subjects return to the study site at approximately 4-week intervals with an additional visit at the end of Week 2 (Day 15). During study visits, subjects undergo ESSDAI and ESSPRI assessments and other scales / questionnaires, safety, and various PK, PD, and biomarker sample collections as indicated in the assessment schedule. Each week, subjects are asked to complete a diary to record their SjS symptoms and medication administration.

[0166] The primary endpoint of this study will be assessed after completion of 24 weeks of treatment at the end of Part 2 (Day 169; End of Week 24 visit). An interim analysis will evaluate efficacy and safety after 12 weeks of treatment, instead of the 24-week treatment outcomes in Part 1.

[0167] Rationale for dose / regimen and duration of treatment Dosage / Regimen for Part 1 The maximum dose planned for this study (100 mg bid or qd) demonstrated maximal efficacy for the compound of Formula (I) based on predicted BTK occupancy in the blood (B cell blockade) and tissues and inhibition of CD63 upregulation in basophils (IB) (results in Example 2). Therefore, it is concluded that this dose provides the greatest clinical benefit in tissues, including lymphoid tissue, against SjS. Doses up to 600 mg as both single and repeated doses and 200 mg as twice-daily doses have been tested in human volunteers in Phase 1 studies and proven safe.

[0168] In Part 1, the dose concluded to provide maximal efficacy (100 mg) will be tested in qd and bid regimens and compared to placebo. Due to the covalent nature of the binding of the compound of Formula (I) to intracellular BTK, the duration of therapeutic effect will depend on the turnover rate of the BTK molecule. Simulation modeling showed that at steady state, a qd regimen using 100 mg of the compound of Formula (I) resulted in an average BTK occupancy of 83% 24 hours after administration (and immediately prior to the next dose), while a bid regimen using the same single dose of 100 mg resulted in an average BTK occupancy of 96% at 24 hours.

[0169] Furthermore, 70% BTK inhibition for approximately 90% of each dosing period at steady state is considered appropriate for optimal clinical efficacy. Therefore, both the qd- and bid-dose regimens of Compound (I) 100 mg tested in Part 1 of this study produce efficacy.

[0170] Dose / Regimen for Part 2 Part 2 will evaluate the full dose range of the selected dosing regimen, ranging from 10 mg to 100 mg. In a first-in-human study using the compound of Formula (I), qd administration of 10 mg of the compound of Formula (I) resulted in near-complete BTK occupancy in the blood and a >80% reduction in CD63 upregulation, but only minimal inhibition of wheal size in skin prick tests (SPTs). Therefore, it is concluded that qd administration of 10 mg of the compound of Formula (I) corresponds to the onset of biological activity in terms of tissue pharmacodynamic activity. As intermediate doses, daily doses of 35 mg qd or 25 mg bid of the compound of Formula (I) are considered appropriate to adequately represent the full dose-response curve of the compound of Formula (I) at qd or bid, respectively. A double-blind treatment period of up to 24 weeks will provide ongoing safety and efficacy data for the compound of Formula (I).

[0171] Rationale for the choice of comparator (placebo) The comparator treatment is a placebo to provide objective evidence of potential AEs and other safety data, as well as clinical efficacy and PD data generated from subjects treated with the compound of Formula (I) or a pharmaceutically acceptable salt thereof during the 24-week study. The use of a placebo is justified because there are no approved systemic treatments for SjS. Current standard of care for patients with SjS is limited to symptomatic treatment of mucosal signs and symptoms (dryness), with steroids and traditional DMARDs often being ineffective. There are no effective pharmacological interventions for the severe, disabling fatigue associated with SjS. The inventions described in the original claims of this application are listed below. [Invention 1] 1. A compound of formula (I) for use in the treatment of Sjögren's syndrome (SjS) in a subject in need thereof: [ka] or a pharmaceutically acceptable salt thereof, wherein the daily dose of the compound of formula (I) is from about 10 mg to about 200 mg. [Invention 2] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to Invention 1, wherein the daily dose is about 10 mg to about 100 mg. [Invention 3] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to invention 1, wherein said daily dose is about 100 mg. [Invention 4] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to invention 1, wherein said daily dose is about 50 mg. [Invention 5] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to invention 1, wherein said daily dose is about 35 mg. [Invention 6] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to invention 1, wherein said daily dose is about 25 mg. [Invention 7] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to invention 1, wherein the daily dose is about 20 mg. [Invention 8] The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to invention 1, wherein the compound of formula (I) is administered once a day at a dose of about 10 mg, about 35 mg, about 50 mg or about 100 mg. [Invention 9] 2. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to invention 1, administered twice daily at a dose of about 10 mg, about 25 mg, about 50 mg or about 100 mg. [Invention 10] 10. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of Inventions 1 to 9, wherein the subject has moderate to severe SjS. [Invention 11] The subject meets the following criteria: a) prior to treatment with a compound of formula (I), the subject has an ESSPRI score of ≧5; b) prior to treatment with a compound of formula (I), the subject has an ESSDAI based on a weighted score of ≥ 5 from eight defined domains selected from biological findings, hematology, joints, skin, glandular symptoms, lymphadenopathy, kidneys, and constitution. 11. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of inventions 1 to 10, selected by at least one of the following: [Invention 12] 12. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of inventions 1 to 11, wherein the subject is an adult. [Invention 13] The subject is one of: a) A decrease in ESSPRI score; and / or b) Decrease in ESSDAI score 13. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of inventions 1 to 12, wherein at least one of the above is achieved by the 12th week or by the 24th week of treatment. [Invention 14] 14. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of inventions 1 to 13, wherein said subject achieves a sustained response as measured by ESSPRI or EDSSDAI 5 weeks after completion of said treatment. [Invention 15] 15. The compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of inventions 1 to 14, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is disposed in a pharmaceutical formulation, and the pharmaceutical formulation further comprises a pharmaceutically acceptable carrier. [Invention 16] T of about 0.5 to 3 hours max 16. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use according to any one of inventions 1 to 15,

Claims

1. 1. A pharmaceutical composition for use in treating Sjögren's syndrome (SjS) in a subject in need thereof, comprising a compound of formula (I): 【Chemistry 1】 wherein the compound of formula (I) is administered at a daily dose of about 100 mg once or twice daily (wherein the term "about" means + / - 10%).

2. 10. The pharmaceutical composition of claim 1, wherein the daily dose is about 100 mg (wherein the term "about" means + / - 10%) once a day.

3. 10. The pharmaceutical composition of claim 1, wherein the daily dose is about 100 mg (wherein "about" means + / - 10%) twice daily.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the subject has moderate to severe SjS.

5. The subject meets the following criteria: a) prior to treatment with a compound of formula (I), the subject has an ESSPRI score of ≧5; b) prior to treatment with a compound of formula (I), the subject has an ESSDAI based on a weighted score of ≥ 5 from eight defined domains selected from biological findings, hematological, joint, skin, glandular symptoms, lymphadenopathy, kidney, and constitutional. The pharmaceutical composition according to any one of claims 1 to 4, wherein the compound is selected from at least one of the following:

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the subject is an adult.

7. The subject is one of: a) a decrease in ESSPRI score; and / or b) Decrease in ESSDAI score The pharmaceutical composition of any one of claims 1 to 6, wherein at least one of the following is achieved by the 12th week or by the 24th week of treatment.

8. 8. The pharmaceutical composition of any one of claims 1 to 7, wherein the subject achieves a sustained response as measured by ESSPRI or EDSSDAI 5 weeks after completing the treatment.

9. T of about 0.5 to 3 hours ｍａｘ 9. The pharmaceutical composition of any one of claims 1 to 8, wherein the term "about" means + / - 10%.

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