How to treat Sjögren's syndrome using Bruton tyrosine kinase inhibitors

Abstract

The present disclosure relates to a method for treating Sjögren's syndrome using a compound of Formula I or a pharmaceutically acceptable salt thereof. The compound of Formula I or a pharmaceutically acceptable salt thereof for treating patients with Sjögren's syndrome, as well as agents, dosing regimens, pharmaceutical formulations, dosage forms, and kits for use in the disclosed uses and methods, are also disclosed herein.

Description

Technology Field

[0001] The present disclosure relates to a method for treating Sjögren's syndrome using a Bruton tyrosine kinase (BTK) inhibitor. Background Technology

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

[0003] This disease primarily affects the lacrimal and salivary glands, but the inflammatory process can target any organ, and approximately 15% of patients exhibit severe extraglandular manifestations ( Baldini C., et al (2014) Primary Sj gren '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) Clinical presentation most commonly features exocrine disorders of the salivary and lacrimal glands causing dryness of the mouth and eyes. However, symptoms can be highly heterogeneous and may range from symptoms of dryness accompanied by musculoskeletal pain and fatigue present in almost all patients, to severe, extra-glandular, and systemic involvement (characterized by periepithelial-lymphocyte infiltration and immune complex deposition) in a more limited subset. The underlying mechanism of SjS development is the destruction of exocrine gland epithelium resulting from autoreactive B and T cells. Brito-Zer n P., et al, (2016) Treating the Underlying Pathophysiology of Primary Sj gren Syndrome: Recent Advances and Future Prospects. Drugs p. 1601-1623 The high prevalence of autoantibodies even at very early stages, particularly against Ro / SSA, suggests that autoreactive B cells are involved in the pathogenesis of SjS( Nocturne G., et al, (2018) B cells in the pathogenesis of primary Sj gren syndrome. Nat Rev Rheumatol p. 133-145 ).

[0004] B-cell pathology also leads to an increased risk of malignant transformation, and in 5% of SjS patients, B-cell lymphoma occurs with a 10-fold increased life expectancy risk ( Baldini C., et al, (2014) Primary Sj gren '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 SjS has an estimated prevalence of 0.3 to 1 per 1,000 people ( Qin B., et al. (2015) Epidemiology of primary Sj gren 's syndrome: a systematic review and meta-analysis. Ann. Rheum. Dis. p. 1983-9 As a systemic autoimmune disease, it is the second most common after rheumatoid arthritis. This disease primarily affects women, with a female-to-male ratio of 9:1, and can occur at any age. The primary symptomatic effect of SjS is a severe impact on quality of life and productivity, usually caused by disease-associated incapacitation and fatigue. Mariette X., et al.(2018) Primary Sj gren 's Syndrome. N. Engl. J. Med. p. 931-939 In addition, there are several potential severe systemic complications involving multiple organ systems and affecting 20% ​​to 40% of patients, including arthritis, cutaneous vasculitis, peripheral neuropathy, glomerulonephritis, interstitial nephritis, cholangitis, and obstructive bronchiolitis ( Seror R., et al (2014) Outcome measures for primary Sj gren 's syndrome: a comprehensive review. J. Autoimmun. p. 51-6 ).

[0005] The clinical features of Sjren's syndrome can be divided into medically evaluable patient-symptom manifestations. Currently, there is no single assessment tool capable of capturing the disease activity of both of these clinical manifestations of SjS. Therefore, the European League Against Rheumatism (EULAR) Sjren's Syndrome (SS) Patient Report Index (ESSPRI) and the EULAR SS Disease Activity Index (ESSDAI) are not only widely accepted but also validated for measuring the symptomatic and systemic manifestations of SjS ( Franceschini F., et al, (2017), BMC Medicine, 15:69) .

[0006] In terms of current treatment prospects, there are no internationally approved systemic therapies available for SjS. When dry mouth and eyes are considered, treatment for SjS patients is limited to symptomatic care. Steroids and typical DMARDs are largely ineffective, and no pharmacological intervention is effective for severe lethargic fatigue. The absence of effective treatment options highlights the need to evaluate newer therapeutic approaches for this high-grade debilitating disease. Since the B-cell autoreactive pattern is somewhat similar to that of systemic lupus erythropoiesis and rheumatoid arthritis, B-cell depletion therapy using the anti-CD20 monoclonal antibody (mAb) rituximab has recently been evaluated for both glandular and extra-glandular expression of SjS, as well as for lymphoma management, and has achieved varying degrees of success. However, this approach is not currently an approved treatment for SjS. The insufficient efficacy of rituximab may be associated with incomplete B-cell depletion in affected tissues ( Brito-Zer n P et al (2016) Treating the Underlying Pathophysiology of Primary Sj gren Syndrome: Recent Advances and Future Prospects. Drugs p. 1601-1623 ).

[0007] Despite available treatments for SjS, there is still a high medical need for new treatment options for SjS patients.

[0008] The objective of the present invention is a therapeutically effective amount N -(3-(6-amino-5-(2-( N The present invention provides a novel method for treating Sjögren's syndrome in a subject requiring treatment for said subject, comprising the step of administering -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, to said subject requiring treatment for said subject's Sjögren's syndrome.

[0009] Accordingly, to subjects requiring treatment for Sjren's syndrome (SjS), 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 daily dose of about 10 mg to about 100 mg N -(3-(6-amino-5-(2-( N A method for treating Sjren's syndrome (SjS) is disclosed herein, comprising the step of administering -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof.

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

[0011] 도 1 : Blood concentration of Compound I after a single ascending dose of 0.5 mg to 600 mg - course of time 도 2 : Blood concentration of Compound I after multiple ascending doses of 10 mg to 400 mg, qd administration - course of time 도 3 : Multiple rising doses 100 mg bid and 200 mg bid .Blood concentration of Compound I after - time course 도 4 : Food effects observed after a single oral dose of 60 mg of compound of chemical formula I 도 5 : Arithmetic mean (SD)% of BTK occupancy in peripheral blood after a single dose of the compound of chemical formula I 도 6 : Median % inhibition of basophilic activity on Day 12 of multiple ascending doses of the compound of Formula I versus the total daily dose of the compound of Formula I 도 7 : Reduction in wheal size in skin prick test for multiple ascending doses Specific details for implementing 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 via the B cell antigen receptor (BCR), as well as the Fc epsilon receptor (FcεR1 for IgE) and the activated Fc gamma receptor (FcγR for IgG). BTK inhibition has emerged as an effective concept for treating B-cell malignancies. Covalent BTK inhibitors such as 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 demonstrated promising efficacy against B-cell autoimmunity in preclinical and clinical studies ( 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. p. 294-309 ; Whang J.A., et al. (2014) Bruton's tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Drug Discov. Today p. 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 concept 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 Disco. Today p. 1200-4 ).

[0013] In addition, BTK levels were found to be associated with high serum rheumatoid factor (RF) levels and increased in circulating B cells of a significant percentage of patients with SjS ( 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)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is a BTK inhibitor referred herein as the compound of Formula I or a pharmaceutically acceptable salt thereof:

[0015] [Chemical Formula I]

[0016] .

[0017] This compound is described in WO2015 / 079417 application (Patent Attorney Document No. PAT056021-WO-PCT) filed on June 4, 2015. This compound is a selective and potent reversible covalent inhibitor of Bruton's tyrosine kinase (BTK) and can be used for BTK-mediated diseases or disorders.

[0018] Therefore, the inventors now [compound] N -(3-(6-amino-5-(2-( NA dosing regimen for treating SjS patients was devised using -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof.

[0019] definition:

[0020] For the purpose of interpreting this specification, the following definitions shall apply, and where appropriate, terms used in the singular shall include the plural form, and vice versa.

[0021] The phrase “pharmaceuticalally acceptable” as used herein refers to a compound, substance, composition, and / or dosage form suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reaction, or other problems or complications, corresponding to a reasonable benefit / risk ratio within the scope of sound medical judgment.

[0022] Any formula provided herein is intended to represent the unlabeled form as well as the isotope-labeled form of the compound. The isotope-labeled compound has the structure illustrated by the formula given herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Isotopes that may be included in the compounds of the present disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, e.g. 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, and 36 Cl is included. Therefore, the present disclosure, for example, 3 H and 14 A compound comprising one or more of any of the aforementioned isotopes, including a radioactive isotope such as C, or 2 H and 13It should be understood that this includes those containing non-radioactive isotopes such as C. These isotope-labeled compounds are used in metabolic studies ( 14 C usage), reaction kinetics study (e.g., 2 H or 3 It is useful for detection or contrast imaging techniques such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT), including the analysis of drug or matrix tissue distribution (using H), or for radiation therapy of patients. In particular, 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotope-labeled compounds can generally be prepared by conventional techniques known to those skilled in the art, for example, by using a suitable isotope-labeled reagent instead of a previously used unlabeled reagent.

[0023] As used herein, the term “pharmaceutical combination” refers to a product resulting from the use, mixing, or combination of one or more active ingredients. As used herein, “pharmaceutical combination” should be understood to include both fixed-dose combinations and non-fixed-dose combinations of active ingredients. The term “fixed combination” means that an active ingredient, e.g., a compound of Formula I or a pharmaceutically acceptable salt thereof, and one or more combination partners are simultaneously administered to a patient as a single entity or in a dosage form. In such cases, this term refers to a fixed-dose combination in a single unit dosage form (e.g., capsule, tablet, or sachet). The terms “non-fixed combination” or “kit of parts” both mean that an active ingredient, e.g., a compound of the present disclosure, and one or more combination partners and / or one or more co-preparations are administered to a patient as separate entities, independently or co-administered simultaneously, concurrently, or sequentially without specific time limits, wherein such administration provides two compounds at therapeutically effective levels in the patient’s body, and in particular, wherein these time intervals allow the combination partners to cooperate, e.g., to exhibit an additive or synergistic effect. The term “non-fixed combination” also applies to cocktail therapies, e.g., the administration of three or more active ingredients. Accordingly, the term “non-fixed combination” defines the administration, use, composition, or formulation, particularly in the sense that the compounds described herein may be administered independently of each other, i.e., simultaneously or at different times. It should also be understood that the term “non-fixed combination” encompasses the use of a single formulation with one or more fixed combination products, each of which has a specific amount of the active ingredient contained therein.It should be further understood that the term “non-fixed combination” as well as the combination products described herein encompasses active ingredients (including compounds described herein) administered in entirely separate pharmaceutical dosage forms or in pharmaceutical formulations sold independently of each other. Instructions for the use of non-fixed combinations may be provided in the form of packaging, e.g., leaflets, or other information provided to physicians and / or medical staff. Subsequently, independent formulations or parts of formulations, products, or compositions may be administered simultaneously or at intervals in chronological order. That is, individual parts of a kit of parts may be administered at different times and / or at the same or different time intervals for any part of a kit of parts. In particular, the time interval for administration is selected such that the effect on the disease treated by the use of the combination of parts is greater than / more than the effect obtained by using only the compound of Formula I, and accordingly, the compounds used in the pharmaceutical combinations described herein are co-active. The ratio of the total amount of compound of formula I to the second agent to be administered as a pharmaceutical combination may be changed or adjusted to better meet the needs of a specific subgroup of patients to be treated or a single patient, which may be attributed, for example, to the patient's age, gender, weight, etc.

[0024] As used herein, terms such as “co-administration” or “combination administration” encompass the administration of one or more compounds described herein together with selected combination partners to a single subject requiring such administration (e.g., a patient or subject), and are intended to include a therapeutic regimen in which the compounds are not necessarily administered via the same route of administration and / or simultaneously.

[0025] The term “pharmaceutical composition” is defined in this specification as referring to a mixture (e.g., solution or emulsion) containing at least one active ingredient or therapeutic agent to be administered to a warm-blooded animal, e.g., mammal or human, to prevent or treat a specific disease or illness affecting warm-blooded animals.

[0026] The term “therapeutic effective dose” of a compound of the present disclosure (i.e., a compound of Formula I or a pharmaceutically acceptable salt thereof) refers to an amount of a compound of the present disclosure that elicits a biological or medical response in a subject (subject patient), e.g., a reduction or inhibition of enzyme or protein activity, alleviates symptoms, relieves disease, slows or delays disease progression, or prevents disease. The therapeutic effective dose of a compound, pharmaceutical composition, or combination thereof depends on the patient’s species, body weight, age, sex, and individual disease, the disorder or disease being treated, or its severity. A physician, clinician, or veterinarian skilled in the art can readily determine the effective dose of each active ingredient required to prevent, treat, or inhibit the progression of the disorder or disease.

[0027] The frequency of administration may vary depending on the compound used and the specific disease to be treated or prevented. In general, it is desirable to use the minimum dose sufficient to provide an effective treatment. Patients may be monitored for the therapeutic effect using assays appropriate for the disease to be treated or prevented, which are generally familiar to those skilled in the art.

[0028] As used herein, the terms “carrier” or “pharmaceutically acceptable carrier” include any solvent, dispersion medium, coating agent, surfactant, antioxidant, preservative (e.g., antimicrobial, antifungal), isotonic agent, absorption retardant, salt, preservative, drug, drug stabilizer, binder, excipient, disintegrant, lubricant, sweetener, flavoring agent, dye, etc., and combinations thereof as known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Any conventional carrier is considered for use in therapeutic or pharmaceutical compositions, except where it is incompatible with the active ingredient.

[0029] As used herein, the term “subject” refers to an animal. Typically, the animal is a mammal. The subject also refers, for example, to primates (e.g., human, male or female), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, etc. In a given embodiment, the subject is a primate. In a preferred embodiment, the subject is a human. When referring to a human, the term “subject” is used interchangeably with “patient.”

[0030] As used herein, if a subject benefits from such treatment biologically, medically, or in terms of quality of life, such subject "needs" the treatment.

[0031] As used in this specification, the phrase "patient group" is used to mean a group of patients.

[0032] The term "comprising" encompasses not only "including" but also "consisting," and, for example, a composition "comprising" X may consist only of X or may include something additional, for example, X + Y.

[0033] The term "about" regarding a numeric value x means, for example, + / -10%. When used before a number range or a list of numbers, the term "about" applies to each number in a series, for example, the phrase "about 1 to 5" should be interpreted as "about 1 to about 5", or for example, the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc."

[0034] The terms “treatment” or “treat” are 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 a tissue or cell line isolated from a subject, where the subject has a specific disease (e.g., SjS), symptoms associated with the disease (e.g., SjS), or a predisposition to the occurrence of the disease (e.g., SjS) (where applicable), and the purpose is to cure the disease (where applicable), delay its onset, reduce its severity, alleviate or relieve one or more of its symptoms, improve the disease, or reduce or improve any associated symptoms of the disease or a predisposition to the occurrence of the disease. The terms “treatment” or “treat” include treating a patient suspected of having the disease as well as a patient diagnosed as being sick or suffering from a disease or medical condition, and include the suppression of clinical recurrence.

[0035] As used herein, with respect to patients, “selecting” and “selected” are used to mean that a specific patient is specifically selected from a larger patient group based on (or due to) specific patients meeting predetermined criteria. Similarly, “selectively treating” refers to providing treatment to a patient where such patient is specifically selected from a larger patient group based on (or due to) specific patients meeting predetermined criteria for a specific disease. Likewise, “selectively administering” refers to administering a drug to a patient specifically selected from a larger patient group based on (or due to) specific patients meeting predetermined criteria. “Selecting,” “selectively treating,” and “selectively administering” mean that personalized treatment is delivered to a patient based on the patient’s personal history (e.g., history of therapeutic interventions, e.g., history of previous treatment with biological agents), biology (e.g., specific genetic markers), and / or expression (e.g., failure to meet specific diagnostic criteria), rather than delivering a standard treatment regimen based solely on the patient’s eligibility within the larger group. With respect to treatment methods as used herein, the act of selection does not refer to the accidental treatment of a patient having specific criteria, but rather refers to an intentional selection to administer treatment to a patient based on a patient having specific criteria. Accordingly, selective treatment / administration differs from standard treatment / administration, which involves delivering a specific drug to all patients with a specific disease regardless of their personal history, disease manifestation, and / or biology. In some embodiments, a patient was selected for treatment based on having SjS.

[0036] Embodiments of the present invention:

[0037] Sjögren's syndrome and the effects of the treatment according to the present invention

[0038] The disclosed BTK inhibitor, i.e., the compound of Formula I or a pharmaceutically acceptable salt thereof, may be used in vitro or in vitro, or may be included in a pharmaceutical composition and administered in vivo to treat SjS patients (e.g., human patients).

[0039] The effectiveness of Sjögren's treatment can be evaluated using various known methods and tools to measure Sjögren's syndrome status and / or Sjögren's clinical response. Some examples include, for instance, the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), the Physician Global Assessment Scale (PhGA), the EULAR Sjögren's Syndrome Patient Report Index (ESSPRI), the Functional Assessment of Chronic Disease Treatments-Fatigue Scale (FACIT-Fatigue), and EQ5D.

[0040] effectiveness

[0041] The clinical efficacy measurements related to primary and secondary objectives are outlined below.

[0042] EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI)

[0043] 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 Sj gren 's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66 This means includes 12 organ-specific domains that contribute to disease activity. For each domain, the characteristics of disease activity are scored at levels 3 or 4 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), glands (2), joints (2), skin (3), lungs (5), kidneys (5), muscles (6), PNS (5), CNS (5), hematological (2), and biological (1). The maximum possible score is 123.

[0044] In this study, to calculate ESSDAI, all 12 institutional domains must be evaluated individually at every scheduled time point (from the screening visit to the end of the study). Domain evaluations are entered into a table (provided by a central provider), and ESSDAI scores are calculated by software.

[0045] Regarding assessments that may be necessary to estimate ESSDAI, including radiography, high-resolution computed tomography (HRCT), pulmonary function tests (DLCO, FVC), estimated glomerular filtration rate (eGFR), electromyography (EMG), and muscle (or any other) biopsy, which are not described in the protocol as mandatory tests, it is at the investigator's discretion to evaluate them based on the patient's signs and symptoms to provide accurate ESSDAI readings. The EULAR Sjögren's Syndrome Disease Index (ESSDAI), domain and item definitions, and weights are summarized in Table 1.

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] Physician General Assessment Scale (PhGA)

[0053] The physician's overall evaluation scale is used to evaluate a patient's disease activity using a 100 mm VAS, which ranges from "no disease activity" (0) to "maximum disease activity" (100).

[0054] To enhance objectivity, physicians must not be aware of specific patient-reported outcome evaluations when performing their own assessment of the patient. Therefore, this assessment should be performed before viewing the patient's overall assessment of the total disease activity score.

[0055] EULAR Sjögren's Syndrome Patient Reporting Index (ESSPRI)

[0056] ESSPRI is an established measure of disease outcome for Sjögren's syndrome. Seror R, et al (2011) EULAR Sj. gren 's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sj gren 's syndrome. Ann. Rheum. Dis. p. 968-72 This consists of three domains: dryness, pain, and fatigue. Subjects can assess the severity of the symptoms they experience for each of the three domains on a single numerical scale of 0 to 10. The ESSPRI score is defined as the mean of the scores from the three scales: (Dryness + Pain + Fatigue) / 3.

[0057] FACIT - fatigue

[0058] The Functional Assessment of Chronic Diseases Treatment—Fatigue Scale (FACIT-F v4) is a short, 13-item, easy-to-administer tool that measures an individual's level of fatigue during general daily activities over the past week. Fatigue levels are measured on a 5-point Likert scale (0 = none, 1 = slight, 2 = somewhat, 3 = significant, 4 = very significant) 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 ).

[0059] EQ5D

[0060] The EQ-5D is a standardized means of measuring health-related quality of life. The EQ-5D consists of a descriptive system and the EQ VAS scale.

[0061] The descriptive system includes five dimensions: mobility, self-care, general activity, pain / discomfort, and anxiety / depression. These can be used as quantitative measures of health outcomes that reflect the patient's own judgment. Scores on these five dimensions can be presented as a health profile or converted into a single summary index value (usefulness) that reflects the potential for preference compared to other health profiles.

[0062] The EQ VAS records a patient's self-assessed health on a vertical visual analog scale, where 0 represents the 'worst possible health condition' and 100 represents the 'best possible health condition'.

[0063] Appropriateness of validity evaluation

[0064] The measurement of validity in this study is primarily based on the ESSDAI (EULAR SS Disease Activity Index), which measures organ-specific disease criteria, and the ESSPRI (European Rheumatology [EULAR] Sjögren's Syndrome [SS] Patient Report Index), which measures the subjective impact of the disease on patients. Both measures are widely accepted and validated gold-standard measures of systemic and symptomatic manifestation of SjS, respectively.

[0065] ESSDAI is a systemic disease activity index that classifies disease activity into 3 to 4 levels across each of 12 differently weighted domains (biological, hematological, joint, glandular, skin, constitutional, lymphadenopathy, renal, pulmonary, PNS, CNS, and muscular). The composite weighted score provides an accurate assessment of disease activity and, as verified in several cohort studies, has excellent sensitivity to changes ( Seror R et al (2015) Validation of EULAR primary Sj gren 's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66 ). On the other hand, the ESSPRI tool is a composite score of patient-reported symptoms of dryness, limb pain, and fatigue evaluated on a visual analog scale of 0 to 10 over the preceding two weeks ( Seror R et al (2011) EULAR Sj gren 's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sj gren 's syndrome. Ann. Rheum. Dis. p. 968-72 While patient-reported scores have poor sensitivity to changes in disease activity, ESSPRI has been reported to have significantly better sensitivity among available tools. Recent preliminary studies reported a poor association between systemic and patient scores, suggesting that the two indices assess complementary components of disease activity; accordingly, this emphasized the importance of evaluating both parameters to arrive at an accurate assessment of disease activity and its changes. Seror R et al (2015) Validation of EULAR primary Sj gren 's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66 ).

[0066] Pharmaceutical composition

[0067] BTK inhibitors, i.e., compounds of Formula I or pharmaceutically acceptable salts thereof, may be used as pharmaceutical compositions when combined with pharmaceutically acceptable carriers. In addition to the compound of Formula I, such compositions may contain a carrier, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other substances known in the art. The characteristics of the carrier depend on the route of administration. Pharmaceutical compositions for use in the disclosed method may also contain additional therapeutic agents for the treatment of specific target disorders. For example, the pharmaceutical composition may also include anti-inflammatory agents or antipruritics. These additional factors and / or agents may be included in the pharmaceutical composition to create 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 method comprises the compound of Formula I in doses of 10 mg, 20 mg, 25 mg, 50 mg, or about 100 mg.

[0068] Compositions suitable for oral administration contain an effective amount of the 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 for oral use are prepared according to any method known in the art for the preparation of pharmaceutical compositions, and such compositions may contain one or more agents selected from the group consisting of sweeteners, flavorings, colorings, and preservatives to provide pharmaceutically attractive and tasty products. Tablets may contain the active ingredient mixed with pharmaceutically acceptable non-toxic excipients suitable for the manufacture of tablets. Such excipients include, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, or sodium phosphate; granulating agents and disintegrating agents, for example, corn starch or alginate; binders, for example, starch, gelatin, or acacia; and a lubricant, e.g., magnesium stearate, stearic acid, or talc. The tablets are uncoated or coated with known techniques to delay disintegration and absorption in the gastrointestinal tract to provide sustained action over a long period. For example, a time-delaying agent, 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, e.g., calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with a water or oil medium, e.g., peanut oil, liquid paraffin, or olive oil.

[0069] A pharmaceutical composition for use in the disclosed method may 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 an active ingredient with the following:

[0070] a) Diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine;

[0071] b) Lubricants, e.g., silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; also, for refining

[0072] c) If necessary, a binder, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone;

[0073] d) a disintegrant, e.g., starch, agar, alginic acid or its sodium salt, or an effervescent mixture; and / or

[0074] e) Absorbents, coloring agents, flavoring agents, and sweeteners.

[0075] The tablets may be film-coated or enteric-coated according to methods known in the art.

[0076] Combination:

[0077] In carrying out part of the therapeutic method or use of the present disclosure, a therapeutically effective amount of the compound of Formula I or a pharmaceutically acceptable salt thereof is administered to a patient, e.g., a mammal (e.g., human). While the disclosed method is understood to be provided for the treatment of a Sjögren's patient using the compound of Formula I or a pharmaceutically acceptable salt thereof, the treatment is not necessarily a monotherapy. In practice, if a patient is selected for treatment using the compound of Formula I, the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered according to the method of the present disclosure, either alone or in combination with other agents and treatments for treating a Sjögren's patient, e.g., in combination with at least one additional Sjögren's agent. When co-administered with one or more additional SjS agent(s), the compound of Formula I or a pharmaceutically acceptable salt thereof may be administered simultaneously or sequentially with the other agent. If administered sequentially, the attending physician will determine the appropriate order of administration of the compound of Formula I or a pharmaceutically acceptable salt thereof in combination with other agents and the appropriate dosage for co-delivery.

[0078] Various therapies may be beneficially combined with compounds of Formula I or pharmaceutically acceptable salts thereof initiated during the treatment of SjS. These therapies include steroids (corticosteroids, e.g., prednisone or equivalents); DMARDS, e.g., hydroxychloroquine (Plaquenil), methotrexate (Trexall), sulfasalazine (Azulfidine), minocycline (Minocin) or leflunomide (Arava); or B-cell depletion drugs, e.g., rituximab.

[0079] A person skilled in the art will be able to identify an appropriate dosage of the said SjS formulation for co-delivery with the compound of the disclosed formula I or a pharmaceutically acceptable salt thereof.

[0080] Kit of the present invention

[0081] The present disclosure also covers a kit for treating SjS. Such a kit includes a BTK inhibitor, for example, N -(3-(6-amino-5-(2-( N It includes -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide or a pharmaceutical composition thereof. Additionally, such kits may include instructions for use.

[0082] In one embodiment, the kit comprises two or more individual 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 means for holding the compositions individually, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack typically used for packaging tablets, capsules, etc.

[0083] The kit of the present invention may be used for different dosage forms, e.g., oral and parenteral administration, to administer individual compositions at different dosing intervals, or to titrate individual compositions against one another. For compliance with relevant regulations, the kit of the present invention typically includes dosing instructions.

[0084] In the combination therapy of the present invention, the compound of Formula I or its pharmaceutically acceptable salt, and other SjS preparations (as defined herein) may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of Formula I or its pharmaceutically acceptable salt, and other SjS preparations may be combined into a combination therapy by (i) before providing the combination product to a physician (e.g., in the case of a kit containing the compound of Formula I or its pharmaceutically acceptable salt, and other SjS preparations); (ii) immediately before administration by the physician himself (or under the guidance of the physician); or (iii) during the sequential administration of, for example, the compound of Formula I or its pharmaceutically acceptable salt, and other SjS preparations.

[0085] Additional implementation example

[0086] A compound of formula I or a pharmaceutically acceptable salt thereof is conveniently administered to a patient (preferably orally) at a dose of about 10 mg to about 200 mg per day.

[0087] A compound of formula I or a pharmaceutically acceptable salt thereof is conveniently administered to a patient (preferably orally) at a daily dose of about 10 mg to about 200 mg.

[0088] In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 10 mg to about 100 mg.

[0089] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 100 mg.

[0090] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 50 mg.

[0091] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 35 mg.

[0092] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 25 mg.

[0093] In another embodiment, the compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 20 mg.

[0094] 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.

[0095] In one 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.

[0096] It will be understood that a dose increase may be necessary for certain patients, e.g., Sjögren's patients who exhibit an inappropriate response (e.g., as measured by any Sjögren scoring system disclosed herein). It will also be understood that a dose reduction may be necessary for certain patients, e.g., Sjögren's patients who exhibit an adverse event or adverse reaction to treatment with the compound of Formula I or a pharmaceutically acceptable salt thereof. Accordingly, 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.

[0097] The time of administration is generally measured from the first day of administration of the compound of Formula I or its pharmaceutically acceptable salt (also known as the "baseline").

[0098] However, healthcare providers typically use different naming conventions to identify dosing schedules. For clarity, as disclosed herein, the first dosing day is 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 interpreted as limiting, that is, that the daily dosing 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 specific day as "Day 0" or "Day 1".

[0099] A method for treating Sjögren's syndrome (SjS) is disclosed herein, comprising the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient requiring treatment for Sjögren's syndrome (SjS), wherein the dose is about 10 mg to about 200 mg.

[0100] Additionally, a method for treating Sjren's syndrome (SjS) is disclosed herein, comprising the step of administering a compound of formula I or a pharmaceutically acceptable salt thereof to a patient requiring treatment for Sjren's syndrome (SjS), wherein the daily dose is about 10 mg to about 200 mg.

[0101] Additionally, a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of SjS is disclosed herein, wherein the daily dose of the compound is about 10 mg to about 200 mg.

[0102] In one embodiment of the disclosed method, use and kit, a compound of Formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 10 mg to 100 mg.

[0103] In another embodiment of the disclosed method, use and kit, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered at 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.

[0104] In another embodiment of the disclosed method, use and kit, a compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 100 mg.

[0105] In another embodiment of the disclosed method, use and kit, a compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 50 mg.

[0106] In another embodiment of the disclosed method, use and kit, a compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 35 mg.

[0107] In another embodiment of the disclosed method, use and kit, a compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 25 mg.

[0108] In another embodiment of the disclosed method, use and kit, a compound of formula I or a pharmaceutically acceptable salt thereof is administered at a daily dose of about 20 mg.

[0109] In another embodiment of the disclosed method, use and kit, 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.

[0110] In another embodiment of the disclosed method, use and kit, 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.

[0111] In another embodiment of the disclosed method, use and kit, the patient has moderate to severe SjS. A patient with moderate to severe SjS is defined as a patient having an ESSDAI score (based on weighted scores as shown in Table 1) ≥ 5 (i.e., at least 5) and an ESSPRI score of at least 5 from eight defined domains (biological, hematological, joint, skin, glandular, lymphadenopathy, renal, constitutional) prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0112] In another embodiment of the disclosed method, use, and kit, the patient is an adult.

[0113] In another embodiment of the disclosed method, use, and kit, the patient achieves a change from baseline in at least one of the patient and / or physician-reported results (i.e., ESSPRI, FACIT-F, EQ-5D, PhGA) by week 12 or week 24 of treatment.

[0114] In another embodiment of the disclosed method, use, and kit, the patient achieves a change from baseline in the ESSPRI score by week 12 or week 24 of treatment.

[0115] In another embodiment of the disclosed method, use, and kit, the patient achieves a reduction in the ESSPRI score by week 12 or week 24 of treatment.

[0116] In another embodiment of the disclosed method, use, and kit, the patient achieves a reduction in the ESSPRI score by at least 1 point, preferably at least 2 points, by week 12 or week 24 of treatment.

[0117] In another embodiment of the disclosed method, use, and kit, the patient achieves a reduction in the ESSPRI score by week 12 or week 24 of treatment. In another embodiment of the disclosed method, use, and kit, the patient achieves a reduction in the ESSPRI score of at least 15%, at least 25%, at least 35%, at least 50%, or at least 60% by week 12 or week 24 of treatment. The reduction in the ESSPRI score is calculated as follows:

[0118]

[0119] In another embodiment of the disclosed method, use, and kit, the patient achieves a reduction in the ESSDAI score by week 12 or week 24 of treatment.

[0120] In another embodiment of the disclosed method, use, and kit, the patient achieves a reduction in the ESSDAI score of at least 3 points by week 12 or week 24 of treatment.

[0121] In another embodiment of the disclosed method, use, and kit, the patient achieves a change from the baseline of the ESSDAI score by week 12 or week 24 of treatment.

[0122] In a preferred embodiment of the disclosed method, use, and kit, the patient is an adult. In some embodiments of the disclosed method, use, and kit, the patient is an adolescent.

[0123] Additional enumeration implementation example

[0124] 1. For subjects requiring treatment for Sjren's syndrome (SjS), at a daily dose of about 10 mg to about 200 mg N A method for treating Sjögren's syndrome (SjS), comprising the step of administering -(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof.

[0125] 2. In Embodiment 1, N A method in which the daily dose of -(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is about 10 mg to about 100 mg.

[0126] 3. In Embodiment 1, N A method in which the daily dose of -(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is about 100 mg.

[0127] 4. In Embodiment 1, N A method in which the daily dose of -(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is about 50 mg.

[0128] 5. In Embodiment 1, N A method in which the daily dose of -(3-(6-amino-5-(2-(N-methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is about 35 mg.

[0129] 5. In Embodiment 1, N -(3-(6-amino-5-(2-( N A method in which the daily dose of -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is about 25 mg.

[0130] 7. In Embodiment 1, N -(3-(6-amino-5-(2-( NA method in which the daily dose of -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, is about 20 mg.

[0131] 8. In Embodiment 1, N -(3-(6-amino-5-(2-( N A method in which -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, 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.

[0132] 9. In Embodiment 1, N -(3-(6-amino-5-(2-( N A method in which -methylacrylamido)ethoxy)pyrimidine-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.

[0133] 10. A method in any one of embodiments 1 to 9, wherein the subject has moderate to severe SjS.

[0134] 11. A method in any one of embodiments 1 to 10, wherein the object is selected according to at least one of the following criteria:

[0135] a) Prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, the subject has an ESSPRI score of 5 or higher;

[0136] b) Prior to treatment with a compound of Formula I or a pharmaceutically acceptable salt thereof, the subject has an ESSDAI score of 5 or higher based on weighted scores from 8 defined domains selected from biological, hematological, joint, skin, gland, lymphadenopathy, renal, and constitution.

[0137] 12. A method in any one of embodiments 1 to 11, wherein the subject is an adult.

[0138] 13. A method in any one of embodiments 1 to 12, wherein the subject achieves at least one of the following by week 12 or week 24 of treatment:

[0139] a) Decrease in ESSPRI score; and / or

[0140] b) Decrease in ESSDAI score.

[0141] 14. A method in any one of embodiments 1 to 13, wherein the subject achieves a sustained response measured by ESSPRI or ESSDAI at week 5 after completion of treatment:

[0142] 15. In any one of embodiments 1 to 14, N -(3-(6-amino-5-(2-( N -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof is disposed in a pharmaceutical formulation, and said pharmaceutical formulation further comprises a pharmaceutically acceptable carrier.

[0143] 16. In any one of Embodiments 1 to 15, N -(3-(6-amino-5-(2-( N -methylacrylamido)ethoxy)pyrimidine-4-yl)-5-fluoro-2-methylphenyl)-4-cyclopropyl-2-fluorobenzamide, or a pharmaceutically acceptable salt thereof, at a time of about 0.5 to 3 hours T max A method having.

[0144] Details of one or more embodiments of the present disclosure are set forth in the appended description. Any method and material similar or equivalent to that described herein may be used to practice or test the present disclosure, but preferred methods and materials are described hereafter. Other features, purposes, and benefits of the present disclosure will be apparent from the description and claims. In the specification and appended claims, the singular form includes the plural unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which the present disclosure pertains. All patents and publications cited in this specification are incorporated by reference. The following examples are presented to more fully illustrate preferred embodiments of the present disclosure. These examples should not be construed as limiting the scope of the main subject matter disclosed as defined by the appended claims.

[0145] abbreviation

[0146] AE harmful incident

[0147] Area under the AUC curve

[0148] AUCinf Area under the plasma (or serum or blood) concentration-time curve from 0 to infinity (mass x time / volume)

[0149] Area under the plasma (or serum or blood) concentration-time curve from AUClast time 0 to the time of the last quantifiable concentration (mass x time / volume)

[0150] Area under the plasma (or serum or blood) concentration-time curve (mass x time / volume) from AUCtau time 0 to the end of the dosing interval tau

[0151] BCR B cell receptor

[0152] Bid or bid twice a day (Latin: "bis in die")

[0153] BMI Body Mass Index

[0154] BTK Bruton Tyrosine Kinase

[0155] CBC total blood cell count

[0156] centimeters

[0157] Apparent systemic (or whole body) elimination rate (mass / volume) from plasma (or serum or blood) after CL / F administration

[0158] CNS Central Nervous System

[0159] CV coefficient of variation

[0160] DMARDs (Disease-Modified Anti-Rheumatic Drugs)

[0161] ECG

[0162] eGFR (Estimated Glomerular Filtration Rate)

[0163] ELISA Enzyme-Associated Immunoassay

[0164] EMG electromyography

[0165] EQ-5D EuroQual 5 Dimensions (Standard means for measuring health-related quality of life)

[0166] ESSDAI EULAR Sjögren's Syndrome Disease Activity Index

[0167] ESSPRI EULAR Sjögren's Syndrome Patient Reporting Index

[0168] EULAR European Rheumatology Society

[0169] Functional Evaluation of FACIT-F Chronic Disease Treatment - Fatigue

[0170] First in Human Application of FIH

[0171] h time

[0172] HRCT High-resolution computed tomography

[0173] IV intravenous

[0174] IA Interim Analysis

[0175] INR International Standardization Non-

[0176] kilograms

[0177] LC-MS / MS Liquid Chromatography / Mass Spectrometry-Mass Spectrometry

[0178] mAb monoclonal antibody

[0179] MCP-Mod Multiple Comparison Procedure - Modeling

[0180] MMRM Mixed Effects Model Repeated Measures

[0181] MRT average time spent

[0182] NOACs (novel oral anticoagulants)

[0183] NSAIDs (non-steroidal anti-inflammatory drugs)

[0184] PD pharmacodynamics(s)

[0185] PhGA physician overall evaluation scale

[0186] PK pharmacokinetics(s)

[0187] PNS Peripheral Nervous System

[0188] PT Prothrombin Time

[0189] PTT partial thromboplastin time

[0190] Qd or qd once a day (Latin "quaque die")

[0191] QT interval corrected by Fridericia's formula QTcF

[0192] Accumulation ratio of Racc drugs

[0193] SAE serious hazardous incidents

[0194] Sjs Sjögren's syndrome

[0195] SOM Field Operations Manual

[0196] SPT Skin Prick Test

[0197] SS Safety Set

[0198] TEC tyrosine-protein kinase

[0199] Apparent distribution volume during terminal clearance phase after Vz / F administration

[0200] Example 1: Preclinical study

[0201] Example 1a: BTK Occupancy and Preclinical PK / PD Correlation

[0202] The in vivo PD effect of irreversible BTK inhibitors, such as Compound I, is determined by the degree and duration of co-occupancy of BTK by the inhibitor. BTK occupancy after treatment with the compound of Formula I (also referred to as Compound I) was measured by an in vitro immunoassay. Since Compound I and the probe bind to BTK in a mutually exclusive manner, the fraction of unoccupied BTK protein was evaluated after in vitro incubation with a co-biotinized BTK probe. Levels of total BTK-related proteins, as well as unoccupied BTK, were determined in the lysates of selected tissues, and the levels of unoccupied BTK were standardized against the levels of total BTK proteins in the same samples.

[0203] In female rats, a single oral dose of 3 mg / kg of Compound I resulted in total splenic BTK occupancy, and a dose of 1 mg / kg resulted in 76% to 81% occupancy, whereas after a single dose of 0.3 mg / kg, only 30% partial occupancy was reached. Blood BTK occupancy reached levels consistent with those observed in the spleen. From the experimental data, it was evident that the short, transient systemic exposure of Compound I was sufficient to achieve total BTK occupancy in some tissues at low oral doses of 1 mg / kg to 3 mg / kg. Blood exposure to Compound I after 1 mg / kg administration reached 49.1 nM at 0.5 hours and was 5.6 nM at 5 hours post-administration. These very low and transient systemic exposures are consistent with the PK / PD model typical of irreversible inhibitors.

[0204] The duration of BTK occupancy was determined in rats and mice following a single oral dose of Compound I in the spleen, blood, lymph nodes, and lungs. In rats, BTK occupancy exhibited a long blood half-life of approximately 87 hours. The estimated half-life of BTK occupancy in the rat spleen is significantly shorter than in the blood, having only about 5 hours. The different turnover rates may reflect the fact that BTK-expressing B cells and monocytes in peripheral blood are in a quiescent state and are metabolically relatively inactive compared to the spleen. Longer duration of BTK occupancy in the blood has been previously reported (Advani et al 2013, J Clin Onc; 31(1):88-94). All other tissues analyzed (lungs and lymph nodes) exhibited BTK turnover and occupancy half-lives similar to those of the spleen.

[0205] Since the levels of BTK-expressing cells in the skin were too low to enable occupancy measurements, the duration of the PD effect in the skin after a single dose was evaluated in a reverse passive artus (RPA) model of mast cell FcγRIII-mediated inflammation. In this model, inhibition of skin swelling was maximum when Compound I was administered 2 hours prior to inducing the artus response. The effect gradually diminished and reached baseline when the artus response was triggered more than 45 hours after administration of Compound I. This suggests that BTK occupancy in the skin exhibits a time course similar to that of the spleen, lungs, and lymph nodes.

[0206] In these preclinical pharmacological studies, BTK occupancy and each pharmacological readout showed a strong association. Therefore, BTK occupancy is a PD biomarker suitable for use in clinical studies and was accordingly used in a Phase 1 clinical study.

[0207] Example 2: Phase 1 clinical trial

[0208] To support the further clinical development of Compound I in autoimmune diseases, the first human study was conducted to evaluate the safety and tolerance, pharmacokinetics (PK), and pharmacodynamics (PD) of single and multiple doses of Compound I administered orally at both once daily (qd) and twice daily (bid) in healthy volunteers and individuals with an atopic constitution. This study also explored the effects of food intake.

[0209] In the first human study of up to approximately 168 healthy volunteers (HV), 64 of them (in parts 2 and 4) had an asymptomatic atopic constitution.

[0210] ● Part 1 was a 10-cohort (N=80) double-blind (subject and investigator blinded, sponsor unblinded), placebo-controlled single-dose escalation (SAD) study.

[0211] ● Part 2 was a double-blind (subject and investigator blinded, sponsor unblinded), placebo-controlled multiple dose escalation (MAD) study (13 doses over 12 days) using once-daily administration in 6 cohorts (N=48) of healthy volunteers with an asymptomatic atopic constitution.

[0212] ● Part 3 was a single-dose open-label crossover food effect study in 12 HVs.

[0213] ● Part 4 was a double-blind (subject and investigator blinded, sponsor unblinded), placebo-controlled multiple-dose (25 doses over 12 days) study using twice-daily administration in 2 cohorts (N=16) of healthy volunteers with an asymptomatic atopic constitution.

[0214] 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 in Part 2 used a single daily dose, and 2 cohorts in Part 4 used a twice-daily dose). Eight subjects were randomized into their respective cohorts to receive Compound I or the corresponding placebo in a 6:2 (active:placebo) ratio in the SAD and MAD parts. Within the SAD part, the estimated pharmacologically active dose (PAD) had to be evaluated at a maximum of approximately 4 doses prior to the start of the MAD part of the study, provided there were no safety signals derived from the SAD part up to that point. 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 highest SAD dose level explored. Additionally, the total daily dose in Part 4 did not exceed the total daily dose in Part 2.

[0215] In Part 1 (SAD), the entire course of treatment had to be administered for the first dose at each dose level as follows. The first two subjects were administered on Day 1 (one received the active drug, and one received a placebo). After a 48-hour observation period, the remaining six subjects of the cohort were administered (five received the active drug, and one received a placebo).

[0216] Standard safety monitoring was used throughout all study parts. Dedicated evaluation of potential skin bruising cases was included. For each cohort prior to dose escalation, all vital signs, physical examination and subject history, ECG, adverse events, and laboratory safety parameters (blood chemistry, hematology, and urinalysis) up to 96 hours after final dosing, as well as PK data from the previous dose group (where available) up to 48 hours after final dosing, had to be reviewed in a blinded manner. Summary safety reports of reported adverse events, clinical safety laboratory parameters, QTc, and heart rate were provided after completion of each dose level.

[0217] 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 including an end-of-study evaluation.

[0218] In Part 1, subjects were admitted to the study site on Day -2 or Day -1 for baseline safety assessment and eligibility confirmation. Eligible subjects received a single dose of Compound I or a placebo on Day 1 under fasting conditions. They were administered intravenously from Day -1 until the morning of Day 5 (96 hours after the last drug administration).

[0219] In Parts 2 and 4, subjects were admitted on Day -2 or Day -1 for baseline safety assessment and eligibility confirmation. Eligible subjects received the first dose of Compound I on Day 1 under fasting conditions and continued to take the study agent under fasting conditions up to Day 12 (including Day 12). Subjects were administered intravenously starting on Day -2 or Day -1 until the morning of Day 16, which corresponds to 96 hours after the final dose of Compound I was administered. In Parts 2 and 4, the study agent was administered once and twice daily, respectively (details can be found in the evaluation schedule).

[0220] Part 3 was an open-label, randomized, two-way crossover, single-dose study designed to investigate the effects of the food. In Part 3, each subject participated in a 28-day screening period (from Day 29 to Day 2), two baseline periods (Day 1), and two treatment periods, each consisting of a single-dose administration on Day 1 followed by safety and PK assessments up to Day 5. Treatment period 2 consisted of follow-up visits and end-of-study assessments at Days 22 and 40, respectively. The two study periods were separated by a washout period of at least 18 days (+ / - 1 day).

[0221] primary purpose(s)

[0222]

[0223] secondary purpose

[0224]

[0225] Search Objective

[0226]

[0227] Inclusion criteria :

[0228] 1. Healthy male and female subjects in the age range of 18 to 65 (including borderline) who are in good health as determined by past medical history, physical examination, vital signs, electrocardiogram, and laboratory tests at screening. Healthy subjects participating in Part 2 or Part 4 who have an atopic constitution according to eligibility for these specific study parts. Healthy atopic volunteers must have been positive on a skin prick test for a known allergen at screening (atopic constitution), but were clinically asymptomatic and did not require any systemic medication.

[0229] 2. Subjects were required to have a Body Mass Index (BMI) within the range of 18 kg / m² to 30 kg / m² (including boundaries) and a body weight of at least 50 kg. BMI = Body weight (kg) / [Height (m)] 2 .

[0230] 3. At screening and from the first baseline, vital signs (body temperature, systolic and diastolic blood pressure, and pulse rate) were evaluated in a seated position and again (if required) in a standing position after 3 minutes, after the subject had rested for at least 3 minutes. Vital signs in the seated position were required to be within the following ranges (including the boundaries):

[0231] ● Oral body temperature of 35.0℃ to 37.5℃

[0232] ● Systolic blood pressure 90 mm Hg to 139 mm Hg

[0233] ● Diastolic blood pressure 50 mm Hg to 89 mm Hg

[0234] ● Pulse rate 50 bpm to 90 bpm

[0235] Key exclusion criteria

[0236] 1. History of hypersensitivity to any study drug or drugs of a similar chemical class.

[0237] 2. Clinically significant ECG abnormalities at screening and / or prior to treatment, or a history of any of the following ECG abnormalities:

[0238] ● PR interval > 200 msec

[0239] ● QRS complex > 120 msec

[0240] ● QTcF > 450 msec (male)

[0241] ● QTcF > 460 msec (female)

[0242] 3. Hemoglobin levels less than 12.0 g / dL at screening or the first baseline.

[0243] 4. Platelet count outside the normal range at screening or the first baseline (150 x 10⁶ 9 Less than / L or 450 x 10 9 over).

[0244] 5. Any clinically significant abnormality in any standard coagulation test, including prothrombin time (PT), partial thromboplastin time (PTT), or International Normalized Ratio (INR), at screening and / or baseline.

[0245] 6. History or presence of a case of thrombosis or thromboembolism, or increased risk of a case of thrombosis or thromboembolism.

[0246] Treatment being performed

[0247] Part 1 (SAD)

[0248] Subjects were assigned to one of the following 10 cohorts. In each cohort, 8 subjects were randomized to Compound I or the corresponding placebo in a 6:2 ratio. The first sub-cohort was randomized in a 1:1 ratio, with 1 subject for Compound I and 1 subject for the corresponding placebo. The remaining 6 subjects per cohort, who would receive the treatment after a 48-hour observation period for the first 2 subjects, were randomized in a 5:1 ratio.

[0249] ● Cohort 1: A single oral dose of 0.5 mg Compound I or the equivalent placebo

[0250] ● Cohort 2: A single oral dose of 1.5 mg Compound I or the equivalent placebo

[0251] ● Cohort 3: A single oral dose of 5 mg Compound I or the equivalent placebo

[0252] ● Cohort 4: A single oral dose of 15 mg Compound I or the equivalent placebo

[0253] ● Cohort 5: A single oral dose of 30 mg Compound I or the equivalent placebo

[0254] ● Cohort 6: A single oral dose of 60 mg of Compound I or the equivalent placebo

[0255] ● Cohort 7: A single oral dose of 100 mg Compound I or the equivalent placebo

[0256] ● Cohort 8: A single oral dose of 200 mg Compound I or the equivalent placebo

[0257] ● Cohort 9: A single oral dose of 400 mg Compound I or the equivalent placebo

[0258] ● Cohort 10: A single oral dose of 600 mg Compound I or the equivalent placebo

[0259] Part 2 (MAD, qd therapy)

[0260] Subjects were assigned to one of the following six cohorts. In each cohort, eight subjects were randomized to compound I or the corresponding placebo in a 6:2 ratio.

[0261] ● Cohort 1: Multiple oral doses of 10 mg of Compound I or the equivalent placebo

[0262] ● Cohort 2: Multiple oral doses of 25 mg of Compound I or the equivalent placebo

[0263] ● Cohort 3: Multiple oral doses of 50 mg of Compound I or the equivalent placebo

[0264] ● Cohort 4: Multiple oral doses of 100 mg of Compound I or the equivalent placebo

[0265] ● Cohort 5: Multiple oral doses of 400 mg of Compound I or the equivalent placebo

[0266] ● Cohort 6: Multiple oral doses of up to 600 mg of Compound I or the equivalent placebo

[0267] Part 3 (Food Effects)

[0268] Subjects were randomized into one of two treatment sequences in a 1:1 ratio.

[0269]

[0270] Part 4 (MAD, bid therapy)

[0271] Subjects were assigned to one of the following cohorts. In each cohort, 8 subjects were randomized to compound I or the corresponding placebo in a 6:2 ratio.

[0272] ● Cohort 1: Multiple oral doses of 100 mg of Compound I or the equivalent placebo as bid therapy

[0273] ● Cohort 2: Multiple oral doses of 200 mg of Compound I or the equivalent placebo as bid therapy

[0274] Pharmacokinetic data

[0275] bioanalysis methods :

[0276] Pharmacokinetic samples were obtained from the blood of all subjects at all dose levels and evaluated. Samples from placebo subjects were not analyzed. Samples for PK evaluation from subjects were collected at the time points defined in the study. Compound I concentrations were determined in the blood by validated LC-MS / MS methods.

[0277] Pharmacokinetics of single rising doses of 0.5 mg to 600 mg :

[0278] Figure 1 shows the average blood concentration-time course for Compound I after a single elevated dose.

[0279] Compound I was rapidly absorbed across all doses with a time to reach Cmax of approximately 1 to 1.5 hours. The absorption phase was characterized by a single distinct absorption peak in most subjects. Drug disposition exhibited a double-exponential decrease. Most of the drug was cleared under the initial distribution phase, suggesting that substantial drug elimination could occur before systemic tissue equilibrium was reached. An apparent terminal elimination phase was not reached until 12 hours after administration and was measurable only in subjects receiving doses of 100 mg or more. Measurable terminal half-lives ranged from 4 hours (100 mg) to a maximum of 18 hours (600 mg), resulting in an mean retention time (MRT) in circulation of 1 hour to a maximum of 5 hours.

[0280] (MRT T1 / 2 / ln2). The distribution pattern demonstrated a dominant dose-independent T1 / 2 of approximately 1 h. The calculated geometric mean (CL / F) of oral blood clearance rates after a single dose administration ranged from 250 L / h to 506 L / h across the SAD cohort, with an estimate of approximately 383 L / h across all cohorts.

[0281] Multiple oral dose pharmacokinetics

[0282] Figure 2 shows the average blood concentration-time course of Compound I after multiple ascending doses of 10 mg to 400 mg.

[0283] The geometric mean apparent clearance rate (CLss / F, Day 12 MAD, qd) at steady state after oral administration ranged from 246 L / h to 414 L / h across the cohort. Generally, lower clearance rates were observed at steady state compared to Day 1, but this difference was almost lost at doses greater than 100 mg (Table 2-1 (Day 1) Table 2-2 (Day 12)). This behavior may be due to the binding of the covalent target (BTK) contributing to the initial clearance of compound I. Since residual target occupancy at the trough reduces the fraction of the contribution of target binding to clearance (CLss / F) day by day, this effect is most pronounced on Day 1. Naturally, this difference decreases with increasing dose when target occupancy at the trough is nearly complete. Consequently, drug exposure (AUC, Cmax) was found to be higher on day 12 compared to day 1, as exemplified by the (subject-intra-drug) accumulation ratio (Racc), which ranged from 5 (low dose) to 1.2 (high dose), and generally, AUC was higher than Cmax, confirming that this may be accompanied by an effect of systemic elimination.

[0284] [Table 2-1]

[0285] Summary of PK parameters of Compound I at multiple ascending doses of 10 to 600 mg, qd administration

[0286]

[0287] [Table 2-2]

[0288]

[0289]

[0290] Generally, blood concentrations at 24 hours after the last dose were typically less than 1 ng / ml (with the exception of a few subjects at 100 mg or more), which suggested nearly complete washing out of compound I during two consecutive doses. The latter also suggests that a steady state is reached during some doses.

[0291] Due to the higher tissue BTK turnover, bid administration was also studied. Mean blood concentration time profiles obtained after multiple escalation twice daily administrations of 100 mg and 200 mg are shown in Figure 3. Similar to results from other cohorts, rapid absorption with a Tmax of approximately 1 h was observed for the doses following bid therapy. The observed accumulation factor (Racc) corresponded to 1.5 (100 mg) and 2.0 (200 mg) for AUC and approximately 1.65 (for both doses) for Cmax. A dose-proportional increase in AUCtau was observed on day 12, while only a slight increase (1.33-fold) was confirmed for Cmax. In conclusion, bid administration of Compound I provides an option to address faster target resynthesis within tissues during the dosing interval without compromising the overall PK profile or the need for high-dose qd therapy.

[0292] Food Effects: Results Part 3:

[0293] PK data from the food effect cohort summarized in Tables 2 and 3 below suggested a lower absorption rate, indicated by a 1.25-fold lower Max, and more complete total absorption, indicated by a 1.4-fold higher AUC0-24. Most importantly, the mean Tmax changed from 1 hr (fasting) to >3 hr (meal). (Fig. 4)

[0294] [Table 2-3]

[0295] Summary of PK Parameters: Food Effects of Compound I After a Single Dose of 60 mg

[0296]

[0297] CV(Coefficient of Variation (%) = SD / Mean * 100

[0298] Pharmacodynamics

[0299] Pharmacodynamics (PD) was characterized by evaluating target occupancy and distal pathway inhibition. Measurement of BTK occupancy in human whole blood (derived from the ratio of free to total BTK) served as a direct marker of therapeutic target involvement.

[0300] Correlations between BTK occupancy, dose, systemic compound exposure, and efficacy for complex in vivo pathways and disease readouts were established across preclinical models for the compound of Formula I. (e.g., Example 1)

[0301] The compound of formula I is an irreversible inhibitor of BTK, and the extent and duration of BTK occupancy were determined. The PD effect of compound I was evaluated by measuring both free BTK (unbound) and total BTK in whole blood using enzyme-linked immunosorbent assay (ELISA) on the Meso Scale Diagnostics (MSD) platform in two separate assays.

[0302] The correlation between dose and pharmacodynamics was characterized by the measurement of human blood BTK occupancy, a direct marker of therapeutic target involvement (derived from the ratio of free to total BTK). BTK occupancy was determined to be in the range of 0.5 mg to 400 mg for single boost doses, in the range of 10 mg to 400 mg for qd multiple boost doses, and in the range of 100 mg and 200 mg for bid multiple boost doses.

[0303] The compound of Formula I exhibited a clear dose-dependent increase in both the degree and duration of peripheral blood BTK occupancy. Peak target occupancy generally occurred as early as 0.5 h after administration, suggesting a rapid onset with no relevant history regarding drug effect relative to peak drug exposure. As concluded from its ability to covalently bind to BTK, target occupancy persisted well beyond the batch in systemic circulation, suggesting a non-equilibrium PK-PD correlation. Therefore, it is concluded that the duration of BTK occupancy is governed by the rate of novel synthesis of BTK.

[0304] Unlike the lower dose cohort (0.5 to 1.5 mg), a single dose of Compound I of 15 mg or more established peak target occupancy reaching 100% in almost all subjects, which was maintained at over 80% at 24 h. While inter-subject responses at 15 mg varied significantly, doses of 30 mg or more exhibited clearly reduced inter-subject variability in all subjects and delivered sustained (> 24 h) and nearly complete (>90%) occupancy. The time to return the BTK protein pool to pre-dose levels was approximately 10 days, corresponding to a median turnover T1 / 2 of approximately 48 hours (Fig. 5).

[0305] After multiple doses of compound I, an administration-pre-blood blood BTK occupancy of >96% was achieved on day 12 with nearly 10 mg of compound I qd.

[0306] In addition, the downstream PD effect of Compound I was tested using in vitro inhibition of basophil activation (monitored by surface expression of CD63 and CD203c) as a distal mechanochemical biomarker. To determine the PD effect of Compound I on basophil activation, whole blood was in vitro stimulated with anti-IgE. Degranulation was evaluated by the percentage of CD63+ and CD203+ basophils via flow cytometry.

[0307] Following a single elevated dose of Compound I, the data suggest a dose-dependent inhibition of FcεR1-mediated basophil activation. In vitro blood basophil activation, measured by CD63, was almost completely inhibited (>89%) at a dose of 60 mg and reached nearly 100% inhibition at higher doses 24 h after administration. In contrast, maximum inhibition of CD203c (approximately 50% inhibition) at 24 h after a single dose of Compound I was achieved only with 200 mg of Compound I.

[0308] On day 12, 8 h after qd or bid administration of the MAD of compound of formula I, the tested trough dose of compound I (10 mg qd) already resulted in >90% inhibition of CD63 upregulation, and inhibition of CD63 trough levels was >90% at compound I doses ≥50 mg qd (Fig. 6). On day 12, maximum trough inhibition of CD203c activation was consistently higher compared to after a single dose of compound I and was achieved only with bid administration of 100 mg and 200 mg of compound I.

[0309] The ability of compound I to inhibit defined allergen reactions was evaluated by a skin prick test (SPT) in healthy atopic subjects in the first human application of the MAD study. The SPT was performed at different time points before administration (at screening, baseline, and before administration on day 1), after the first administration (day 1), and after the once-daily administration on day 11 (day 12).

[0310] Similar to the inhibition of in vitro basophil activation, a dose-dependent effect on wheal diameter, suggested by a decrease in mean post-dose wheal size relative to baseline, was identifiable in the multiple escalating dose cohort (Fig. 7). The effect began to plateau at approximately 100 mg compound 1 qd.

[0311] Theory / Conclusion on Dose Selection

[0312] Healthy volunteers were exposed to Compound I in a Phase 1 clinical study at doses ranging from 0.5 mg to 600 mg, administered as a single dose or once or twice daily for up to 18 days. Compound I was well tolerated, and no serious or severe adverse events associated with the intake of Compound I were present. In the clinical study, observed adverse events (AEs) did not appear to be dose-dependent, most were single-occurrence, and were generally of a mild nature. Therefore, the clinical safety information supports the doses selected for this Phase 2b study.

[0313] The dose-levels of the present invention were derived from the following analyses in healthy volunteers (BTK occupancy, inhibition of basophil activation (monitored by CD63 and CD203c upregulation); and the effects on the skin prick test (SPT) in healthy asymptomatic atopic volunteers—proxys for inhibition of mast cells and basophils in the skin.

[0314] In the aforementioned clinical trials, qd administration of 10 mg of Compound I resulted in near-complete blood BTK occupancy, a >90% reduction in CD63 upregulation (8 h after administration of Compound I at steady state), and minimal inhibition of wheal size at SPT. Therefore, 10 mg of Compound I qd corresponds to the onset of biological activity. At 100 mg of Compound of Formula I, the average reduction in wheal size at SPT began to plateau. Thus, 100 mg of Compound I corresponds to the maximum effect of Compound I. The intermediate dose of 35 mg of Compound I qd is highly suitable for accurately describing the dose-response curve of Compound I qd.

[0315] Compounds of Formula I inhibit BTK via covalent bonding. While blood BTK occupancy is > 24 hours (h), rapid BTK turnover in tissues (e.g., approximately 5 hours in the spleen of rodents) may require a bid administration of Compound I to reach maximum efficacy. The dose-response curves of Compound I are accurately described when doses of 10 mg, 25 mg, and 100 mg bid are administered twice daily, respectively.

[0316] Safety in humans

[0317] For the analysis of adverse events, placebo subjects (2 per cohort) from all SAD and MAD cohorts were separated by SAD and MAD parts and pooled into a single Compound I treatment group (n=6 each) and a placebo group (n=20 for SAD and n=16 for MAD) to be compared with the entire Compound I group (n=60 for SAD and n=48 for MAD), respectively. There were no significant demographic differences between the placebo and active groups in both the SAD and MAD populations. Safety studies of the FIH study in healthy volunteers do not reveal significant safety concerns at doses up to 600 mg.

[0318] Example 3: Efficacy and safety data in subjects with moderate to severe SjS

[0319] A Phase 2 study was conducted with a compound of Formula I designed to establish the safety and efficacy of the compound of Formula I and characterize the dose-response in subjects with moderate to severe SjS to allow for the further development of compounds for the treatment of this disease.

[0320] Protocol Summary

[0321]

[0322]

[0323]

[0324] Objectives and Endpoints

[0325] [Table 2-4]

[0326] Objectives and related endpoints

[0327]

[0328]

[0329]

[0330] Research Design

[0331] This is an indication Phase 2 randomized, double-blind, placebo-controlled, multi-center, integrated dose-range study to evaluate the safety and efficacy of multiple doses of Compound I in patients with moderate to severe Sjren's syndrome (SjS). In this study, moderate to severe SjS is defined as Sjren's syndrome according to ACR / EULAR criteria, at least 5 ESSDAIs (in 8 of 12 domains), and at least 5 ESSPRIs. If a subject receives a prescribed concurrent treatment for their underlying disease and still meets the entry criteria, they will be maintained on this treatment as long as they remain stable until the end of the study.

[0332] The study consists of two parts. In Part 1 of the study, the determined maximum biologically active single dose (100 mg of the compound of Formula I or its pharmaceutically acceptable salt) is tested with two different dosing regimens: once daily (qd) or twice daily (bid) and compared to a placebo subarm. Approximately a total of 72 study subjects are equally randomized into these three treatment groups for an estimated sample size of 24 subjects per group. In Part 2, the selected dosing regimen (qd or bid) is extended to lower doses to evaluate the safety and dose-response of this regimen between the determined lowest (10 mg of the compound of Formula I) and highest (100 mg of the compound of Formula I) doses. This results in four treatment subarms: placebo and three dose levels of the compound of Formula I (100 mg bid / qd, 25 mg bid or 35 mg qd, and 10 mg bid / qd). Approximately 180 total study subjects will be equally randomized into these four treatment sub-arms, resulting in a sample size of 45 subjects per group.

[0333] Each individual study subject first undergoes a screening period of up to 6 weeks, a treatment duration of 24 weeks, and a follow-up period of 30 days after the last administration of the study treatment before the end of the study visit. Including screening, the total duration for each subject in the study is up to approximately 35 weeks.

[0334] For the entire duration of the treatment period (24 weeks), subjects are provided with a twice-daily dose of the compound of Formula I or a placebo regardless of the selected drug regimen, and accordingly, blinding is maintained throughout the entire study.

[0335] Safety assessment includes physical examination, ECG, vital signs, and standard clinical laboratory evaluation (hematology, biochemistry, and urinalysis), as well as monitoring of adverse events and serious adverse events.

[0336] Screening

[0337] After signing the informed consent form, subjects are evaluated for ESSDAI and ESSPRI to assess eligibility, as well as complete safety and other assessments. For operational reasons, assessments are performed on different days during the 6-week screening period, provided that it is deemed appropriate by the researcher. Subjects who are rejected during screening may be re-screened once more. Subjects are also given instructions on how to use the wearable device (if selected to use it), which is provided if they are confirmed to be eligible for the study.

[0338] base line

[0339] The eligible subject returns for a baseline visit on Day 1. The subject may stay overnight at the site for work-related reasons, but this will not be considered a hospital admission.

[0340] Eligibility is confirmed prior to randomization, and baseline assessment is required to be completed before Day 1 dosing. Where preferred in the field for scheduling purposes, some baseline assessment is performed on the evening of the day before Day 1.

[0341] Research Treatment

[0342] The study drug is provided in appropriately blinded, labeled vials. The vials contain capsules with 10 mg, 25 mg, or 50 mg of the active ingredient (compound of Formula I) or a corresponding 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. Details regarding storage and handling requirements for the study treatment, subject number assignment, and instructions for the distribution and administration of the study treatment are outlined in the SOM.

[0343] Treatment Aam / Gun

[0344] In Part 1, the subject is assigned to one of the following three treatment arms in a 1:1:1 ratio on Day 1.

[0345] ● Compound of Chemical Formula I, 100 mg bid

[0346] ● Compound of chemical formula I, 100 mg qd

[0347] ● Penalty

[0348] The dosing schedule and dosage range for Part 2 are based on data from IA. In Part 2, subjects are assigned to one of the following four treatment sub-arms in a 1:1:1:1 ratio on Day 1.

[0349] ● Compound of Formula I, 100 mg bid or qd

[0350] ● Compound of Chemical Formula I, 35 mg qd or 25 mg bid

[0351] ● Compound of Formula I, 10 mg bid or qd

[0352] ● Penalty

[0353] The subjects take two capsules at each dose. In both parts, morning and evening doses (two capsules each) are available for all subjects.

[0354] Subjects receive the morning dose of compound of formula I or a placebo at the site on Day 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). Other morning doses and all evening doses are typically taken by the participating subjects at home. All subjects receive a supply of either compound of formula I or a placebo capsule every four weeks during site visits according to a set schedule.

[0355] Subjects are randomized into each treatment sub-arm per study part. Except for Japan, randomization is stratified by baseline ESSDAI (based on weighted scores <10 or ≥10).

[0356] For subjects within Japan, a separate block of randomization is created, and other countries participate to ensure that Japanese subjects are evenly distributed across all treatment groups in the study. Subjects receive the morning dose of the compound of Formula I or a placebo at the 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). Subsequently, subjects receive the study drug and return home to continue its daily dosing regimen (self-administration). At the Week 4 and Week 24 visits, subjects also undergo post-dose safety and PK assessments.

[0357] Subjects return to the site at approximately 4-week intervals and undergo an additional visit at the end of the 2nd week (Day 15). During the study visit, subjects undergo ESSDAI and ESSPRI evaluations as indicated in the evaluation schedule, as well as other scales / questionnaires, safety, and the collection of various PK, PD, and biomarker samples.

[0358] Weekly, the subject is asked to keep a log recording their SjS symptoms and treatment implementation.

[0359] The primary endpoint of the study is evaluated after the completion of the 24-week treatment (Day 169; 24-week end visit) at the end of Part 2. The interim analysis evaluates efficacy and safety after 12 weeks of treatment as a surrogate for the 24-week treatment results in Part 1.

[0360] Theories regarding dosage / therapy and duration of treatment

[0361] Dosage / therapy for Part 1

[0362] The maximum dose planned for this study (100 mg bid or qd) demonstrated the maximum effect of the compound of Formula I based on the predicted BTK occupancy in blood (B-cell blockade) and tissues, and inhibition of CD63 upregulation in basophils (IB) (results from Example 2). Therefore, it is concluded that this dose provides the maximum clinical effect in tissues including lymphoid tissues against SjS. In Phase 1, up to 600 mg as both single and multiple doses and 200 mg as a twice-daily dose were tested in human volunteers and were proven to be safe.

[0363] In Part 1, the dose (100 mg) concluded to provide the maximum effect is tested in qd and bid regimens and compared to placebo. Due to the covalent bonding nature of the compound of Formula I to intracellular BTK, the duration of the therapeutic effect depends on the turnover rate of BTK molecules. The simulation model indicated that, at steady state, the qd regimen using 100 mg of the compound of Formula I provided an average 83% BTK occupancy 24 hours after administration (and immediately before the next administration), whereas the bid regimen using the same single dose of 100 mg had an average 96% BTK occupancy at 24 hours.

[0364] In addition, 70% BTK inhibition at steady state for approximately 90% of each dosing period is considered appropriate for optimal clinical efficacy. Therefore, the dosing regimen of 100 mg of Compound I provides efficacy for both the qd and bid regimens tested in Part 1 of this study.

[0365] Dosage / therapy for Part 2

[0366] Part 2 will evaluate the full dose range of selected dosing regimens at doses ranging from 10 mg to 100 mg. In the initial human application involving the compound of Formula I, qd administration of 10 mg of the compound of Formula I resulted in a reduction of more than 80% in nearly complete blood BTK occupancy and CD63 upregulation, but resulted in minimal inhibition of wheal size in the skin prick test (SPT). Therefore, it is concluded that qd of 10 mg of the compound of Formula I corresponds to the initiation of biological activity for pharmacodynamic activity in tissues. As intermediate doses, a daily dose of 35 mg of the compound of Formula I qd or 25 mg bid is considered appropriate to accurately describe the full dose-response curves of the compound of Formula I, qd, or bid, respectively. Continued double-blind treatment periods of up to 24 weeks will provide continued safety and efficacy data for the compound of Formula I.

[0367] Theory on the selection of a control drug (placebo)

[0368] The comparator treatment is a placebo intended to provide objective evidence of clinical efficacy and PD data, as well as potential AEs and other safety data generated from subjects treated with the compound of Formula I or its pharmaceutically acceptable salt during a 24-week study. Since there is no approved systemic treatment for SjS, the use of a placebo is justified. Current standard care for SjS patients is limited to symptomatic care for mucosal signs and symptoms (dryness), and steroids and conventional DMARDs are generally ineffective. There are no effective pharmacological interventions for severe, disabling fatigue associated with SjS.

Claims

Claim 1 A pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof for use in the treatment of a subject requiring treatment for Sjren's syndrome (SjS), wherein the compound of Formula I is administered once or twice daily at a daily dose of about 100 mg, and the term "about" means + / -10%: [Formula I] . Claim 2 A pharmaceutical composition according to claim 1, wherein the daily dose is about 100 mg once a day, and the term "about" means + / -10%. Claim 3 A pharmaceutical composition according to claim 1, wherein the daily dose is about 100 mg twice a day, and the term "about" means + / -10%. Claim 4 A pharmaceutical composition according to any one of claims 1 to 3, wherein the subject has moderate to severe SjS. Claim 5 A pharmaceutical composition according to any one of claims 1 to 3, wherein the subject is selected according to at least one of the following criteria: a) prior to treatment with a compound of formula I, the subject has an ESSPRI score of 5 or higher; b) prior to treatment with a compound of formula I, the subject has an ESSDAI score of 5 or higher based on weighted scores from 8 defined domains selected from biological, hematological, joint, skin, gland, lymphadenopathy, kidney, and constitution. Claim 6 A pharmaceutical composition according to any one of paragraphs 1 to 3, wherein the subject is an adult. Claim 7 A pharmaceutical composition according to any one of claims 1 to 3, wherein the subject achieves at least one of the following by week 12 or week 24 of treatment: a) a reduction in the ESSPRI score; and b) a reduction in the ESSDAI score. Claim 8 A pharmaceutical composition according to any one of claims 1 to 3, wherein the subject achieves a sustained response as measured by ESSPRI or EDSSDAI at the 5th week after completion of treatment. Claim 9 In any one of claims 1 to 3, the compound of formula I or a pharmaceutically acceptable salt thereof has a T of about 0.5 to 3 hours. max A pharmaceutical composition having, wherein the term "about" means + / -10%. Claim 10 delete Claim 11 delete Claim 12 delete Claim 13 delete Claim 14 delete Claim 15 delete Claim 16 delete

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