TLR7 / 8-antagonists for treating Sjogren's syndrome or mixed connective tissue disease

Abstract

The present disclosure relates to methods of treating Sjogren's syndrome or mixed connective tissue disease using a compound of formula (I) or a pharma- ceutically acceptable salt thereof. Also disclosed herein are compounds of formula (I) or a pharma- ceutically acceptable salt thereof for treating patients with Sjogren's syndrome or mixed connective tissue disease, as well as medicaments, dosing regimens, pharmaceutical formulations, dosage forms and kits for use in the disclosed uses and methods.

Description

[Technical field]

[0001] The present disclosure relates to methods of treating Sjögren's syndrome (SjS) or mixed connective tissue disease (MCTD) using TLR7 and TLR8 antagonists. [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-Zeron P.,et al,(2016)Treating the Underlying Pathophysiology of Primary Sjögren's Syndrome:Recent Advances and Future Prospects.Drugs p.1601-1623). The disease primarily affects the lacrimal and salivary glands, but the inflammatory process can target any organ, with approximately 15% of patients showing severe extraglandular manifestations (Baldini C.,et al(2014)Primary Sjögren's syndrome as a multi-organ disease:impact of the serological profile on the clinical presentation of the disease in a large cohort of Italian patients.Rheumatology(Oxford)p.839-44). Clinical symptoms are most often characterized by exocrine adenopathy of the salivary and lacrimal glands, mainly presenting with dry mouth and eyes. The mechanism underlying the development of SjS is the destruction of the epithelium of the exocrine glands as a result of autoreactive B and T cells (Brito-Zeron P.,et al,(2016)Treating the Underlying Pathophysiology of Primary Sjogren Syndrome:Recent Advances and Future Prospects.Drugs p.1601-1623). Even at a very early stage of the disease, the high prevalence of autoantibodies, especially 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 Sjogren syndrome.Nat Rev Rheumatol p.133-145). Sjögren's syndrome is also associated with an increased risk of malignancies, with a 10-fold increased lifetime risk of B-cell lymphoma in individuals with SjS (Baldini et al., 2014).SjS is observed in 0.3-1 per 1,000 people, and its prevalence is second only to rheumatoid arthritis among systemic autoimmune diseases. The disease mainly affects women, with a female / male ratio of 9:1, and can occur at any age (Qin B, Wang J, Yang Z, et al (2015) Epidemiology of primary Sjoegren's syndrome: a systematic review and meta-analysis. Ann. Rheum. Dis. p. 1983-9). SjS has a severe impact on quality of life and productivity, which is often caused by the disabling fatigue associated with the disease (Mariette X., et al. (2018) Primary Sjogren's Syndrome. N. Engl. J. Med. p. 931-939).

[0003] Mixed connective tissue disease (MCTD) was first described in 1972 as a disease syndrome with overlapping features of other systemic autoimmune diseases associated with an antibody against RNAse-sensitive soluble nuclear antigen (ENA) (Sharp, et al (1972) Mixed connective tissue disease-an apparently distinct rheumatic disease syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). The American journal of medicine, 52 (2), pp. 148-159). Patients with MCTD often have symptoms present in SjS. Of note, 42% of patients with MCTD have been reported to have dry eye symptoms (Ramos-Casals et al. (2007). The overlap of Sjogren's syndrome with other systemic autoimmune diseases. Seminars in arthritis and rheumatism, 36 (4), pp. 246-255). Clinical manifestations include frequent Raynaud's syndrome, swollen hands, sclerodactyly, arthritis, polymyositis, and interstitial lung disease (Venables, (2006) Mixed connective tissue disease. Lupus, 15(3), pp. 132-137). The female to male ratio is approximately 3:1, and the average age at diagnosis of adult-onset MCTD is 35-40 years. MCTD is rare, with a point prevalence of less than 4 per 100,000 adults (Gunarsson et al, (2011) The prevalence and incidence of mixed connective tissue disease: a national multicentre survey of Norwegian patients. Annals of the rheumatic diseases, 70(6), pp. 1047-1051). Currently, there is no cure for either SjS or MCTD.

[0004] Toll-like receptors (TLRs) are part of the innate immune system and recognize conserved microbial structures. TLR7 and TLR8 are expressed intracellularly in endosomes and both recognize guanosine-uridine (GU)-rich single-stranded RNA (ssRNA) (Heil et al, (2004) Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 303(5663):1526-1529). In several autoimmune diseases, including both SjS and MCTD, TLR7 / 8 are activated by self-RNA following shuttling of ribonucleoprotein (RNP) autoantigens such as Ro60 into endosomes in the form of immune complexes with autoantibodies (Bave et al,(2005)Activation of the type I interferon system in primary Sjogren's syndrome:a possible etiopathogenic mechanism.Arthritis and rheumatism,52(4),p.1185-1195;Junt et al,(2015)Translating nucleic acid-sensing pathways into therapies.Nat Rev Immunol;15:529-544). The presence of autoantibodies against another ribonucleoprotein (RNP), U1-RNP, is a diagnostic criterion for MCTD (Tani et al,(2014)The diagnosis and classification of mixed connective tissue disease.J Autoimmun.48-49:46-9), and immune complexes between autoantibodies and U1-RNP lead to activation of TLR7 (Savarese et al(2006)U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7.Blood,107(8),p.3229-3234) and possibly also TLR8.

[0005] (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (WO 2018 / 047081) is an orally bioavailable, low molecular weight (LMW) antagonist of human TLR7 and TLR8, intended for the treatment of systemic autoimmune diseases such as SjS or MCTD, whose pathology is believed to be driven by excessive activation of TLR7 / 8 via RNP autoantigen-containing immune complexes.

[0006] Currently, there is no adequate cure for SjS or MCTD. As a result, there is a high medical need for new treatment options for SjS and MCTD patients. Summary of the Invention

[0007] The present invention provides a method of treating Sjogren's syndrome or mixed connective tissue disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of formula (I). [ka]

[0008] The compound of formula (I) is also known as (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide. Dosage amounts herein refer to the amount of anhydrous free base of the compound of formula (I).

[0009] Sjögren's syndrome Embodiment 1A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof twice daily, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg.

[0010] Embodiment 2A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, twice daily, e.g., about every 12 hours, at a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg or about 400 mg.

[0011] Embodiment 3A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, twice daily, e.g., about every 12 hours, at a dose of about 100 mg to about 200 mg.

[0012] Embodiment 4A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 250 mg twice daily, e.g., about every 12 hours.

[0013] Embodiment 5A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 200 mg twice daily, e.g., about every 12 hours.

[0014] Embodiment 6A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 100 mg twice daily, e.g., about every 12 hours.

[0015] Embodiment 7A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 75 mg twice daily, e.g., about every 12 hours.

[0016] Embodiment 8A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 50 mg twice daily, e.g., about every 12 hours.

[0017] Embodiment 9A: A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, at a dose of about 25 mg twice daily, e.g., about every 12 hours.

[0018] Embodiment 10A: The method of any of embodiments 1A-9A, wherein the subject, e.g., patient, is positive, e.g., seropositive, for anti-soluble nuclear (ENA) antibodies, e.g., anti-Sjogren's syndrome associated antigen A (anti-Ro / SSA) antibodies.

[0019] Embodiment 11A: The method of any of embodiments 1A-10A, wherein the subject has mild or moderate-to-severe Sjogren's syndrome.

[0020] Embodiment 12A: Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the manufacture of a medicament for treating Sjogren's syndrome in a subject, e.g., a patient, in need thereof, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to any of embodiments 1A to 11A.

[0021] Embodiment 13A: A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of Sjogren's syndrome, administered according to any of Embodiments 1A to 11A.

[0022] mixed connective tissue disease Embodiment 1B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, twice daily, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg.

[0023] Embodiment 2B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, twice daily, e.g., about every 12 hours, at a dose of about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, or about 400 mg.

[0024] Embodiment 3B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, twice daily, e.g., about every 12 hours, at a dose of about 100 mg to about 200 mg.

[0025] Embodiment 4B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 250 mg twice daily, e.g., about every 12 hours.

[0026] Embodiment 5B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 200 mg twice daily, e.g., about every 12 hours.

[0027] Embodiment 6B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, twice daily, e.g., about every 12 hours, at a dose of about 100 mg.

[0028] Embodiment 7B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 75 mg twice daily, e.g., about every 12 hours.

[0029] Embodiment 8B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 50 mg twice daily, e.g., about every 12 hours.

[0030] Embodiment 9B: A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject, e.g., orally, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., at a dose of about 25 mg twice daily, e.g., about every 12 hours.

[0031] Embodiment 10B: The method of any of embodiments 1B-8B, wherein the subject, e.g., patient, is positive, e.g., seropositive, for ribonucleoprotein (RNP) antinuclear antibodies, e.g., anti-U1-RNP antibodies.

[0032] Embodiment 11B: Use of a compound of formula (I), or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating mixed connective tissue disease in a subject, e.g., a patient, in need thereof, wherein the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered according to any of embodiments 1B to 10B.

[0033] Embodiment 12B: A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of mixed connective tissue disease, administered according to any of embodiments 1B to 10B. [Brief description of the drawings]

[0034] [Figure 1] Time course of compound of formula (I) concentrations in plasma following single ascending doses of 3 mg to 1000 mg. [Diagram 2] Time course of compound of formula (I) concentrations in plasma following repeated ascending doses from 25 mg twice daily to 400 mg twice daily. [Diagram 3] Food effect observed following administration of 200 mg of a compound of formula (I) either in the presence or absence of standardized food. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0035] Toll-like receptors (TLR) 7 and TLR8 are endosomal receptors for GU-rich single-stranded RNA (ssRNA). In humans, TLR7 is highly expressed in interferon alpha (IFNα)-producing plasmacytoid dendritic cells (pDCs) and B cells, and TLR8 is highly expressed by monocytes, macrophages, and neutrophils. TLR7 / 8 activation leads to monocyte and B cell activation via NFκB and pDC activation via IRF7.

[0036] (S)—N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide, or a pharma- ceutically acceptable salt thereof, is referred to herein as the compound of formula (I). [ka]

[0037] The compound of formula (I) is highly selective for TLR7 and TLR8 over other TLRs and IL-1 receptors on human PBMC. The compound was described in WO 2018 / 047081. The compound is a selective and potent antagonist of TLR7 and TLR8 and can be used for TLR7 or TLR8 mediated diseases or disorders.

[0038] Thus, described herein are dosing regimens for treating SjS patients with the compound (S)—N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide or a pharma- ceutically acceptable salt thereof.

[0039] Thus, described herein are dosing regimens for treating MCTD patients with the compound (S)—N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide or a pharma- ceutically acceptable salt thereof.

[0040] Thus, described herein are methods for selecting a target patient population, methods for monitoring treatment of a target patient population, and methods for evaluating the safety and efficacy of treatment of a target patient population.

[0041] definition For the purpose of interpreting this specification, the following definitions will apply and whenever appropriate, terms used in the singular will also include the plural and vice versa.

[0042] The phrase "pharmacologically acceptable" as used herein refers to compounds, materials, compositions and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0043] Any formula given herein is intended to represent unlabeled and isotopically labeled forms of the compound. Isotopically labeled compounds have the structure depicted by the formula given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be incorporated into the compounds of the present disclosure include, for example, 3 H, 11 C. 13 C. 14 C. 15 N, 18 F and 36 These include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine and chlorine, such as Cl. Thus, the present disclosure includes, for example, 3 H and 14 Compounds incorporating one or more of any of the aforementioned isotopes, including radioisotopes such as C or 2 H and 13 It should be understood that this includes compounds incorporating one or more of any of the aforementioned isotopes, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds may be used in metabolic studies ( 14 C), reaction rate tests (e.g. 2 H or 3 H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution assays, or radiation treatment of patients. 18 F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds may generally be prepared by conventional techniques known to those of skill in the art, for example, by substituting an appropriate isotopically labeled reagent for a previously utilized non-labeled reagent.

[0044] As used herein, the term "pharmaceutical combination" refers to a product resulting from the use or mixture or combination of two or more active ingredients. It is to be understood that as used herein, pharmaceutical combination includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of formula (I) or a pharmaceutically acceptable salt thereof, and one or more combination partners are administered simultaneously to a patient as a single entity or dosage form. In such a case, the term refers to a fixed-dose combination in one unit dosage form (e.g., capsule, tablet or sachet). The term "non-fixed combination" or "kit of parts" refers both to the active ingredients, e.g., a compound of the present disclosure and one or more combination partners and / or one or more co-drugs, being administered simultaneously, in parallel or sequentially without a specific time limit or simultaneously to a patient independently as separate entities, such administration provides therapeutically effective levels of the two compounds in the patient's body, especially when these time intervals allow the combination partners to exhibit a joint effect, e.g., an additive or synergistic effect. The term "non-fixed combination" also applies to cocktail therapy, e.g., the administration of three or more active ingredients. Thus, the term "non-fixed combination" particularly defines the administration, use, composition or formulation in the sense that the compounds described herein can be administered independently of each other, i.e., at the same time or at different times. It should be understood that the term "non-fixed combination" also encompasses the use of a single agent together with one or more fixed combination products, where each independent formulation contains different amounts of active ingredients. It should be further understood that the terms combination products and "non-fixed combination" described herein encompass active ingredients (including the compounds described herein) where the combination partners are administered as completely separate pharmaceutical dosage forms or pharmaceutical formulations that are also sold independently of each other. Instructions for the use of non-fixed combinations are or can be provided in the packaging, e.g., in leaflets, etc., or in other information provided to physicians and / or medical staff.Then, the parts of the independent preparation or its preparation, product or composition can be administered simultaneously or chronologically staggered, i.e., each individual part of the set of parts can be administered at different time points and / or at equal or different time intervals relative to any of the parts of the set of parts. In particular, the time intervals for administration are selected so that the effect on the disease to be treated by the combined use of the parts is greater / higher than the effect obtained by using only the compound of formula (I); thus, the compounds used in the pharmaceutical combinations described herein are active together. The ratio of the total amount of the compound of formula I and the second drug to be administered as a pharmaceutical combination can be changed or adjusted to better address the needs of a specific patient subpopulation to be treated or the needs of a single patient, which may be due to, for example, the age, sex, weight, etc. of the patient.

[0045] As used herein, terms such as "co-administration" or "administration in combination" are meant to encompass the administration of one or more compounds described herein together with a selected combination partner to a single subject (e.g., a patient or subject) in need thereof, and are intended to include therapeutic regimens in which the compounds are not necessarily administered by the same route of administration and / or at the same time.

[0046] The term "pharmaceutical composition" is defined herein to refer to a mixture (e.g., a solution or emulsion) containing at least one active ingredient or therapeutic agent to be administered to a warm-blooded animal, such as a mammal or a human, to prevent or treat a particular disease or condition affecting said animal.

[0047] The term "therapeutically effective amount" of a compound of the present disclosure (i.e., a compound of formula (I) or a pharma- ceutically acceptable salt thereof) refers to an amount of a compound of the present disclosure that induces a biological or medical response in a subject (patient or subject), such as a decrease or inhibition of an enzyme or protein activity, or that improves symptoms, alleviates a pathological condition, slows or retards the progression of a disease, or prevents a disease, etc. The therapeutically effective dose of a compound, pharmaceutical composition, or combination thereof depends on the patient's ethnicity, weight, age, sex, and individual condition, disorder or disease being treated or its severity. A physician, clinician, or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient required to prevent, treat, or inhibit the progression of a disorder or disease.

[0048] As used herein, the term "carrier" or "pharmaceutical acceptable carrier" includes any solvent, dispersion medium, coating agent, surfactant, antioxidant, preservative (e.g., antibacterial agent, antifungal agent), isotonicity agent, absorption delaying agent, salt, preservative, drug, drug stabilizer, binder, excipient, disintegrant, lubricant, sweetener, flavoring agent, dye, and the like, and combinations thereof, which would be known to those skilled in the art (see, for example, Remington's Pharmaceutical Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the therapeutic or pharmaceutical compositions is contemplated.

[0049] As used herein, the term "subject" refers to an animal. Typically, an animal is a mammal. A subject also refers to, for example, a primate (e.g., a human, male or female), cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird, etc. In certain embodiments, the subject is a primate. In preferred embodiments, the subject is a human. The term "subject" is used interchangeably with "patient" when it refers to a human.

[0050] As used herein, a subject is "in need of" a treatment if such subject would benefit biologically, medically, or in quality of life from such treatment.

[0051] As used herein, the phrase "patient population" is used to mean a group of patients.

[0052] The term "comprising" encompasses "including" and "consisting of," e.g., a composition "comprising" X may consist exclusively of X or may include some additional items (e.g., X+Y).

[0053] The term "about" in reference to a numerical value x means, for example, + / - 10%. When used before a numerical range or list of values, the term "about" applies to each numerical value in turn, e.g., the phrase "about 1 to 5" should be interpreted as "about 1 to about 5", or, for example, the phrase "about 1, 2, 3, 4" should be interpreted as "about 1, about 2, about 3, about 4, etc."

[0054] The term "treatment" or "treating" is defined herein as the application or administration of a compound according to the present disclosure (a compound of formula (I) or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising said compound) to a subject or an isolated tissue or cell line derived from a subject, the subject having a particular disease (e.g., SjS), a symptom associated with the disease (e.g., SjS), or a predisposition (if applicable) towards the development of the disease (e.g., SjS), with the objective of curing (if applicable), delaying the onset of, reducing the severity of, alleviating, ameliorating, ameliorating the disease, reducing or ameliorating any associated symptoms of the disease or predisposition towards the development of the disease. The term "treatment" or "treating" includes treating patients suspected of having a disease as well as patients who have been diagnosed as being ill or suffering from a disease or condition, including suppression of clinical recurrence.

[0055] As used herein, "selecting" and "selected" in relation to a patient are used to mean that a particular patient is specifically selected from a larger group of patients based on (and because of) the particular patient having a certain criterion. Similarly, "selectively treating" refers to providing treatment to a patient with a particular disease, where the particular patient is specifically selected from a larger group of patients based on (and because) the particular patient has a certain criterion. Similarly, "selectively administering" refers to administering a drug to a patient who is specifically selected from a larger group of patients based on (and because) the particular patient has a certain criterion. "Selecting," "selectively treating," and "selectively administering" mean that a standard treatment regimen is not delivered based solely on the patient's membership in a larger group, but rather that an individualized therapy is delivered to a patient based on the patient's individual medical history (e.g., previous therapeutic interventions, e.g., pretreatment with a biologic), biological factors (e.g., certain genetic markers), and / or symptoms (e.g., not meeting certain diagnostic criteria). As used herein, selecting in the context of a method of treatment does not refer to the incidental treatment of a patient with a particular criterion, but rather to the deliberate selection of administering a treatment to a patient based on the patient having a particular criterion. As such, selective treatment / administration differs from standard treatment / administration, which delivers a particular drug to all patients with a particular disease, regardless of the patient's individual medical history, symptoms of the disease, and / or biological factors. In some embodiments, a patient is selected for treatment based on having SjS. In some embodiments, a patient is selected for treatment based on having MCTD.

[0056] Use in Sjogren's Syndrome The present invention provides a method for treating SjS in a subject, e.g., a patient, in need thereof, comprising the step of orally administering to the subject, e.g., the patient, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., the 3.5-hydrate of the compound of formula (I), twice a day, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg. The dosage refers to the amount of the compound of formula (I) in anhydrous free form.

[0057] The present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., compound 3.5 hydrate of formula (I) is administered twice daily, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg. Dosage refers to the amount of compound of formula (I) in anhydrous free form.

[0058] The present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for example the 3.5-hydrate of the compound of formula (I), in the treatment of SjS in a subject, e.g. a patient, in need thereof, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof, for example the 3.5-hydrate of the compound of formula (I), is administered twice daily, e.g. about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g. about 50 mg to about 300 mg, e.g. about 100 mg to about 200 mg. Dosage refers to the amount of the compound of formula (I) in anhydrous free form.

[0059] The present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of SjS in a subject, e.g., a patient, in need thereof, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., the 3.5-hydrate of the compound of formula (I) is administered twice daily, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg. Dosage refers to the amount of the compound of formula (I) in anhydrous free form.

[0060] In one embodiment of any of the inventions described above, the dosage is about 25 mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, twice daily, for example about every 12 hours.

[0061] In one embodiment of any of the above inventions, the dosage is about 200 mg twice daily, for example about every 12 hours.

[0062] In one embodiment of any of the inventions described above, the subject, e.g., patient, is positive, e.g., seropositive, for anti-soluble nuclear (ENA) antibodies, e.g., anti-Sjogren's syndrome associated antigen A (anti-Ro / SSA) antibodies.

[0063] In one embodiment of any of the above-described inventions, the subject, e.g., patient, has mild SjS.

[0064] In one embodiment of any of the inventions described above, the subject, e.g., patient, has moderate to severe SjS.

[0065] Methods of Use in Mixed Connective Tissue Disease The present invention provides a method for treating MCTD in a subject, e.g., a patient, in need thereof, comprising the step of orally administering to the subject, e.g., patient, a compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., compound 3.5 hydrate of formula (I) twice a day, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg. The dosage refers to the amount of the compound of formula (I) in anhydrous free form.

[0066] The present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for example a 3.5-hydrate of the compound of formula (I), for use in the treatment of MCTD, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered twice a day, for example about every 12 hours, at a dose of about 25 mg to about 400 mg, for example about 50 mg to about 300 mg, for example about 100 mg to about 200 mg. The dosage refers to the amount of the compound of formula (I) in anhydrous free form.

[0067] The present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, for example a 3.5-hydrate compound of formula (I), in the treatment of MCTD in a subject, e.g. a patient, in need thereof, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof, for example a 3.5-hydrate compound of formula (I), is administered twice daily, e.g. about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g. about 50 mg to about 300 mg, e.g. about 100 mg to about 200 mg. Dosage refers to the amount of the compound of formula (I) in anhydrous free form.

[0068] The present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of mixed connective tissue disease in a subject, e.g., a patient, in need thereof, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., the 3.5-hydrate of the compound of formula (I) is administered twice daily, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg. Dosage refers to the amount of the compound of formula (I) in anhydrous free form.

[0069] In one embodiment of any of the inventions described above, the dosage is about 25 mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, twice daily, for example about every 12 hours.

[0070] In one embodiment of any of the above inventions, the dosage is about 200 mg twice daily, for example about every 12 hours.

[0071] In one embodiment of any of the invention described above, the subject, e.g., patient, is positive, e.g., seropositive, for anti-soluble nuclear (ENA) antibodies, e.g., anti-U1-RNP antibodies.

[0072] Effectiveness of Treatment for Sjögren's Syndrome and MCTD The disclosed TLR7 and TLR8 antagonists, i.e., compounds of formula (I) or pharma- ceutically acceptable salts thereof, can be used in vitro, ex vivo, or can be incorporated into pharmaceutical compositions and administered in vivo to treat SjS patients (e.g., human patients).

[0073] The disclosed TLR7 and TLR8 antagonists, i.e., compounds of formula (I) or pharma- ceutically acceptable salts thereof, can be used in vitro, ex vivo, or can be incorporated into pharmaceutical compositions and administered in vivo to treat MCTD patients (e.g., human patients).

[0074] The efficacy of SjS or MCTD treatment can be evaluated using various known methods and tools to measure the state and / or clinical response of the respective diseases, some examples include, for example, the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), the Physician Global Assessment (PhGA), the EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) and the Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-Fatigue).

[0075] efficacy Clinical efficacy measures related to the primary and secondary objectives are outlined below.

[0076] EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) The ESSDAI is a validated disease outcome measure for SjS and is applied to study subjects (Seror R, et al (2015) Validation of EULAR primary Sjogren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66). The instrument includes 12 organ-specific domains that contribute to disease activity. In each domain, disease activity features are scored at 3 or 4 levels depending on their severity. These scores are then weighted and summed across the 12 domains to provide a total score. The domains (weights) are: constitution (3), lymphadenopathy (4), glands (2), joints (2), skin (3), lungs (5), kidneys (5), muscles (6), PNS (5), CNS (5), blood (2) and biological findings (1). The maximum possible score is 123.

[0077] In our study, all 12 organ regions must be assessed separately at all planned time points (from screening visit to end of study) to calculate the ESSDAI. The region assessments are entered into a table (provided by a central vendor) and the ESSDAI score is calculated by the software.

[0078] For evaluations not listed as mandatory in the protocol but that may be required to assess the ESSDAI, including X-rays, High Resolution Computed Tomography (HRCT), Pulmonary Function Tests (DLCO, FVC), Estimated Glomerular Filtration Rate (eGFR), Electromyography (EMG), muscle (or any other) biopsy, it is at the investigator's discretion to have these evaluated based on the patient's signs and symptoms to provide a correct ESSDAI reading.

[0079] Participants with MCTD will complete only the joint (0 "no activity" to 3 "high activity") and pulmonary (0 "no activity" to 3 "high activity") domains of the ESSDAI. These domains will be assessed separately over the treatment period.

[0080] Physician Global Assessment Scale (PhGA) (SjS and MCTD participants) A physician's global assessment scale will be used by the investigator to estimate the patient's disease activity using a 100 mm VAS ranging from "no disease activity" (0) to "maximal disease activity" (100).

[0081] To promote objectivity, physicians should not be aware of a particular patient's reported outcome assessment when they perform their own assessment of that patient, and therefore this assessment must be performed before seeing the patient's reported outcomes.

[0082] FACIT-Fatigue (SjS and MCTD participants) The Functional Assessment of Chronic Illness Therapy-Fatigue scale (FACIT-F v4) is a short, 13-item, easy-to-complete tool that measures an individual's level of fatigue during their usual daily activities over the past week. Levels of fatigue are measured on a 5-point Likert scale (0=not at all, 1=a little, 2=somewhat, 3=quite a lot, 4=extremely (Webster et al 2003)).

[0083] EULAR Sjögren's Syndrome Patient-Reported Index (ESSPRI) (SjS participants) The ESSPRI is an established disease outcome measure for Sjogren's syndrome (Seror R, et al (2011) EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjogren's syndrome. Ann. Rheum. Dis. p. 968-72). It consists of three domains: dryness, pain, and fatigue. Subjects can rate the severity of the symptoms they experience on a single 0-10 numeric scale for each of the three domains. The ESSPRI score is defined as the average of the scores on the three scales: (dryness + pain + fatigue) / 3.

[0084] Schirmer test (SjS participants) The Schirmer test is used to measure the amount of tear production, particularly in individuals suffering from dry eye syndrome.

[0085] Participants sit in an examination chair with their head resting on a headrest for comfort in a dimmed room. Both eyes are evaluated simultaneously.

[0086] The procedure is briefly outlined below. Gently wipe away excess tears from your eyes Fold the Schirmer strip 5 mm from one end and place it in the inferior fornix at the intersection of the lateral 1 / 3 and medial 2 / 3 (do not touch the cornea or eyelashes) Ask participants to close their eyes - Tears in the conjunctival sac promote wetting of the paper strip. After 5 minutes, remove the filter paper and measure the distance between the leading edge of the wetting and the initial crease using a millimeter ruler.

[0087] Saliva flow rate (no stimulation) (SjS participants) Unstimulated whole saliva will be obtained from participants at screening, baseline, weeks 12 and 24.

[0088] Unstimulated saliva secretions are collected over a 5-minute period. All assessments should be performed at fixed times of day to minimize circadian rhythm-related variations in saliva flow and composition. Participants are instructed not to eat, drink, or smoke for 90 minutes prior to assessment. The start and end times of saliva collection are recorded and the saliva flow rate per minute is calculated.

[0089] Forced vital capacity (FVC) and forced expiratory volume (FEV) (MCTD participants) Forced expiratory volume (FEV) measures how much air a person can exhale during a forced breath. The amount of air exhaled can be measured during the first second (FEV1), second (FEV2) and / or third (FEV3) of a forced breath. Forced vital capacity (FVC) is the total amount of air exhaled during an FEV test. Forced expiratory volume and forced vital capacity are measured during spirometry, a pulmonary function test, and are important measures of lung function.

[0090] Diffusing capacity of the lung for carbon monoxide (DLCO) (MCTD participants) DLCO is a measurement that assesses the lungs' ability to transfer gas from inspired air to the bloodstream. Inhaled carbon monoxide (CO) is used for this test due to its high affinity for hemoglobin. Briefly, during a 10-second breath hold, DLCO measures the uptake of CO per CO pressure per time (cc of CO / sec / mm of Hg; (Ogilvie et al., 1957; Cotes et al., 1993; Modi et al., 2020).

[0091] Raynaud's Condition Score (RCS) (MCTD participants) The Raynaud's Condition Score (RCS) is a participant's rating of the number of attacks caused by Raynaud's phenomenon in the fingers each day, the duration, the amount of pain, the difficulty considering numbness or other symptoms (including painful sores), and the impact of Raynaud's phenomenon alone on daily hand use. An 11-point Likert scale is used to rate the difficulty caused by the condition each day as 0 = no difficulty and 10 = extreme difficulty. Participants are asked to select the number that best describes their difficulty, with higher scores indicating a worse condition.

[0092] King's Brief Interstitial Lung Disease (K-BILD) (MCTD participants) The K-BILD questionnaire is a self-administered health status questionnaire developed in patients with interstitial lung disease. It consists of 15 items in three domains: i) shortness of breath and activity, ii) psychological factors, and iii) chest symptoms. Domain and total scores range from 0 to 100, with higher scores representing better health status (Patel et al., 2013; Sinha et al., 2019; Nolan et al., 2019; Flaherty et al., 2019).

[0093] Efficacy evaluation Efficacy measures in this study were based primarily on the ESSDAI (EULAR SS Disease Activity Index), which measures organ-specific disease criteria, and the ESSPRI (European League Against Rheumatism [EULAR] Sjögren's Syndrome [SS] Patient-Reported Index), which measures the patient's subjective disease impact. Both instruments are widely accepted and validated gold standard measures of systemic and symptomatic manifestations of SjS, respectively.

[0094] The ESSDAI is a systemic disease activity index that categorizes disease activity into 3-4 levels across 12 differently weighted domains (biological findings, blood, joints, glands, skin, constitution, lymphadenopathy, kidney, lung, PNS, CNS and muscle). The composite weighted score provides an accurate assessment of disease activity with good sensitivity to change, as validated in multiple cohort studies (Seror R et al (2015) Validation of EULAR primary Sjogren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66). On the other hand, the ESSPRI tool is a patient-reported composite score of symptoms of dryness, pain in the limbs, and fatigue rated on a visual analogue scale of 0 to 10 during the preceding 2 weeks (Seror R et al (2011) EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjogren's syndrome. Ann. Rheum. Dis. p. 968-72). Patient-reported scores have low sensitivity to changes in disease activity, but among the available tools, the ESSPRI was reported to have a significantly better sensitivity. A recent prospective study reported low correlations between systemic and patient scores, but suggested that the two indexes assess complementary components of disease activity, thus highlighting the importance of assessment of both parameters to arrive at an accurate assessment of disease activity and its changes (Seror R et al (2015) Validation of EULAR primary Sjogren's syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann. Rheum. Dis. p. 859-66).

[0095] Pharmaceutical Compositions The TLR7 / 8 antagonist, i.e., the compound of formula (I) or its pharma- ceutically acceptable salt, can be used as a pharmaceutical composition when combined with a pharma- ceutically acceptable carrier. Such compositions can contain, in addition to the compound of formula (I), a carrier, various diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials known in the art. The characteristics of the carrier depend on the route of administration. The pharmaceutical composition used in the disclosed method can also contain additional therapeutic agents for the treatment of a particular target disorder. For example, the pharmaceutical composition can also contain an anti-inflammatory or antipruritic agent. Such additional factors and / or agents can be included in the pharmaceutical composition to produce a synergistic effect with the compound of formula (I) or to minimize side effects caused by the compound of formula (I). In a preferred embodiment, the pharmaceutical composition for use in the disclosed method contains the compound of formula (I) in a dose of about 10 mg, about 20 mg, about 25 mg, about 50 mg, about 100 mg, or about 200 mg.

[0096] The composition suitable for oral administration contains 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. The composition for oral use can be prepared by any method known in the art for the manufacture of pharmaceutical compositions, and such compositions can contain one or more agents selected from the group consisting of sweeteners, flavorings, colorings and preservatives to provide pharma-ceutically elegant and palatable preparations. The tablet can contain the active ingredient mixed with non-toxic pharma-ceutically acceptable excipients suitable for the manufacture of tablets. These excipients are, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binding agents such as starch, gelatin or acacia; and lubricants such as magnesium stearate, stearic acid or talc. The tablets are uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over a longer period. For example, a time-delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can be provided as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

[0097] The pharmaceutical compositions used in the methods of the present disclosure 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 the active ingredient together with: a) diluents, such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine; b) lubricants, such as silica, talc, stearic acid, its magnesium or calcium salts and / or polyethylene glycol; in the case of tablets, additionally c) binders, such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone; optionally, d) disintegrants, such as starch, agar, alginic acid or its sodium salt or effervescent mixtures; and / or e) Absorbents, colouring agents, flavouring agents and sweeteners.

[0098] Tablets may be film coated or enteric coated by methods known in the art.

[0099] combination In carrying out some of the methods of treatment or use of the present disclosure, a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient, such as a mammal (e.g., a human). It is understood that the disclosed methods provide treatment of SjS or MCTD patients using a compound of formula (I) or a pharma- ceutically acceptable salt thereof, but the therapy is not necessarily a monotherapy. Indeed, once a patient is selected for treatment with a compound of formula (I), the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered according to the methods of the present disclosure either alone or in combination with other agents and therapies for treating SjS or MCTD patients, for example in combination with at least one additional agent for treating SjS or MCTD. When co-administered with one or more additional agents for treating SjS or MCTD, the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered either simultaneously or sequentially with the other agents. If administered sequentially, the attending physician will determine the appropriate sequence of administering a compound of formula (I) or a pharma- ceutically acceptable salt thereof in combination with other agents and appropriate dosages for simultaneous delivery.

[0100] Various therapies may be beneficially combined with the disclosed compounds of formula (I) or pharma- ceutically acceptable salts thereof during the treatment of SjS or MCTD, including steroids (corticosteroids such as prednisone or equivalents); antimalarials, such as hydroxychloroquine; disease-modifying antirheumatic drugs (DMARDSs), such as methotrexate, sulfasalazine, minocycline, and leflunomide; or B-cell depleting drugs, such as rituximab.

[0101] Kits of the Invention The present disclosure also encompasses kits for treating SjS or MCTD. Such kits include a TLR7 / 8 antagonist, such as (S)-N-(4-((5-(1,6-dimethyl-1H-pyrazolo[3,4-b]pyridin-4-yl)-3-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)bicyclo[2.2.2]octan-1-yl)morpholine-3-carboxamide (see formula (I)) or a pharmaceutical composition thereof. Additionally, such kits may include instructions for use.

[0102] In one embodiment, the kit comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In one embodiment, the kit comprises a means for keeping said compositions separate, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack, such as those commonly used for packaging tablets, capsules, and the like.

[0103] The kits of the invention may be used to administer different dosage forms, e.g., oral and parenteral, to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to one another. To aid in compliance, the kits of the invention typically include directions for administration.

[0104] In the combination therapy of the present invention, the compound of formula (I) or its pharmaceutically acceptable salt and other drugs for treating SjS or MCTD (as defined herein) may be manufactured and / or formulated by the same manufacturer or different manufacturers. Furthermore, the compound of formula (I) or its pharmaceutically acceptable salt and other drugs for treating SjS or MCTD may be combined in the combination therapy: (i) before the release of the combination product to the physician (e.g., in the case of a kit containing the compound of formula (I) or its pharmaceutically acceptable salt and other drugs for treating SjS or MCTD); (ii) immediately before administration by the physician (or under the guidance of the physician); (iii) in the patient himself, for example, during the continuous administration of the compound of formula (I) or its pharmaceutically acceptable salt and other drugs for treating SjS or MCTD.

[0105] Additional Embodiments In another embodiment of the disclosed methods, uses, and kits, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient with SjS or MCTD twice daily at a dose of about 10 mg, about 20 mg, about 25 mg, about 35 mg, about 50 mg, about 60 mg, about 75 mg, about 90 mg, about 100 mg, about 150 mg, about 200 mg, or about 250 mg.

[0106] In another embodiment of the disclosed methods, uses, and kits, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in a dose of about 100 mg twice daily.

[0107] In another embodiment of the disclosed methods, uses, and kits, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in a dose of about 150 mg twice daily.

[0108] In another embodiment of the disclosed methods, uses, and kits, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered in a dose of about 200 mg twice daily.

[0109] In another embodiment of the disclosed methods, uses and kits, the patient has mild or moderate-severe SjS. Patients with moderate-severe SjS are defined as those with an ESSDAI score of 5 or more (i.e., at least 5) and an ESSPRI score of at least 5 in 8 defined domains (biological findings, blood, joints, skin, glands, lymphadenopathy, kidneys, constitution) prior to treatment with a compound of formula (I) or a pharmacologic salt thereof.

[0110] In another embodiment of the disclosed methods, uses, and kits, the patient is an adult.

[0111] In another embodiment of the disclosed methods, uses and kits, the patient achieves a change from baseline in at least one patient and / or physician reported outcome (i.e. ESSPRI, FACIT-F, EQ-5D, PhGA) by week 12 or by week 24 of treatment for SjS.

[0112] In another embodiment of the disclosed methods, uses and kits, the patient achieves a reduction in ESSDAI score by week 12 or by week 24 of treatment for SjS.

[0113] In another embodiment of the disclosed methods, uses and kits, the patient achieves a change from baseline in ESSDAI score by week 12 or by week 24 of treatment for SjS.

[0114] In another embodiment of the disclosed methods, uses, and kits, the patient achieves a change from baseline in at least one patient and / or physician reported outcome (i.e., ESSPRI, FACIT-F, EQ-5D, PhGA) by week 12 or by week 24 of treatment for MCTD.

[0115] In another embodiment of the disclosed methods, uses and kits, the patient achieves a reduction in PhGA score by week 12 or by week 24 of treatment for MCTD.

[0116] In another embodiment of the disclosed methods, uses and kits, the patient achieves a change from baseline in PhGA score by week 12 or by week 24 of treatment for MCTD.

[0117] In another embodiment of the disclosed methods, uses, and kits, the patient is an adult. In some embodiments of the disclosed methods, uses, and kits, the patient is an adolescent.

[0118] The details of one or more embodiments of the present disclosure are set forth in the accompanying description above. In the practice or testing of the present disclosure, any methods and materials similar or equivalent to those described herein may be used, but the preferred methods and materials are described herein. Other features, objects, and advantages of the present disclosure will become apparent from the description and claims. In this specification and the appended claims, the singular forms include plural referents unless the context clearly dictates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which the present disclosure belongs. All patents and publications cited herein are incorporated by reference. The following examples are provided to more specifically illustrate the preferred embodiments of the present disclosure. These examples should not be construed in any way as limiting the scope of the disclosed subject matter as defined by the appended claims. EXAMPLES

[0119] Abbreviation AE Adverse Event Area under the AUC curve AUCinf Area under the plasma (or serum or whole blood) concentration-time curve from time zero to infinity (mass x time / volume) AUClast Area under the plasma (or serum or whole blood) concentration-time curve from time zero to the time of the last quantifiable concentration (mass x time / volume) AUCtau Area under the plasma (or serum or whole blood) concentration-time curve from time zero to the end of the dosing interval tau (mass x time / volume) Bid or bid twice a day (in Latin: "bis in die") BMI body mass index CBC complete blood count cm centimeters CL / F Apparent systemic (or total body) clearance from plasma (or serum or whole blood) after administration (mass / volume) CNS Central Nervous System CV Coefficient of variation DMARDs Disease-modifying antirheumatic drugs ECG Electrocardiogram eGFR Estimated glomerular filtration rate ELISA enzyme-linked immunosorbent assay EMG Electromyography EQ-5D EuroQual 5 dimensions (a standardized instrument for measuring health-related quality of life) ESSDAI EULAR Sjögren's Syndrome Disease Activity Index ESSPRI EULAR Sjögren's syndrome patient-reported indicators EULAR European League Against Rheumatism FACIT-F Functional Assessment of Chronic Illness Therapy-Fatigue FIH First in Human h time HRCT High Resolution Computed Tomography iv IA interim analysis INR International Normalized Ratio IFNa Interferon alpha kg Kilogram LC-MS / MS Liquid Chromatography / Mass Spectrometry-Mass Spectrometry mAb Monoclonal Antibody MCP-Mod Multiple Comparison Procedures - Modeling MCTD mixed connective tissue disease MMRM Mixed Effects Model Repeated Measures MRT average residence time NOACs: Novel oral anticoagulants NSAIDs Nonsteroidal Anti-inflammatory Drugs PD Pharmacodynamics PhGA Physician Global Assessment Scale PK Pharmacokinetics PNS Peripheral Nervous System PT Prothrombin Time PTT Partial thromboplastin time Qd or qd once a day (Latin: "quaque die") QTcF = QT interval corrected by Fridericia formula Racc Drug accumulation coefficient RNP ribonucleoprotein SAE Serious Adverse Event SjS Sjögren's syndrome SOM Facility Operation Manual SPT Skin prick test SS Safety Set TLR Toll-like receptor Apparent volume of distribution (volume) during the terminal elimination phase after Vz / F administration

[0120] Example 1: Phase 1 Clinical Trial A first-in-human (FIH) study was conducted to evaluate the safety and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single and repeated doses of the compound of formula (I) administered orally twice daily (bid) in healthy volunteers to support further clinical development of the compound of formula (I) in autoimmune diseases. The study also investigated the effect of feeding.

[0121] First-in-human trials in healthy volunteers (HV) included: Part A was a randomized, subject-blinded, placebo-controlled, single ascending dose (SAD) study with 10 cohorts. Each cohort received a single dose of 1 mg, 3 mg, 10 mg, 20 mg, 40 mg, 80 mg, 160 mg, 320 mg, 640 mg, or 1000 mg of the compound of formula (I) in ascending order. Part B was a randomized, subject-blinded, placebo-controlled, multiple ascending dose (MAD) study with 5 cohorts. Each cohort received, in ascending order, 25 mg, 50 mg, 100 mg, 200 mg, or 400 mg doses of the compound of formula (I) twice daily for 14 days. Part C was a randomized, open-label, two-arm, two-period crossover study in which a dose of 200 mg of the compound of formula (I) was administered in the fed or fasted state, respectively, to evaluate the food effect.

[0122] In the FIH trial, increased exposure was observed in the single ascending-dose (Figure 1, dose proportional at the higher dose) and repeat ascending-dose portion of the study (Figure 2, dose proportional at steady state at the lower dose). With the expected exception of a slight delay in Cmax under fed conditions, no relevant food effects were observed (Figure 3).

[0123] Single oral doses of up to 1000 mg and repeat doses of up to 400 mg twice daily for 14 days of a compound of formula (I) were safe and well tolerated in healthy subjects.

[0124] CD69 and TNF are biomarkers intended to inform the pharmacodynamic (PD) effect of the compound of formula (I). Whole blood samples from SAD and MAD cohorts were stimulated ex vivo with TLR7 / 8 agonists to increase the levels of CD69 and TNF. Over a range of doses, the compound of formula (I) inhibited B cell activation after TLR7 stimulation, as it blocked the upregulation of activation markers such as CD69. Furthermore, over a range of doses, the compound of formula (I) inhibited the activation of human monocytes to produce TNF after TLR8 stimulation.

[0125] Example 2: Efficacy and Safety in Subjects with Sjogren's Syndrome or Mixed Connective Tissue Disease To enable further development of the compound for the treatment of SjS and MCTD, a Phase 2 trial designed to establish the safety, tolerability and efficacy of the compound of formula (I) in subjects with SjS or MCTD will be conducted with the compound of formula (I).

[0126] [Table 1]

[0127] [Table 2]

[0128] [Table 3]

[0129] [Table 4]

[0130] Objectives and Evaluation Items

[0131] [Table 5]

[0132] Test Design This is a Phase 2 randomized, participant- and investigator-blinded, placebo-controlled, multicenter, parallel-group basket study to determine the safety, tolerability, and efficacy of the compound of formula (I) in patients with moderate-to-severe SjS or patients with a diagnosis of MCTD. If study participants receive concomitant therapy for their underlying disease and still meet the inclusion criteria, they will remain on this therapy if it remains stable by the end of the study.

[0133] A total of approximately 48 participants with SjS will be randomized in a 1:1 ratio to a compound of formula (I) or a placebo. A total of approximately 12 participants with MCTD will be randomized in a 1:1 ratio to a compound of formula (I) or a placebo.

[0134] Participants will first undergo a screening period of up to six weeks, followed by a 24-week treatment period and four weeks of follow-up. Each participant's total time in the study will be up to 34 weeks.

[0135] Participants receive a dose of 200 mg twice daily (200 mg twice daily) of a compound of formula (I) or a placebo.

[0136] Safety assessments included physical examination, electrocardiogram, vital signs, standard clinical laboratory evaluations (haematology, biochemistry, and urinalysis), and adverse events and serious adverse events monitoring.

[0137] screening After signing informed consent, participants will be assessed on the ESSDAI (SjS participants) and the RCS and K-BILD (MCTD participants) and complete safety and other assessments to confirm RNP positivity and determine eligibility. For logistical reasons, assessments may be conducted on different days during the 6-week screening period, if deemed appropriate by the investigator. Participants who fail screening may be rescreened for one additional opportunity.

[0138] Baseline Eligible participants will return for a baseline visit on Day 1. Participants may stay at the facility overnight for logistical reasons, but this is not considered a hospital stay. Eligibility must be confirmed prior to randomization, and required baseline assessments must be completed prior to dosing on Day 1. If preferred by the site for scheduling purposes, some baseline assessments may be conducted the day before Day 1.

[0139] treatment The treatment period will last for 24 weeks, from week 0 (day 1) to week 24 (day 169). On day 1, participants will be randomized to their respective SjS or MCTD treatment arm. Randomization of SjS participants will be stratified by screening ESSDAI (<10 or ≥10 based on weighted score) at baseline, and randomization of MCTD participants will be stratified by pulmonary involvement (yes / no) at baseline.

[0140] Participants will return to the site approximately every 4 weeks, except for Week 16 (Day 113), when only safety phone calls will be conducted. An additional visit will be conducted in Week 2 (Day 15) for safety and compliance purposes, as the compound of Formula (I) will be administered for the first time to patients with SjS and MCTD.

[0141] At the study visit, all participants will complete and / or undergo surveys (eg, FACIT, PhGA), safety, PK, PD and biomarker sample collection.

[0142] PK assessments will be performed pre-dose and at various time points post-dose (up to 4 hours post-dose) at Weeks 4, 12, and 24. At Week 4, an additional PK sample will be collected at 6 hours post-dose at selected sites.

[0143] Furthermore, according to the assessment schedule, participants with SjS: -ESSDAI, salivary flow rate and Schirmer test evaluation Complete the ESSPRI assessment.

[0144] Participants with MCTD: Underwent ESSDAI (joint and lung regions only), in-house spirometry, pulmonary diffusion capacity for carbon monoxide (DLCO) test and nailfold capillaroscopy; - Fill out the Raynaud's Status Score (RCS) and K-BILD assessment. · Perform exercise-induced desaturation testing.

[0145] On the day of the visit, participants will be asked to take that morning's dose of study medication at the site. Participants will return their used medication supply pack for adherence and accountability assessments and will receive a new supply of study medication for the next 4-week treatment period (except for week 12, when participants may choose to receive a medication supply for the 8-week treatment period).

[0146] Each week, participants will be asked to complete a diary recording the administration of treatment.

[0147] All study visits will be outpatient; however, for logistical reasons, it may be necessary for participants to come to the site the evening before their scheduled evaluation visit. In these cases, participants may stay overnight at the site, but this will not be considered a hospital stay.

[0148] Participants may contact investigator / site staff during the study to ensure compliance / monitor safety by phone or other means, as deemed appropriate or necessary by the investigator.

[0149] The primary endpoint of the study will be assessed after completion of 24 weeks of treatment (day 169; end of week 24 visit).

[0150] Follow-up and End-of-Study Visits (EoS) After the last day of dosing, participants will enter a 4-week follow-up period free of study drug treatment. Participants will be asked to return to the site for an End-of-Study Visit at Week 28. At this visit, participants will undergo a final evaluation.

[0151] Upon completion of this visit, participants will be discharged from the study.

[0152] Rationale for dose / regimen and duration of treatment The planned dose for this trial is 200 mg bid (200 mg twice daily). This dose is expected to be safe and effective based on data from first-in-human (FIH) clinical trials: In FIH trials, single doses of up to 1000 mg and doses of up to 400 mg bid (twice daily) for 14 days have been tested in healthy volunteers and shown to be safe and well tolerated. In the FIH trial, a dose of 200 mg bid (twice daily) for 14 days resulted in complete pathway inhibition of both TLR7 and TLR8 and is therefore expected to provide maximal clinical efficacy.

[0153] The study treatment period will be 24 weeks to allow for a meaningful evaluation of the safety, tolerability and efficacy of the compound of formula (I) in SjS and MCTD. The 24-week treatment period is based on recent internal clinical trial data suggesting that a meaningful treatment difference versus placebo in terms of clinical efficacy can be expected by week 24, and that a plateau of pharmacological efficacy can be reached within 12-24 weeks of treatment.

[0154] Based on analysis of PK and PD data from first-in-human clinical trials, the compound of formula (I) is expected to have a fast onset of pharmacological action, but the time to meaningful improvement in clinical efficacy parameters such as ESSDAI or ESSPRI may take up to 24 weeks.

[0155] A follow-up period of 4 weeks after the last dose will be performed for adverse event monitoring. Based on the short terminal half-life of the compound of formula (I) of up to 14.4 hours, no pharmacological effect is expected beyond 3 days (= 5 terminal half-lives) after the end of treatment.

[0156] Rationale for choosing a control (placebo) The comparator treatment in the trial is placebo to provide an objective control for the assessment of safety, clinical efficacy and PD during the 24-week treatment with the compound of formula (I).

[0157] In the absence of approved systemic treatments for SjS and MCTD, the use of placebo as a comparator is considered justified. Current standard treatments for patients with SjS and MCTD are often limited to symptomatic care of symptoms (e.g., dryness or Raynaud's phenomenon). Steroids and traditional DMARDs are often ineffective. No pharmacological interventions are effective against the disabling fatigue associated with SjS.

Claims

1. A method of treating Sjogren's syndrome in a subject in need thereof, comprising administering to the subject a compound of formula (I). 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, e.g., orally, twice daily, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg.

2. 10. The method of claim 1, wherein the dose is about 100 mg to about 200 mg twice daily, for example about every 12 hours.

3. 10. The method of claim 1, wherein the dose is about 200 mg twice daily, for example about every 12 hours.

4. The method of claim 1, wherein the subject has moderate to severe Sjogren's syndrome.

5. 2. The method of claim 1, wherein the subject, e.g., patient, is positive, e.g., seropositive, for anti-soluble nuclear (ENA) antibodies, e.g., anti-Sjogren's syndrome associated antigen A (anti-Ro / SSA) antibodies.

6. 2. A compound of formula (I): 【Chemistry 2】 or a pharma- ceutically acceptable salt thereof, administered twice a day, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg, or a pharma- ceutically acceptable salt thereof.

7. A method of treating mixed connective tissue disease in a subject in need thereof, comprising administering to the subject a compound of formula (I). 【Chemistry 3】 or a pharma- ceutically acceptable salt thereof, e.g., orally, twice daily, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg.

8. 8. The method of claim 7, wherein the dose is about 100 mg to about 200 mg twice daily, for example about every 12 hours.

9. 8. The method of claim 7, wherein the dose is about 200 mg twice daily, for example about every 12 hours.

10. The method of claim 1, wherein the subject, e.g., patient, is positive, e.g., seropositive, for anti-soluble nuclear (ENA) antibodies, e.g., anti-U1-RNP antibodies.

11. 2. A compound of formula (I): 【Chemistry 4】 or a pharma- ceutically acceptable salt thereof, administered twice a day, e.g., about every 12 hours, at a dose of about 25 mg to about 400 mg, e.g., about 50 mg to about 300 mg, e.g., about 100 mg to about 200 mg, or a pharma- ceutically acceptable salt thereof.

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