TYK2 inhibitor and application thereof

Abstract

Described herein are methods and compositions for the treatment of TYK2 mediated disorders. In some embodiments, the TYK2-mediated disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, and a disorder associated with transplantation.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 324,754, filed on March 29, 2022; U.S. Provisional Patent Application No. 63 / 344,126, filed on May 20, 2022; U.S. Provisional Patent Application No. 63 / 408,572, filed on September 21, 2022; and U.S. Provisional Patent Application No. 63 / 429,720, filed on December 2, 2022; the entire contents of which are incorporated herein by reference. Background Art

[0003] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAK) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins (including TYK2) are essential for cytokine signaling. TYK2 binds to the cytoplasmic domains of type I and type II cytokine receptors and interferon type I and type III receptors, and is activated by those receptors after cytokine binding. Cytokines involved in TYK2 activation include interferons (e.g., IFN-α, IFN-β, IFN-κ, IFN-δ, IFN-ε, IFN-τ, IFN-ω, and IFN-ζ (also known as limitins) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, L-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then proceeds to phosphorylate other signaling proteins such as STAT family members, including STAT1, STAT2, STAT4, and STAT6.

[0004] TYK2 activation by IL-23 is associated with inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome-wide association study of 2,622 individuals with psoriasis identified an association between disease susceptibility and TYK2. Knockout or tyrphostin inhibition of TYK2 significantly reduced IL-23- and IL-22-induced dermatitis.

[0005] TYK2 also plays a role in respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer and cystic fibrosis. Goblet cell hyperplasia (GCH) and mucus hypersecretion are mediated by IL-13-induced TYK2 activation, which further activates STAT6.

[0006] Reduced TYK2 activity protects joints from collagen antibody-induced arthritis, a model of human rheumatoid arthritis. Mechanistically, reduced Tyk2 activity reduces the production of Th1 / Th17-related cytokines and matrix metalloproteinases, as well as other key inflammatory markers.

[0007] Compared to controls, TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), with no CD4 T cells infiltrating the spinal cord, indicating that TYK2 is essential for pathogenic CD4-mediated disease development in MS. This confirms earlier studies linking increased TYK2 expression to MS susceptibility. Loss-of-function mutations in TYK2 lead to reduced demyelination and increased remyelination of neurons, which further suggests that TYK2 inhibitors play a role in treating MS and other CNS demyelinating disorders.

[0008] TYK2 is the only signaling messenger shared by IL-12 and IL-23. TYK2 knockout reduces methylated BSA injection-induced footpad thickness, imiquimod-induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid-induced colitis in mice.

[0009] Joint linkage and association studies of various type I IFN signaling genes with systemic lupus erythematosus (SLE), an autoimmune disorder, showed that loss-of-function mutations in TYK2 were strongly and significantly associated with a reduced prevalence of SLE in families with affected members. A genome-wide association study of individuals with SLE and a cohort without the disease showed a highly significant association between the TYK2 locus and SLE.

[0010] TYK2 has been shown to play an important role in maintaining tumor surveillance, and TYK2 knockout mice show impaired cytotoxic T cell responses and accelerated tumor development. However, these effects are associated with potent inhibition of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be well suited for treating autoimmune disorders or transplant rejection. Although other JAK family members, such as JAK3, have similar roles in the immune system, TYK2 has been suggested as a superior target because it is involved in fewer and more closely associated signaling pathways, resulting in fewer off-target effects.

[0011] However, studies on T-cell acute lymphoblastic leukemia (T-ALL) have shown that T-ALL is highly dependent on IL-10 to maintain cancer cell survival through upregulation of the anti-apoptotic protein BCL2 via STAT1-mediated signaling via TYK2. Gene knockdown of TYK2, but not other JAK family members, slows cell growth. Specific activating mutations against TYK2 that promote cancer cell survival include those against the FERM domain (G36D, S47N, and R425H), the JH2 domain (V731I), and the kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required to increase cancer cell survival, because TYK2 enzymes characterized by kinase-dead mutations (M978Y or M978F) in addition to the activating mutation (E957D) result in a failure to transform.

[0012] Therefore, selective inhibition of TYK2 has been suggested as an appropriate target for patients with IL-10 and / or BCL2-addicted tumors, such as 70% of adult T-cell leukemia cases. TYK2-mediated STAT3 signaling has been shown to also mediate neuronal cell death caused by the amyloid-β (Aβ) polypeptide. Reduced TYK2 phosphorylation of STAT3 following Aβ administration results in reduced neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. Inhibition of the JAK-STAT signaling pathway has also been implicated in hair growth and reversing hair loss associated with alopecia areata.

[0013] Therefore, there is a need to provide methods for inhibiting TYK2 activity to treat one or more of the disorders described herein without the side effects associated with JAK2 inhibition. Summary of the invention

[0014] Methods and compositions useful for treating TYK2-mediated disorders are described in part herein. For example, disclosed herein is a method of treating a TYK2-mediated disease or disorder in a patient in need thereof, the method comprising orally administering to the patient once or twice daily 30 mg, 40 mg, 60 mg, or 80 mg of a compound represented by the formula:

[0015]

[0016] Also disclosed herein are methods of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising:

[0017] Two oral tablet compositions are administered to the patient once daily, each composition comprising:

[0018] 30 mg of the compound represented by the following formula:

[0019] and

[0020] Pharmaceutically acceptable excipients;

[0021] administering rabeprazole orally to the patient as needed; and

[0022] If necessary, the patient is given food after administration of the compound.

[0023] Further disclosed herein are methods of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising:

[0024] The patient is orally administered 30 mg, 60 mg or 80 mg of a compound represented by the following formula once or twice daily:

[0025] and

[0026] The patients were either in a fasting or eating state.

[0027] Also disclosed herein are fixed unit dose pharmaceutical compositions for oral administration comprising:

[0028] 30 mg, 40 mg, 60 mg or 80 mg of a compound represented by the following formula:

[0029] and

[0030] Pharmaceutically acceptable excipients.

[0031] For example, disclosed herein is an oral tablet composition comprising:

[0032] About 30 mg of the compound represented by the following formula:

[0033] and

[0034] Pharmaceutically acceptable excipients.

[0035] BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 A study is described that investigates the relative bioavailability of Compound A as an oral tablet composition versus a liquid formulation in healthy participants, and the effects of food or gastric acid reduction on the pharmacokinetics of the disclosed compounds or oral tablet compositions. DETAILED DESCRIPTION

[0037] The features and other details of the present disclosure will now be described in more detail. Before further describing the present disclosure, certain terms used in the present specification, examples and appended claims are collected herein. Such definitions should be understood by those skilled in the art in accordance with the remainder of the present disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as commonly understood by those of ordinary skill in the art.

[0038] definition

[0039] As used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. When referring to a number or numerical range, the term "about" means that the referenced number or numerical range is an approximation within experimental variation (or within statistical experimental error), and thus, in some cases, the number or numerical range will vary between 1% and 15% of the number or numerical range. The term "comprising" (and related terms such as "comprise / comprises" or "having" or "including") is not intended to exclude that in certain other embodiments, for example, any composition of matter, composition, method or process described herein, or the like, "consists of" or "consists essentially of" the features.

[0040] As used herein, the terms "treat", "prevent", "improve" and "inhibit" and words derived therefrom do not necessarily mean 100% or complete treatment, prevention, improvement or inhibition. On the contrary, there are different degrees of treatment, prevention, improvement and inhibition that are considered by the skilled person to have potential benefits or therapeutic effects. In this regard, the disclosed methods can provide any amount of any degree of treatment, prevention, improvement or inhibition of the disorder in a mammal. For example, the disorder (including its symptoms or symptoms) can be alleviated by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20% or about 10%. In addition, the treatment, prevention, improvement or inhibition provided by the methods disclosed herein may include treating, preventing, improving or inhibiting one or more symptoms or symptoms of a disorder (e.g., cancer or inflammatory disease). Similarly, for the purposes of this article, "treat", "prevent", "improve" and "inhibit" cover delaying the onset of a disorder or its symptoms or symptoms.

[0041] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a compound or composition (e.g., oral tablet composition) disclosed herein that will be sufficient to alleviate to some extent one or more of the symptoms of the disease or disorder being treated. In some embodiments, the result is to reduce and / or alleviate the signs, symptoms, or causes of the disease, or any other desired change in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition including a compound as disclosed herein required to provide a clinically significant reduction in disease symptoms. In some embodiments, the appropriate "effective" amount in any individual case is determined using techniques such as dose escalation studies.

[0042] As used herein, the term "TYK2-mediated" disorder, disease and / or condition as used herein means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Thus, another embodiment is directed to treating or lessening the severity of one or more diseases in which TYK2 or a mutant thereof is known to play a role. Such TYK2-mediated disorders include, but are not limited to, autoimmune disorders, inflammatory disorders, proliferative disorders, endocrine disorders, neurological disorders, and disorders related to transplantation.

[0043] Methods and compositions

[0044] Disclosed herein, for example, is a method of treating a TYK2-mediated disease or condition in a patient in need thereof, the method comprising orally administering to the patient once or twice daily 30 mg, 40 mg, 60 mg, or 80 mg of a compound represented by the formula:

[0045]

[0046] In some embodiments, the methods described herein further comprise orally administering a proton pump inhibitor to the patient. For example, in some embodiments, the proton pump inhibitor is selected from the group consisting of rabeprazole, omeprazole, esomeprazole, lansoprazole, pantoprazole, and dexlansoprazole. In certain embodiments, the proton pump inhibitor is rabeprazole.

[0047] In some embodiments, the disclosed compounds are administered to a patient in a fasting state. In other examples, the methods described herein further comprise giving the patient food prior to or while administering the disclosed compounds.

[0048] In further embodiments, the TYK2-mediated disease or disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis.

[0049] For example, described herein is a method of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising:

[0050] Two oral tablet compositions are administered to the patient once daily, each composition comprising:

[0051] 30 mg of the compound represented by the following formula:

[0052] and

[0053] Pharmaceutically acceptable excipients;

[0054] administering rabeprazole orally to the patient as needed; and

[0055] If necessary, the patient is given food after administration of the compound.

[0056] Also described herein is a method of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising:

[0057] The patient is orally administered 30 mg, 60 mg or 80 mg of a compound represented by the following formula once or twice daily:

[0058]

[0059] The patients were either in a fasting or eating state.

[0060] In addition, disclosed herein is a fixed unit dose pharmaceutical composition for oral administration, comprising:

[0061] 30 mg, 40 mg, 60 mg or 80 mg of a compound represented by the following formula:

[0062] and

[0063] Pharmaceutically acceptable excipients.

[0064] In some embodiments, the disclosed fixed dose pharmaceutical compositions are formulated as tablets.

[0065] Further disclosed herein is an oral tablet composition comprising:

[0066] About 30 mg of the compound represented by the following formula:

[0067] and

[0068] Pharmaceutically acceptable excipients.

[0069] Also described herein are methods of treating a TYK2-mediated disease or condition in a patient in need thereof, the methods comprising administering to the patient an effective amount of a disclosed oral tablet composition. In some embodiments, the administration is once daily administration. In other embodiments, the administration is twice daily administration.

[0070] Pharmaceutical composition

[0071] In certain embodiments, the compounds described herein will be administered as the neat chemical. In some embodiments, the compounds described herein are combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, a physiologically suitable (or acceptable) excipient, or a physiologically suitable (or acceptable) carrier) selected based on the chosen route of administration (e.g., oral administration) and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21st ed. Mack Pub. Co., Easton, PA (2005)).

[0072] In certain embodiments, the compounds provided herein are substantially pure in that they contain less than about 5%, or less than about 1%, or less than about 0.1% of other small organic molecules, such as unreacted intermediates or synthesis byproducts produced, for example, in one or more steps of the synthetic methods.

[0073] The pharmaceutical composition is administered in a manner suitable for the disease to be treated (or prevented). The appropriate dosage and suitable duration and frequency of administration will be determined by factors such as the patient's condition, the type and severity of the patient's disease, the specific form of the active ingredient, and the method of administration. In general, the appropriate dosage and treatment regimen provide a composition sufficient to provide an amount of treatment and / or prevention benefit (e.g., improved clinical results, such as more frequent complete or partial remission, or longer disease-free and / or total survival, or reduced symptom severity). The optimal dose is generally determined using experimental models and / or clinical trials. The optimal dose depends on the patient's body mass, weight, or blood volume.

[0074] For example, in some embodiments, the disclosed compounds or compositions (e.g., oral tablet compositions) can be administered once daily to a patient. In other embodiments, the disclosed compounds or compositions (e.g., oral tablet compositions) can be administered twice daily to a patient.

[0075] In some embodiments, the disclosed compound or pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, intrapulmonary, intradermal, intrathecal, epidural and intranasal administration. Parenteral administration includes intramuscular, intravenous, intraarterial, intraperitoneal or subcutaneous administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection, oral administration, inhalation, nasal administration, topical administration or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for intravenous injection. In some embodiments, the pharmaceutical composition is formulated into tablets, pills, capsules, liquids, inhalants, nasal spray solutions, suppositories, suspensions, gels, colloids, dispersions, suspensions, solutions, emulsions, ointments, lotions, eye drops or ear drops. In some embodiments, the pharmaceutical composition is formulated into tablets.

[0076] In some embodiments, for example, the disclosed compounds or pharmaceutical compositions are formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated into tablets, pills, capsules, liquids, suspensions, dispersions, solutions, or emulsions. In some embodiments, the pharmaceutical composition is formulated into tablets, for example, formulated into tablets for oral administration.

[0077] Suitable dosages and dosing regimens are determined by conventional assay techniques known to those of ordinary skill. In general, treatment is started with a smaller dose than the optimal dose of the compound disclosed herein. Thereafter, the dose is increased in small increments until the optimal effect in such cases is achieved. In some embodiments, the method involves administering about 0.1 μg to about 50 mg of at least one compound described herein per kg of individual body weight. For a 70 kg patient, a more commonly used dose is from about 10 μg to about 200 mg of a compound disclosed herein, depending on the individual's physiological response.

[0078] By way of example only, the dosage of a compound described herein for a method of treating a disease as described herein is from about 0.001 to about 1 mg / kg of body weight of the individual per day, such as about 0.001 mg, about 0.002 mg, about 0.005 mg, about 0.010 mg, 0.015 mg, about 0.020 mg, about 0.025 mg, about 0.050 mg, about 0.075 mg, about 0.1 mg, about 0.15 mg, about 0.2 mg, about 0.25 mg, about 0.5 mg, about 0.75 mg, or about 1 mg per kilogram of body weight per day. In some embodiments, the dosage of a compound described herein for the methods described herein is from about 1 to about 1000 mg / kg body weight of the subject being treated per day, such as about 1 mg, about 2 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 50 mg, about 75 mg, about 80 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0079] In addition, by way of example only, the dosage of the compound of the method of treating a disease as described herein can be a fixed dose, for example, a fixed dose of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg or 80 mg.

[0080] Treatment

[0081] The methods described herein can be used to inhibit the kinase activity of one or more enzymes. In some embodiments, the kinase is TYK2.

[0082] Provided herein are methods of treating a disease or disorder, wherein the disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a transplantation-related disorder, the method comprising administering to a patient in need thereof an effective amount of a compound or composition described herein (e.g., an oral tablet composition).

[0083] In some embodiments, the disease or condition is an autoimmune disorder. In some embodiments, the disease or condition is selected from type 1 diabetes, systemic lupus erythematosus, multiple sclerosis, psoriasis, Behcet's disease ( disease), POEMS syndrome, Crohn's disease, ulcerative colitis, and inflammatory bowel disease.

[0084] In some embodiments, the disease or disorder is an inflammatory disorder. In some embodiments, the inflammatory disorder is rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, psoriasis, hepatomegaly, Crohn's disease, ulcerative colitis, inflammatory bowel disease.

[0085] In some embodiments, the disease or disorder is a proliferative disorder. In some embodiments, the proliferative disorder is cancer. In some embodiments, the proliferative disorder is a blood cancer. In some embodiments, the proliferative disorder is a leukemia. In some embodiments, the leukemia is a T-cell leukemia. In some embodiments, the T-cell leukemia is T-cell acute lymphoblastic leukemia (T-ALL). In some embodiments, the proliferative disorder is polycythemia vera, myelofibrosis, essential or thrombocythemia.

[0086] In some embodiments, the disease or disorder is an endocrine disorder. In some embodiments, the endocrine disorder is polycystic ovary syndrome, Crouzon's syndrome, or type 1 diabetes.

[0087] In some embodiments, the disease or disorder is a neurological disorder. In some embodiments, the neurological disorder is Alzheimer's disease.

[0088] In some embodiments, the proliferative disorder is associated with one or more activating mutations in TYK2. In some embodiments, the activating mutation in TYK2 is a mutation in the FERM domain, the JH2 domain, or the kinase domain. In some embodiments, the activating mutation in TYK2 is selected from G36D, S47N, R425H, V731I, E957D, and R1027H.

[0089] In some embodiments, the disease or disorder is associated with transplantation. In some embodiments, the disease or disorder associated with transplantation is transplant rejection or graft-versus-host disease.

[0090] In some embodiments, the disease or condition is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments, the disease or condition is associated with type I interferon signaling. In some embodiments, the disease or condition is associated with IL-10 signaling. In some embodiments, the disease or condition is associated with IL-12 signaling. In some embodiments, the disease or condition is associated with IL-23 signaling.

[0091] Provided herein are methods for treating inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, pemphigus with tumors, epidermolysis bullosa acquired, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0092] Provided herein are methods for treating other diseases or conditions (e.g., diseases or conditions with an inflammatory component), for example, treating eye diseases and conditions, such as eye allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose (including allergic rhinitis), and inflammatory diseases in which an autoimmune response is involved or has an autoimmune component or etiology, including autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener granulamatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, syndrome), idiopathic steatorrhea, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, drusenosis, nephropathy, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine eye disease, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryptopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (with or without nephrotic syndrome,Examples include idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis nephropathy, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiomegaly, muscle wasting, catabolic disorders, obesity, fetal growth retardation, hypersterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behcet's disease, incontinence pigmenti, Paget's disease disease), pancreatitis, hereditary periodic fever syndrome, asthma (allergic and non-allergic, mild, moderate, severe, bronchial and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, severe allergies, sinusitis, eye allergies, silica-induced diseases, COPD (reduction damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), lung disease, cystic fibrosis, acid lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroid adenitis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic transplant rejection, colitis, conjunctivitis, Crohn's disease, cystitis, lacrimal gland inflammation, dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schonlein purpura purpura), hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis, mumps, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0093] In some embodiments, the inflammatory disease is acute and chronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile rheumatoid arthritis, systemic juvenile idiopathic arthritis (SJIA), cryptopyrin-associated periodic syndrome (CAPS), or osteoarthritis.

[0094] In some embodiments, the inflammatory disease is a Th1 or Th17 mediated disease. In some embodiments, the Th17 mediated disease is selected from systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease (including Crohn's disease or ulcerative colitis).

[0095] In some embodiments, the inflammatory disease is Dove syndrome, an allergic disorder, osteoarthritis, a disorder of the eye (such as eye allergies, conjunctivitis, keratoconjunctivitis sicca, vernal conjunctivitis), or a disease affecting the nose (such as allergic rhinitis).

[0096] Combination therapy

[0097] In certain instances, a compound or composition described herein (eg, a disclosed oral tablet composition) is administered in combination with a second therapeutic agent (eg, a proton pump inhibitor, such as rabeprazole).

[0098] In some embodiments, the benefit experienced by a patient is increased by administering a compound described herein with a second therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit.

[0099] In a specific embodiment, a compound or composition described herein is co-administered with a second therapeutic agent, wherein the compound or composition described herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than either therapeutic agent administered alone.

[0100] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply additive of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0101] In certain embodiments, different therapeutically effective doses of compounds disclosed herein are used to formulate pharmaceutical compositions (e.g., oral tablet compositions) and / or for use in treatment regimens when compounds disclosed herein are administered in combination with a second therapeutic agent. The therapeutically effective doses of drugs and other agents used in combination treatment regimens are measured as needed by methods similar to those of the above-mentioned active substances themselves. In addition, the methods of prevention / treatment described herein encompass the use of metronomic dosing, i.e., providing more frequent, lower doses to minimize toxic side effects. In some embodiments, the combination treatment regimen encompasses a treatment regimen in which the administration of a compound or composition begins before, during, or after treatment with a second agent as described herein, and continues to any time during treatment with the second agent or after treatment with the second agent is terminated. It also includes treatment of a compound or composition and a second agent used in combination at the same time or at different times and / or at decreasing or increasing intervals during the treatment period. Combination therapy further includes periodic treatments that start and stop at different times to assist in the clinical management of patients.

[0102] It should be understood that the dosage regimen for treating, preventing or improving the condition for which relief is sought is adjusted according to various factors (e.g., the disease, condition or condition suffered by the individual; the age, weight, sex, diet and medical condition of the individual). Therefore, in some cases, the actual dosage regimen used is different, and in some embodiments, deviates from the dosage regimen set forth herein.

[0103] For the combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, the specific drug employed, the disease or condition being treated, etc. In additional embodiments, when co-administered with a second therapeutic agent, the compounds provided herein are administered simultaneously with the second therapeutic agent, or are administered sequentially.

[0104] In combination therapy, multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administered simultaneously, the multiple therapeutic agents are provided by way of example only in a single, unified form or in multiple forms (e.g., as a single pill or as two separate pills).

[0105] The compounds and compositions described herein are applied before, during or after the occurrence of a disease or condition, and the timing of applying the composition containing the compound is different. Therefore, in one embodiment, the compounds and compositions described herein are used as preventive agents, and individuals with a tendency to develop a disease or disease are continuously applied to prevent the occurrence of a disease or condition. In another embodiment, the compounds and compositions are applied to individuals as quickly as possible during or after the onset of symptoms. In a specific embodiment, the compounds or compositions described herein are applied as soon as possible within a feasible range after the detection or suspicion of the onset of a disease or condition, and the length of time required for the treatment of the disease is applied. In some embodiments, the duration required for treatment is different, and the duration of treatment is adjusted to meet the specific needs of each individual. For example, in a specific embodiment, the compound described herein or the formulation containing the compound is applied for at least 2 weeks, about 1 month to about 5 years.

[0106] In some embodiments, the compound or composition described herein is administered in combination with an adjuvant. In one embodiment, the therapeutic effect of one of the compound or composition described herein is enhanced by administering an adjuvant (e.g., the adjuvant itself has a minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).

[0107] Example

[0108] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0109] N-(4-((2-methoxy-3-(1-(methyl-d3)-1H-1,2,4-triazol-3-yl)phenyl)amino)-5-(propionyl-3,3,3-d3)pyridin-2-yl)cyclopropanecarboxamide (Compound A) can be prepared according to the synthetic procedure described in WO 2020 / 086616, the entire text of which is incorporated herein by reference.

[0110] Example 1: Study Description:

[0111] The relative bioavailability of Compound A as an oral tablet composition versus a liquid formulation in healthy participants and the effect of food or gastric acid reduction on the pharmacokinetics of the disclosed compounds or oral tablet compositions were studied.

[0112] Primary objectives: To evaluate the relative bioavailability of 60 mg of Compound A administered as two 30 mg immediate release tablets versus a liquid formulation in healthy participants; To evaluate the effect of food on the pharmacokinetics (PK) of 60 mg of Compound A administered as two immediate release 30 mg tablets in healthy participants; To evaluate the effect of gastric acid reduction with rabeprazole on the PK of 60 mg of Compound A administered as two immediate release 30 mg tablets in healthy participants. Secondary objectives include evaluating the safety and tolerability of a single 60 mg dose of Compound A in healthy participants and / or evaluating the effect of a single 60 mg dose of Compound A in healthy participants on selected pharmacodynamic (PD) markers.

[0113] Study Design:

[0114] The study was a single-center, in-house, open-label, 4-period, partially randomized crossover study conducted in approximately 15 healthy participants. The study population included healthy male and female participants aged 18 to 60 years with a body mass index (BMI) between 18 and 34 kg / m 2 The estimated study duration includes: Screening Period: up to 28 days; Treatment Period: 17 days; and Follow-up Period: 6 to 10 days after the last dose.

[0115] Each participant will receive a single dose of Compound A in 4 doses:

[0116] A. Administer 60 mg of liquid formulation in the fasting state.

[0117] B. Administer 60 mg (two 30 mg tablets) in the fasting state.

[0118] C. 60 mg (two 30 mg tablets) administered with a high-calorie breakfast.

[0119] D. Administer 60 mg (two 30 mg tablets) once daily in the fasting state on day 5 of a 5-day course of rabeprazole 20 mg.

[0120] Schedule D will be performed last, but the order of Schedules A, B, and C will be randomized (ABC, BCA, CAB). Eligible participants will enter the Clinical Research Unit (CRU) one day before the first study drug administration (Day -1, Period 1) and remain in the CRU for 18 days. The End of Study (EOS) visit will be conducted 6 to 10 days after the last Compound A administration.

[0121] Compound A administration (A and B) during fasting:

[0122] Compound A 60 mg as two 30 mg tablets or 60 mg as a liquid formulation was administered with 240 mL of water after at least 10 hours overnight fasting, followed by an additional 4 hours of fasting. Water was allowed ad libitum, except for 1 hour before and 1 hour after Compound A administration.

[0123] Compound A administration with fasting (C):

[0124] Compound A 60 mg was administered in the form of two 30 mg tablets at the end of a standardized high-calorie meal with 240 mL of water. The meal was administered after at least 10 hours of overnight fasting, followed by another 4 hours of fasting. Water was allowed ad libitum, except for 1 hour before and 1 hour after Compound A administration.

[0125] Fasting rabeprazole and fasting compound A administration (D):

[0126] Rabeprazole 20 mg was administered with 240 mL of water on days 3, 4, 5, and 6 of period 3 after an overnight fast of at least 10 hours; fast for another 1 hour after administration. On day 1 of period 4, rabeprazole 20 mg and Compound A 60 mg (two 30 mg tablets) were administered with 240 mL of water after an overnight fast of at least 10 hours, followed by an additional 4-hour fast. Water was allowed ad libitum, except for 1 hour before and 1 hour after administration of rabeprazole and / or Compound A.

[0127] The following PK parameters of Compound A were determined as needed:

[0128] ·C max : Maximum plasma Compound A concentration, determined directly from the concentration-time curve

[0129] ·T max : Time of maximum plasma Compound A concentration, determined directly from the concentration-time curve

[0130] AUC 0-last : The time from before administration (time 0) to the last quantifiable concentration (tlast ) concentration-time curve area under

[0131] AUC 0-inf : Extrapolated from before drug administration (time 0) to infinite time (AUC 0-last +C last / λz ) concentration-time curve area under

[0132] AUC ％extrap : Due to exceeding t last The AUC resulting from the extrapolation of 0-inf Percentage

[0133] ·λ z : The terminal elimination rate constant determined by selecting at least three data points at the terminal phase of the concentration-time curve

[0134] ·t 1 / 2 : Terminal elimination half-life, calculated as: ln2 / λ z

[0135] CL / F: Based on total clearance, calculated as: dose / AUC inf

[0136] Vz / F: The distribution volume is calculated as: dose / (AUC inf *λ z )

[0137] ·Ae 0-48 : Cumulative urinary excretion of the parent drug for a complete collection of up to 48 hours, calculated as: Compound A urine concentration * urine volume

[0138] %Fe: The percentage of unchanged drug excreted in urine, calculated as: (Ae / dose)*100

[0139] CLr: Renal clearance of the parent drug in plasma, calculated as Ae 0-48 / AUC 0-48 :

[0140] Participants who meet the following criteria will be considered eligible for clinical research:

[0141] Participants were able to understand and comply with the study procedures, were aware of the risks involved in the study, and provided written informed consent in accordance with federal, local, and institutional guidelines prior to any clinical screening activities; participants were male or female aged 18 to 60 years (inclusive) at the screening visit; participants had a minimum weight of 18 kg / m 2 With 34kg / m 2(inclusive); participants were healthy as determined by medical history, physical examination, vital signs and routine laboratory parameters (chemistry, hematology, serology and urinalysis), and ECG at the screening visit and on day -1. Laboratory values ​​outside the normal range were acceptable if they were considered clinically insignificant. The screening assessment could be repeated 1 time at the investigator's discretion; female participants must not be pregnant (negative pregnancy test for women of childbearing potential at screening and registration) or breastfeeding, and if sexually active, must meet the following criteria: if of childbearing potential, they must use a highly effective contraceptive (failure rate <1%) method (<e.g., non-hormonal intrauterine contraceptive device, azoospermic partner, sexual abstinence) during participation in the study until at least 3 months after the last dose of study drug, or surgical sterilization (i.e., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) at least 6 months before the first administration of study drug, or postmenopausal (defined as 12 consecutive months of amenorrhea and documented plasma follicle stimulating hormone (FSH) level >40 IU / mL). Sexually active male participants with female sex partners must be surgically sterilized (e.g., vasectomy) for 6 months or use condoms with spermicidal foam / gel / film / cream / suppository from screening until 3 months after the last dose of study drug (even when with female partners of non-fertile potential to prevent semen transmission of the drug) and must refrain from sperm donation during the same time period.

[0142] Participants who meet one or more of the following criteria will not be considered eligible for this clinical study: Participants with a history of prior exposure to Compound A; Participants with a history of hypersensitivity to Compound A or any component of rabeprazole; Participants with a history of immunosuppression or significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immune, skin, or neurological disease or the presence of any of the above diseases, including any acute illness or major surgery within the past 3 months that the investigator determines to be clinically significant; Participants with gastrointestinal, liver (including Gilbert's syndrome) syndrome), renal or other conditions known to interfere with drug absorption, distribution, metabolism, or excretion (s / p cholecystectomy was permitted); participants had a history of malignancy within 10 years of Day -1 (5 years for cervical cancer in situ and 2 years for surgically resected non-melanoma skin cancer); participants had a positive serological test at screening for infection with human immunodeficiency virus (HIV-1 and HIV-2), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV) antibodies; participants had a history of active, latent, or inadequately treated tuberculosis infection or a positive Quantiferon test at screening; participants tested positive for alcohol or drugs of abuse at screening or on Day -1. Participants who use prescription drugs within 28 days of Day -1 or receive vaccines within 14 days of Day -1, or use OTC drugs (including herbal preparations and supplements) within 14 days of Day -1 (up to 1.5g of acetaminophen is allowed per day); Participants use or plan to use systemic immunosuppressants (such as corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulatory drugs (such as IFN) during the study or within 3 months before the first study drug administration; Participants have a history or evidence of any other clinically significant condition, illness or disease that the investigator believes will pose a risk to the safety of the participant or interfere with the study assessment, procedures or completion; Participants have any condition or treatment that may interfere with the conduct of this study or that the investigator believes will put the participant's participation in the study at risk. This includes, but is not limited to, alcoholism, drug dependence or abuse, and psychiatric disorders; the participant currently uses any tobacco or nicotine-containing product exceeding 10 cigarettes or their equivalent per day; the participant has received study medication (or, is currently using an investigational device) within 30 days prior to screening, or for at least 5 times the respective elimination half-life (t1 / 2), whichever is longer; the participant is unable to comply with study restrictions / requirements, including consuming a high-calorie diet, e.g., is lactose intolerant, is allergic to eggs, is a vegetarian; the participant has donated 500 mL or more of blood in the past 60 days, or donated plasma in the last two weeks prior to the screening visit.

[0143] Dosing day: Dosing for regimens A, B, and D will be performed after an overnight fast of at least 10 hours. Water intake is allowed up to 1 hour before and 1 hour after dosing. Fasting restrictions continue for at least 4 hours after dosing (no food or drink except water). Compound A is administered with 240 mL of water at the end of a meal.

[0144] Fed conditions: A standardized high-calorie breakfast was administered after an overnight fast of at least 10 hours and should be ingested within approximately 30 minutes. Compound A was administered at the end of the meal with 240 mL of water.

[0145] Example 2: Study Description

[0146] A blinded, randomized, placebo-controlled, multiple-dose study was conducted to determine the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound A tablets administered to healthy participants over 14 days.

[0147] Primary objectives: To evaluate the safety and tolerability of Compound A tablets administered to healthy participants over 14 days; To evaluate the pharmacokinetics (PK) of Compound A tablets in healthy participants at steady state.

[0148] Study Design:

[0149] It is a single-center, self-controlled, double-blind and trial sponsor-unblinded, randomized, placebo-controlled, parallel-group, multiple-dose study conducted in up to 6 cohorts of healthy participants. Participants will enter the clinical research unit one day before the first dose (Day -1) of the investigational drug (IMP) and stay until 48 hours after the last dose of the 14-day IMP course. In the case of more than one dose per day, the last dose will be the first (morning) dose of the 14th day. The end of the study visit will be 5 to 7 days after the last dose of IMP. The number of participants will be approximately 48 healthy adult participants (up to 6 cohorts, 8 participants in each cohort, and a randomization ratio of 3:1 for Compound A to placebo). It is planned to recruit healthy male and female participants aged 18 to 60 years with a body mass index (BMI) between 18 and 32 kg / m 2 between.

[0150] The IMP will consist of 10 and 30 mg tablets of Compound A and their matching placebo. In the FIH study, single doses up to 100 mg of Compound A have been administered to healthy participants without clinically significant safety issues. max The mean was 949 ng / mL (maximum 1,160 n / mL), and the AUC0-inf was 11,286 ng*h / mL (maximum 13,705 ng*h / ml). Up to 40 mg q12h for 7 days has been studied in this study (steady state [C max,ss The average C maxis 433 ng / mL, steady-state [AUC 0-12,ss ] The average AUC from 0 to 12 hours was 3620 ng*h / mL) and was well tolerated. The doses for the first two cohorts will be 20 mg qd and 20 mg q12h, respectively. Other doses will depend on the relative bioavailability of the tablet to the suspension. Administration can occur qd or q12h, and the maximum dose to be studied will have a predicted average steady-state C of no more than 949 ng / mL and 11,286 ng*h / mL, respectively. max and AUC 0-24 Assuming bioequivalence between tablet and suspension, the maximum dose to be studied is 60 mg q12h or 80 mg qd. If the bioavailability of the tablet to the suspension is reduced by 50%, the maximum dose to be studied would be 120 mg q12h or 160 mg qd; these are the highest possible doses planned for this study.

[0151] During the study, the following safety variables will be recorded regularly: adverse events (AEs); clinical laboratory tests (hematology, clinical chemistry, and urinalysis); vital signs (systolic and diastolic blood pressure, temperature, pulse, and respiratory rate); 12-lead electrocardiogram (ECG) and continuous Holter ECG; and physical examination. The pharmacokinetic endpoints to be recorded will be: maximum observed concentration (C max ); C after the first and last dose max (T max ) time; AM trough concentrations on days 3, 5, 7, 9, 12, 13, and 14 (C trough ); from 0 to the last quantifiable concentration after the last dose (AUC 0-t The area under the concentration-time curve (AUC) during the dosing interval between the first and last doses 0-tau ); cumulative ratio (RAUC = AUC after the last dose 0-tau / AUC after first dose 0-tau ); Use C max (Rac[C max ]) calculated as the cumulative ratio; the terminal elimination half-life after the last dose (t 1 / 2 ); terminal elimination rate constant after the last dose (λ z ); total volumetric clearance at steady state after oral administration (CL / F); total volume of distribution at steady state (V ss / F); Ae 0-24 : Cumulative urinary excretion of the prototype drug in the complete 24-hour collection, calculated as: Compound A urine concentration * urine volume; %Fe: Percentage of prototype drug excreted in urine, calculated as: (Ae 0-24 / dose administered over 24 hours)*100; CLr: renal clearance of parent drug in plasma, calculated as: Ae of qd cohort 0-24 / AUC 0-24 and Ae of the q12h cohort 0-24 / 2*AUC 0-12 .

[0152] Example 3: Study Description

[0153] A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy and safety of Compound A in patients with moderate to severe plaque psoriasis.

[0154] Primary objective: To compare the Psoriasis Area and Severity Index (PASI-75) between Compound A and placebo after 12 weeks of treatment.

[0155] Primary endpoint: The proportion of patients with moderate to severe psoriasis who achieved a ≥75% reduction in PASI score between Compound A and placebo at week 12.

[0156] Secondary objectives: To evaluate the safety and tolerability of Compound A doses in patients with moderate to severe psoriasis. To characterize the pharmacokinetics (PK) of Compound A; To evaluate the response rate of static Physician's Global Assessment (sPGA) score after 12 weeks of treatment; To evaluate the response rate of PASI-50, 90 and 100 scores after 12 weeks of treatment; To compare the response rate of PASI-75 in Compound A treatment; To evaluate the effect on the body surface area (%BSA) involved in psoriasis after 12 weeks of treatment; To evaluate the changes in the Dermatology Life Quality Index (DLQI).

[0157] Secondary endpoints: incidence of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs); plasma concentrations and PK parameters of Compound A; proportion of patients achieving sPGA scores of "0" ("cleared") or "1" ("lowest") after 12 weeks of treatment compared with placebo; proportion of patients achieving PASI-50, 90, and 100 after 12 weeks of Compound A treatment compared with placebo; proportion of patients achieving PASI-75 at 12 weeks compared with Compound A treatment; change from baseline in %BSA after 12 weeks of Compound A treatment compared with placebo; change from baseline in DLQI at Week 12 in Compound A compared with placebo.

[0158] Exploratory objectives: To evaluate changes in the Numerical Rating Scale (NRS) for Itch after 12 weeks of treatment; To evaluate changes in EQ-5D; To evaluate changes in skin-based biomarkers related to psoriasis and TYK2 with Compound A; To evaluate changes in blood-based biomarkers related to psoriasis and TYK2 with Compound A; To evaluate changes in transcriptome- and proteome-based biomarkers in blood and skin with Compound A.

[0159] Exploratory endpoints: Change from baseline in NRS score after 12 weeks of treatment with Compound A compared with placebo; Change from baseline in EQ-5D at week 12 with Compound A compared with placebo; Change from baseline in psoriasis and TYK2-related skin biomarkers after Compound A treatment; Change from baseline in psoriasis and TYK2-related skin biomarkers that respond to Compound A treatment; Change from baseline in transcriptome and proteome expression that responds to Compound A treatment.

[0160] Study Design:

[0161] This is a randomized, double-blind, placebo-controlled study in patients with moderate to severe psoriasis. The purpose of this study is to evaluate the clinical efficacy, safety, PK and PD of compound A compared with placebo in patients with moderate to severe psoriasis. The entire study duration will be approximately 20 weeks. The screening period is 4 weeks, the treatment period is 12 weeks, and the safety follow-up period is 4 weeks. For the entire study, study completion is defined as the last visit to the last patient with any experimental plan-related activities (last patient, last visit). For individual patients, study completion is defined as the time of the patient's last data collection. Efficacy (including PASI, sPGA, QoL tests), safety and PK will be evaluated. Exploratory pharmacodynamic (PD) assessments include blood- and skin-based RNA, proteomes and other molecular markers. Continuous treatment will be provided in a separate open-label extension study.

[0162] The study population consists of male and female adult patients with moderate to severe psoriasis. Patients must meet all inclusion criteria and do not meet any exclusion criteria. Patients who meet all eligibility criteria will be randomly assigned to oral doses of Compound A or placebo in one of 5 doses (10mg QD, 20mg QD, 40mg QD, 20mg BID, 40mg BID) in a 1:1:1:1:1 manner. About 210 patients will be randomly assigned to one of 6 study groups (35 patients per group). Compound A is provided in tablets at two dosage strengths (10mg and 20mg). Matching placebo tablets are similar to Compound A 10mg and 20mg active drug tablets in size, shape and appearance. The Compound A doses used in each group of this study are summarized in Table 1. Patients will take designated blind Compound A or placebo.

[0163] Table 1

[0164]

[0165]

[0166] Inclusion criteria included patients diagnosed with plaque psoriasis for ≥6 months; plaques covering ≥10% body surface area (BSA); Psoriasis Area Severity Index (PASI) score ≥12 and static physician global assessment (sPGA) score ≥3.

[0167] Patients were excluded from the study if they had a diagnosis of non-plaque psoriasis (gutticular, inverse, pustular, erythrodermic, drug-induced) and / or other immune-mediated disorders commonly associated with psoriasis (e.g., uveitis, inflammatory bowel disease) or other inflammatory skin disorders that may interfere with study assessments; had a diagnosis of psoriatic arthritis, currently required systemic (oral, SC, IM or IV) immunosuppressant medications (including corticosteroids, immunosuppressants, biologics), or had or were expected to develop unstable disease in the opinion of the investigator.

[0168] Example 4: Study Description

[0169] A Phase 2, randomized, double-blind, placebo-controlled study was conducted to evaluate the safety, efficacy, and pharmacokinetics of multiple doses of Compound A in adult patients with systemic lupus erythematosus (SLE).

[0170] Primary objective: To compare the effects between doses of Compound A and placebo on disease activity measured by the proportion of patients achieving a British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) response at Week 32.

[0171] Primary endpoint: Composite endpoint (BICLA), defined by meeting all of the following criteria: reduction of all BILAG-2004A to B / C / D and reduction of baseline BILAG-2004B to C / D, with no worsening of BILAG-2004 in other organ systems, as defined by ≥1 novel BILAG-2004A or ≥2 novel BILAG-2004B; no worsening of SLE Disease Activity Index 2000 (SLEDAI-2K) from baseline, where worsening was defined as an increase of >0 from baseline in SLEDAI-2K points; no worsening from baseline in the patient's lupus disease activity as assessed by the physician, where worsening was defined as an increase of ≥0.30 points on the 3-point Physician Global Assessment (PGA) visual analog scale (VAS); no discontinuation of the investigational product (IP) or use of rescue medication exceeding the limit allowed by the experimental plan before the assessment; the estimate was the difference in the proportion of treatment success between the treatment conditions (dose of Compound A and placebo, regardless of discontinuation) in patients with moderate to severe SLE, where treatment success was defined as the response of BICLA at Week 32 without the use of additional or alternative medications.

[0172] Secondary objectives: To evaluate the safety and tolerability of multiple doses of Compound A; To compare the effects of Compound A and placebo on skin disease activity measured by the proportion of patients with a baseline cutaneous lupus erythematosus disease area and severity index (CLASI) activity score ≥8 who achieved a ≥50% reduction in CLASI activity score at week 32; To compare the effects of Compound A and placebo on disease activity measured by the proportion of patients achieving a BICLA response at week 32 in the interferon gene signature (IGS) high subgroup; To compare the effects of Compound A and placebo on disease activity measured by the proportion of patients achieving a SLE Responder Index ≥4 (SRI) at week 32. [4]) Effect on disease activity measured by the proportion of patients responding; Comparison of lupus low disease activity state (LLDAS) response at Week 32 between doses of Compound A and placebo; Comparison of steroid use among patients at Week 32; Comparison of effects on health-related quality of life (HRQOL) between doses of Compound A and placebo; Comparison of disease-specific QoL between doses of Compound A and placebo; Comparison of fatigue measured by FACIT-F between doses of Compound A and placebo; Comparison of Patient Global Assessment of Disease Activity (PtGA) between doses of Compound A and placebo.

[0173] Secondary endpoints: incidence of treatment-emergent AEs (TEAEs) and SAEs, vital signs, physical examination, 12-lead ECG, and clinical laboratory tests (hematology, clinical chemistry, urinalysis); 50% reduction in CLASI activity score from baseline, defined by the following criteria: baseline CLASI activity score ≥8 and CLASI activity score reduction ≥50% from baseline at week 32; no discontinuation of IP or use of rescue medication exceeding the protocol-allowed limit before assessment; BICLA response; composite endpoint SRI (4), defined by the following criteria: SLEDAI-2K reduction of ≥4 points from baseline and no novel BILAG A or more than 1 BILAG B domain score and no worsening of PGA from baseline ≥ 0.3; no discontinuation of IP or use of rescue medications exceeding the experimental plan allowed threshold before evaluation; LLDAS measured by achieving the following: SLEDAI-2K ≤ 4, no activity in major organ systems, and no hemolytic anemia or gastrointestinal activity, no new lupus disease activity compared to the previous SLEDAI-2K assessment, and PGA ≤ 1, and current prednisone (or equivalent) dose ≤ 7.5 mg daily; standard maintenance of immunosuppressive drugs and approved biologics good dose tolerance; proportion of patients achieving steroid dose ≤5 mg / day prednisone equivalents; difference between baseline (Day 1) and Week 32 in Short Form 36 Health Survey, 2nd Edition Acute (SF-36v.2 Acute) physical (PCS) and / or mental (MCS) health summary score; difference between baseline (Day 1) and Week 32 in lupus QoL; difference between baseline (Day 1) and Week 32 in FACIT-F; difference between baseline (Day 1) and Week 32 in PtGA.

[0174] Secondary analysis objectives at Week 48: Compare BICLA response between doses of Compound A and placebo at Week 48; compare the effect between doses of Compound A and placebo on dermatitis activity measured by the proportion of patients with a baseline CLASI activity score ≥8 who achieved a 50% reduction in CLASI activity score at Week 48; compare the effect between doses of Compound A and placebo in the IGS high subgroup on disease activity measured by the proportion of patients achieving a BICLA response at Week 48; compare SRI(4) response between doses of Compound A and placebo after 48 weeks of treatment; compare LLDAS response between doses of Compound A and placebo at Week 48; compare annualized flare rate as of Week 48; compare glucocorticoid use in patients at Week 48; compare the effect between doses of Compound A and placebo on HRQOL; compare disease-specific QoL between doses of Compound A and placebo; compare fatigue measured by FACIT-F between doses of Compound A and placebo; compare Patient Global Assessment of Disease Activity (PtGA) between doses of Compound A and placebo.

[0175] Secondary analysis endpoints at Week 48 were: BICLA response at Week 48; CLASI at Week 48; SRI(4) at Week 48; LLDAS at Week 48; annualized flare rate, with a flare defined as ≥1 BILAG A or ≥2 BILAG B scores due to an item rated as new or worsening; proportion of patients reaching a glucocorticoid dose of ≤5 mg / day prednisone equivalents; difference between baseline (Day 1) and Week 48 in SF-36v.2 acute PCS and / or MCS scores; difference between baseline (Day 1) and Week 48 in lupus QoL; difference between baseline (Day 1) and Week 48 in FACIT-F; difference between baseline (Day 1) and Week 48 in PtGA.

[0176] Exploratory objectives: Duration of sustained BICLA response; Compare the proportion of patients with SRI(4) at Week 32 and Week 48 in the IFN high test subgroup; Characterize the PK of multiple doses of Compound A; Assess the change from baseline in 28 joint count differences between Compound A and placebo; Assess the differences between Compound A and placebo in measures of disease activity (including SRI response level, individual components of SRI, and number of swollen and tender joints up to Week 32 and Week 48, and changes in SRI and BICLA over time); Assess the change from baseline in mean and median interferon-regulated gene (IRG) expression between doses of Compound A and placebo up to 48 weeks; Assess changes in transcriptome- and proteome-based biomarkers in the blood with Compound A treatment; Assess the change from baseline in mean complement (C3, C4) and anti-double-stranded DNA (dsDNA) antibodies up to 48 weeks.

[0177] Exploratory endpoints: visit defined as first BICLA response up to and including Week 48; SRI(4) response; plasma PK parameters of Compound A up to Week 32 and Week 48; proportion of patients with at least 6 swollen or tender joint counts at baseline who achieved 50% reduction at Week 32 and Week 48; SRI(4), SRI(5), SRI(6), SRI(7), SRI(8), BICLA response over time, BILAG-2004 score, SLEDAI-2K, PGA, and joint counts; change in mean and median IRG expression up to Week 48; change from baseline in transcriptome and proteome expression in response to Compound A treatment; proportion of patients with abnormal C3 or C4 or anti-dsDNA at baseline who had normal C3 or C4 or anti-dsDNA antibodies at Week 32 or Week 48; evaluation of the effect of Compound A on overall SLE clinical response measures in patients up to Week 48 according to IRG status (i.e., high vs. low IRG signature).

[0178] Study Design:

[0179] It is a Phase 2, randomized, double-blind, placebo-controlled study to evaluate the safety, efficacy, PK, and pharmacodynamics (PD) of 3 doses of Compound A (20 mg once daily [QD], 40 mg [taken as 20 mg twice daily (BID)], and 60 mg [taken as 30 mg twice daily (BID)] in patients with moderately to severely active autoantibody-positive SLE, while receiving standard of care (SOC) treatment in adult patients aged 18 to 70 years. Randomization will be stratified using SLEDAI-2K score at screening (<10 points vs. ≥10 points), steroid dose on Day 1 (<10 mg prednisone equivalents vs. ≥10 mg), and IGS score (high vs. low).

[0180] This study includes a protocol-defined steroid taper. All patients will have a steroid taper attempted. The goal is a steroid dose of ≤5 mg / day prednisone equivalents by Week 24. Tapering will begin at Week 8 (or earlier) and continue until goal is achieved. Tapering will not be allowed between Weeks 24 and 32 but may be resumed after the Week 32 visit up to Week 40 at the investigator's discretion. Tapering will not be allowed between the Week 40 and Week 48 visits.

[0181] Efficacy assessments include SLEDAI-2K, BILAG-2004, PGA VAS, CLASI, tender and swollen joint counts. Patient-reported outcome (PRO) measures include SF-36v.2 acute, lupus QoL, Functional Assessment of Chronic Condition Therapy (FACIT)-Fatigue Questionnaire, and Patient Global Assessment (PtGA). Safety assessments include AE ​​monitoring, clinical laboratory tests, vital signs, ECG, and physical examination. The observed concentration-time data will be used primarily for modeling and simulation purposes. PK parameters include mean maximum observed concentration (C max ) and reach C max Time (T max ); the regional trough observed plasma concentration of compound A (C trough ). Exploratory PD and biomarker assessments include blood-based transcriptome, proteome, and other TYK2-related and disease-related markers.

[0182] Patients who meet all eligibility criteria will be randomized in a 1:1:1:1 ratio to receive an oral dose of Compound A at 1 of 3 doses or placebo as described in Table 2.

[0183] Table 2.

[0184]

[0185]

[0186] The total duration of study participation for each patient will be approximately 57 weeks. The study includes an approximately 35-day screening period, followed by a 48-week double-blind treatment period, followed by a 4-week safety follow-up period or an open-label extension (OLE) study for eligible patients who choose to receive continued long-term treatment in the OLE study. Approximately 388 patients will be randomly assigned to 1 of 4 study groups (3 Compound A active + 1 placebo).

[0187] Participants who meet the following criteria will be considered eligible for clinical research: able and willing to provide written informed consent (signed and dated) to participate in this study and comply with all requirements of the study protocol; male or female aged 18 to 70 years (inclusive) at the time of informed consent; body mass index 18 to 40 kg / m 2, and total body weight >40kg (88lbs); adequate peripheral venous access; diagnosed with SLE ≥6 months prior to screening and meeting the 2019 European League Against Rheumatism (EULAR) / American College of Rheumatology (ACR) criteria at screening, and positive antinuclear antibody test with a titer of ≥1:80 when screened by immunofluorescence analysis in a central laboratory, or elevated anti-dsDNA antibodies or anti-Smith antibodies or C3 or C4 below the lower limit of normal when measured by a central laboratory at screening; SLEDAI score at screening >6 and clinical SLEDAI-2K score during the screening period and before the first administration of study drug ≥4 points (“Clinical” SLEDAI-2K is the SLEDAI-2K assessment score, excluding scores attributable to any urine or laboratory results, including immunological measurements (including scores for the following clinical components: arthritis, myositis, rash, alopecia, mucosal ulcers, pleurisy, pericarditis, and vasculitis, excluding scores due to fever, SLE headache, and organic brain syndrome)); at least one of the following: BILAG-2004 Index Class A disease in at least 1 body / organ system and / or BILAG-2004 Index Class B disease in more than 1 body / organ system (excluding lupus headache score); screening PGA score > 1.0 on 0 to 3 VAS during the examination; clinical SLEDAI-2K score of skin involvement ≥ 4 points before the first administration of study drug; currently receiving at least 1 of the following: oral corticosteroids (≤ 40 mg / day prednisone or equivalent) at a dose of at least 2 weeks before signing the informed consent form (ICF) and / or any of the following drugs for at least 12 weeks before signing the ICF and at a stable dose for at least 8 weeks before signing the ICF until Day 1: azathioprine ≤ 200 mg / day, antimalarials (e.g., chloroquine, hydroxychloroquine, quinacrine), mycophenolate mofetil ≤ 2 g / day or mycophenolic acid ≤ 1.44 g / day, oral, skin The patients were required to receive methotrexate ≤20 mg / week by intramuscular or intramuscular (IM) injection (no more than 1 concurrent immunosuppressant therapy was allowed, and if corticosteroids were the only medication for SLE activity, the dose must have been ≥10 mg and ≤40 mg prednisone equivalents for at least 8 weeks before screening, and stable at ≥10 mg and ≤40 mg for at least 2 weeks before screening 2 weeks ago); negative serum β-human chorionic gonadotropin (β-hCG) test at screening (only women of childbearing potential [WOCBP]); "clinical" SLEDAI-2K score ≥4 on the first day before randomization, and stable OC dose for at least 2 weeks.

[0188] Participants who meet the following general exclusion criteria will be considered ineligible for clinical research: any acute or chronic illness / condition or evidence of unstable clinical conditions that, in the investigator's judgment, would substantially increase the patient's risk if the male or female patient were to participate in the study; presence or history (within 1 year) of a psychiatric disorder that, in the investigator's opinion, is likely to interfere with the patient's ability to provide informed consent, comply with study procedures, or place the patient at increased risk for participation in this study; current alcohol or drug abuse (excluding marijuana) or history within 1 year of screening, in the investigator's clinical judgment; pregnancy, breastfeeding, or planning to become pregnant during the study and within 3 months after completion or discontinuation of the study; patients with a QTcF >450 ms (males) or >470 ms (females) at screening; unstable cardiovascular disease, defined as recent clinical worsening (e.g., unstable angina, rapid atrial fibrillation) or cardiac hospitalization within the last 3 months; any of the following laboratory abnormalities at screening: absolute neutrophil count

[0189] <1×10 9 / L, hemoglobin <8 g / dL, platelet count <25,000 / uL, aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≥2× upper limit of normal (ULN) unless due to lupus hepatitis, total bilirubin ≥2× ULN (unless the patient has Gerbel syndrome), estimated glomerular filtration rate (eGFR calculated by the Modification of Diet in Renal Disease [MDRD] formula) <30 indicating moderate or severe renal impairment, and / or UPCR >3.5 g / day.

[0190] Participants who meet the following exclusion criteria related to SLE and other diseases will be considered ineligible for clinical studies: drug-induced SLE or other autoimmune diseases that the investigator believes are likely to confound the evaluation of efficacy; active proliferative lupus nephritis that the investigator believes may require treatment not permitted by the experimental plan; current diseases other than SLE that the investigator believes are likely to interfere with the evaluation of SLE disease activity (examples include severe fibromyalgia, severe osteoarthritis, other serious cardiopulmonary diseases); active severe or unstable neuropsychiatric SLE, including but not limited to the following: aseptic meningitis; cerebral vasculitis; myelopathy; demyelinating syndromes (ascending, transverse, acute inflammatory demyelinating polyneuropathy); acute confusional state; impaired level of consciousness; psychosis; acute stroke or stroke syndrome; cranial neuropathy ; new seizures; cerebellar ataxia; and mononeuritis multiplex that would prevent the patient from fully understanding the ICF or in which the principal investigator believes that the protocol-specified SOC is inadequate and that a more aggressive approach to treatment is indicated (e.g., the addition of intravenous (IV) cyclophosphamide and / or high-dose IV pulse corticosteroids or other treatment not permitted in the protocol); history or current diagnosis of malignant antiphospholipid syndrome within 12 months prior to signing the ICF (antiphospholipid syndrome adequately controlled with anticoagulation for at least 3 months is acceptable, and positive antiphospholipid antibodies without clinical symptoms are not exclusionary); history of any recurrent non-SLE illness requiring treatment with oral or parenteral corticosteroids for a total of more than 2 weeks within 52 weeks prior to signing the ICF (steroid treatment of conditions not expected to relapse (e.g., poison ivy) is not excluded).

[0191] Participants who meet the following exclusion criteria related to concomitant medications will be considered ineligible for clinical studies: received any investigational product (small molecule or biologic) within 3 months or 5 half-lives (whichever is longer) prior to signing the ICF or are currently participating in an investigational study; received any commercially available biologic within 5 half-lives prior to signing the ICF; received B-cell knockout therapy (including but not limited to obinutuzumab, ocrelizumab, or rituximab) <6 months prior to signing the ICF, or, if treated >6 months prior to signing the ICF, had an absolute B-cell count less than 100% of that received by the patient. The lower limit of normal or baseline value before B-cell knockout therapy (whichever is lower); receiving any therapeutic agent targeting IL-12, IL-17 or IL-23 within 6 months before signing the ICF or any tumor necrosis factor α inhibitor within 12 weeks; receiving JAK inhibitors (such as baricitinib, tofacitinib) or TYK2 inhibitors within 12 weeks before signing the ICF; currently receiving PPIs such as omeprazole or esomeprazole (substitution of histamine 2 receptor blockers or oral antacids before study day 1 is acceptable);Receiving any of the following: intra-articular, IM or IV glucocorticoids within 6 weeks prior to Day 1, any live or attenuated vaccine within 4 weeks prior to signing ICF (killed vaccines are acceptable), blood transfusion within 4 weeks prior to signing ICF, and / or any of the following restricted medications (if washout period has not been reached): abatacept (12 weeks), adalimumab (12 weeks), anakinra (4 weeks), anifrolumab (12 weeks), belimumab (12 weeks), BTK inhibitors (12 weeks), certolizumab pegol (12 weeks), cyclophosphamide (IV or oral, 24 weeks), cyclosporine (oral, 8 weeks), danazol (4 weeks), dapsone (4 weeks), eculizumab (8 weeks), etanercept (12 weeks), golimumab (12 weeks), infliximab (12 weeks), IV immune globulin (8 weeks), JAK inhibitors (12 weeks), leflunomide (36 weeks or 2 weeks after cholinesterase washout), lenalidomide (8 weeks), natalizumab (8 weeks), lizumab (12 weeks), ocrelizumab (48 weeks), pimecrolimus (4 weeks), plasmapheresis (8 weeks), retinoids (4 weeks), rituximab (48 weeks), ruxolitinib (4 weeks), B-cell knockout agents (48 weeks), sulfasalazine (4 weeks), sirolimus (4 weeks), tacrolimus (12 weeks), thalidomide (8 weeks), tocilizumab (12 weeks), investigational agents (30 days, 5 half-lives).

[0192] Participants who met the following exclusion criteria related to infections and other factors were considered ineligible for clinical study participation: history or evidence of suicidal ideation within the past 6 months (severity level 4 [activity: approach and intent, but no plan] or 5 [activity: approach, intent, and plan]); or any suicidal behavior within the past 12 months as assessed at screening based on the Columbia-Suicide Severity Rating Scale (C-SSRS); known history of primary immunodeficiency or underlying conditions (such as HIV infection or splenectomy) that predispose the patient; confirmed positive hepatitis B serology tests as detected by reflex testing at screening: hepatitis B surface antigen, or hepatitis B core antibody (HBcAb) and hepatitis B virus (HBV) DNA (>169 copies / mL [29 IU / mL]); positive hepatitis C antibody test; any serious herpes infection at any time prior to Week 0 (Day 1), including but not limited to disseminated herpes (ever ), herpetic encephalitis (ever), recurrent herpes zoster (defined as 2 episodes within 2 years), or ocular herpes (ever); active herpes zoster infection within 12 weeks prior to signing the ICF; active herpes simplex virus within 4 weeks of Day 1; known current malignancy or history of malignancy within 5 years prior to current evaluation or screening for potential malignancy, except for squamous or basal cell carcinoma of the skin treated with documented curative treatment > 3 months prior to Week 0 (Day 1) and / or in situ cervical carcinoma treated with documented curative treatment > 1 year prior to Week 0 (Day 1); any of the following: currently active clinically significant infection of any type, clinically significant chronic infection (e.g., osteomyelitis, bronchiectasis) within 8 weeks prior to signing the ICF (chronic nail infection allowed), any infection requiring hospitalization or IV anti-infective treatment that was not completed at least 4 weeks prior to signing the ICF, and / or any infection requiring oral anti-infectives (including antivirals) within 2 weeks prior to Day 1.

[0193] Incorporate by reference

[0194] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual publication or patent was individually and individually incorporated by reference. In the event of a conflict, the present application, including any definitions herein, will control.

[0195] Equivalents and scope

[0196] Unless otherwise specified or obvious from the context, in the claim scope, articles such as "a", "an", "the" may mean one or more than one. Unless otherwise specified or obvious from the context, if one, more than one, or all of the group members are present, used in, or otherwise related to a given product or process, a claim scope or description including "or" between one or more members of the group is deemed to be satisfied. The present disclosure includes embodiments in which exactly one member of the group is present, used in, or otherwise related to a given product or process. The present disclosure includes embodiments in which more than one or all of the group members are present, used in, or otherwise related to a given product or process.

[0197] In addition, the present disclosure encompasses all variations, combinations and permutations in which one or more limitations, elements, clauses and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim attached to another claim may be modified to include one or more limitations found in any other claim attached to the same base claim. If the elements are presented in a list form, for example, in a Markush group format, each subgroup of the elements is also disclosed, and any element may be removed from the group. It should be understood that, in general, if the present disclosure or the aspects of the present disclosure are referred to as including specific elements and / or features, certain embodiments of the present disclosure or the aspects of the present disclosure are composed of or substantially composed of such elements and / or features. For simplicity, these embodiments are not specifically described verbatim here. It is also worth noting that the terms "include" and "contain" are meant to be open and allow the inclusion of additional elements or steps. When a range is given, the endpoint is included. Furthermore, unless otherwise indicated or apparent from the context and understanding of the skilled artisan, values ​​expressed as ranges may assume any particular value or sub-range within the specified range in the various embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0198] This application is related to various issued patents, published patent applications, journal articles, and other disclosures, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and this specification, the present specification shall prevail. In addition, any specific embodiment of the present disclosure that is a prior art may be expressly excluded from any one or more of the claims. Because such embodiments are considered to be known to those of ordinary skill, they may be excluded even if the exclusion is not expressly provided herein. Any specific embodiment of the present disclosure may be excluded from any claim scope for any reason, whether or not related to the existence of prior art.

[0199] Those skilled in the art will appreciate or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the foregoing description, but rather to that described in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications may be made to this description without departing from the spirit or scope of the present disclosure as defined in the following claims.

Claims

1. A method for treating a TYK2-mediated disease or condition in a patient in need thereof, the method comprising orally administering to the patient once or twice daily 30 mg, 40 mg, 60 mg or 80 mg of a compound represented by the formula:

2. The method of claim 1, further comprising orally administering a proton pump inhibitor to the patient.

3. The method of claim 1 or 2, wherein the proton pump inhibitor is selected from the group consisting of rabeprazole, omeprazole, esomeprazole, lansoprazole, pantoprazole and dexlansoprazole.

4. The method of any one of claims 1 to 3, wherein the proton pump inhibitor is rabeprazole.

5. The method of any one of claims 1 to 4, wherein the compound is administered to the patient in a fasting state.

6. The method of any one of claims 1 to 4, further comprising giving the patient food before or while administering the compound.

7. The method of any one of claims 1 to 6, wherein the TYK2-mediated disease or disorder is selected from the group consisting of Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis and systemic sclerosis.

8. A method of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising: The patient is administered two oral tablet compositions once daily, each composition comprising: 30 mg of the compound represented by the following formula: and Pharmaceutically acceptable excipients; administering rabeprazole orally to the patient as needed; and The patient is given food as needed following administration of the compound.

9. A method of treating one or more of the following in a patient in need thereof: Crohn's disease, rheumatoid arthritis, psoriasis, systemic lupus erythematosus, ulcerative colitis, psoriatic arthritis, and systemic sclerosis, the method comprising: The patient is orally administered 10 mg, 20 mg, 30 mg, 60 mg or 80 mg of a compound represented by the following formula once a day or twice a day: The patient is in a fasting state or a fed state.

10. A fixed unit dose pharmaceutical composition for oral administration comprising: 10 mg, 20 mg, 30 mg, 40 mg, 60 mg or 80 mg of a compound represented by the following formula: and Pharmaceutically acceptable excipients.

11. The pharmaceutical composition of claim 10, wherein the composition is formulated into a tablet.

12. An oral tablet composition comprising: About 30 mg of the compound represented by the following formula: and Pharmaceutically acceptable excipients.

13. A method of treating a TYK2-mediated disease or condition in a patient in need thereof, the method comprising administering to the patient an effective amount of the oral tablet composition of claim 12.

14. The method of claim 13, wherein the administration is a once-daily administration.

15. A method of treating a TYK2-mediated disease or condition in a patient in need thereof, the method comprising orally administering to the patient once or twice daily 10 mg, 20 mg, 30 mg, 40 mg, 80 mg, 100 mg, 120 mg or 160 mg of a compound represented by the formula:

16. A method of treating moderate to severe psoriasis in a patient in need thereof, the method comprising orally administering to the patient once or twice daily 10 mg, 20 mg, 30 mg, 40 mg, 80 mg or more of a compound represented by the formula: The patient has significant clinical improvement as characterized by Area and Severity Index (PASI-75) score compared to baseline after at least 12 weeks of administration.

17. A method of treating moderate to severe psoriasis in a patient in need thereof, the method comprising orally administering to the patient once or twice daily 10 mg, 20 mg, 30 mg, 40 mg, 80 mg or more of a compound represented by the formula: wherein the patient has a significant clinical improvement as characterized by the % of body surface area affected by psoriasis after at least 12 weeks of administration.

18. The method of claim 16 or 17, wherein the patient suffers from at least one of the following prior to administration: diagnosis of plaque psoriasis for ≥6 months; plaque coverage of ≥10% body surface area (BSA); psoriasis area severity index score (PASI) score ≥12 and / or static Physician's Global Assessment (sPGA) score ≥3.

19. The method of any one of claims 16 to 18, wherein 10 mg, 20 mg, 40 mg of the compound is administered once or twice daily.

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