TYK2 inhibitor for treating neuroinflammatory or neurodegenerative diseases

Abstract

Described herein are methods and compositions, for example a fixed dose oral composition, for treating a TYK2-mediated neuroinflammatory disease or disorder, and / or a TYK2-mediated neurodegenerative disease or disorder. In some embodiments, the TYK2- mediated disorder neuroinflammatory disease is, for example, multiple sclerosis.

Description

Attorney Docket No. ESK-033WOTYK2 INHIBITORS AND USES THEREOFCROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of, and priority to, U.S. Provisional Patent Application No. 63 / 734,531 filed on December 16, 2024; U.S. Provisional Patent Application No. 63 / 735,840 filed on December 18, 2024; and U.S. Provisional Patent Application No. 63 / 783,399 filed on April 4, 2025; the content of each of which is hereby incorporated by reference herein in its entirety.BACKGROUND

[0002] TYK2 is a non-receptor tyrosine kinase member of the Janus kinase (JAKs) family of protein kinases. The mammalian JAK family consists of four members, TYK2, JAK1, JAK2, and JAK3. JAK proteins, including TYK2, are integral to cytokine signaling. TYK2 associates with the cytoplasmic domain of type I and type II cytokine receptors, as well as interferon types I and III receptors, and is activated by those receptors upon cytokine binding. Cytokines implicated in TYK2 activation include interferons (e.g., IFN-a, IFN- , IFN-K, IFN-6, IFN-e, IFN-T, IFN-OJ. and IFN- (also known as limitin), 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). The activated TYK2 then goes on to phosphorylate further signaling proteins such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0003] TYK2 activation by IL-23, has been linked to inflammatory bowel disease (IBD), Crohn's disease, and ulcerative colitis. A genome -wide association study of 2,622 individuals with psoriasis identified associations between disease susceptibility and TYK2. Knockout or tyrphostin inhibition of TYK2 significantly reduces both IL-23 and IL-22- induced dermatitis.

[0004] 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 mucous hypersecretion is mediated by IL-13-induced activation of TYK2, which in turn activates STAT6.

[0005] Decreased TYK2 activity leads to protection of joints from collagen antibody -induced arthritis, a model of human rheumatoid arthritis. Mechanistically, decreasedIPTS / 128801445.1 1Attorney Docket No. ESK-033WOTYK2 activity reduced the production of Thl / Thl7-related cytokines and matrix metalloproteases, and other key markers of inflammation.

[0006] TYK2 knockout mice showed complete resistance in experimental autoimmune encephalomyelitis (EAE, an animal model of multiple sclerosis (MS)), with no infiltration of CD4 T cells in the spinal cord, as compared to controls, suggesting that TYK2 is essential to pathogenic CD4-mediated disease development in MS. This corroborates earlier studies linking increased TYK2 expression with MS susceptibility. Loss of function mutation in TYK2 leads to decreased demyelination and increased remyelination of neurons, further suggesting a role for TYK2 inhibitors in the treatment of MS and other CNS demyelination disorders.

[0007] TYK2 is the sole signaling messenger common to both IL- 12 and IL-23.TYK2 knockout reduced methylated BSA injection-induced footpad thickness, imiquimod- induced psoriasis-like skin inflammation, and dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid-induced colitis in mice.

[0008] Joint linkage and association studies of various type 1 1FN signaling genes with systemic lupus erythematosus (SLE, an autoimmune disorder), showed a strong, and significant correlation between loss of function mutations to TYK2 and decreased prevalence of SLE in families with affected members. Genome-wide association studies of individuals with SLE versus an unaffected cohort showed highly significant correlation between the TYK2 locus and SLE.

[0009] TYK2 has been shown to play an important role in maintaining tumor surveillance and TYK2 knockout mice showed compromised cytotoxic T cell response, and accelerated tumor development. However, these effects were linked to the efficient suppression of natural killer (NK) and cytotoxic T lymphocytes, suggesting that TYK2 inhibitors would be highly suitable for the treatment of 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 of its involvement in fewer and more closely related signaling pathways, leading to fewer off-target effects.

[0010] Studies in T-cell acute lymphoblastic leukemia (T-ALL) indicate that T-ALL is highly dependent on IL-10 via TYK2 via STAT1 -mediated signal transduction to maintain cancer cell survival through upregulation of anti-apoptotic protein BCL2. Knockdown of TYK2, but not other JAK family members, reduced cell growth. Specific activating mutations to TYK2 that promote cancer cell survival include those to the FERM domainIPTS / 128801445.1 2Attorney Docket No. ESK-033WO(G36D, S47N, and R425H), the JH2 domain (V73 II), and the kinase domain (E957D and R1027H). However, it was also identified that the kinase function of TYK2 is required for increased cancer cell survival, as TYK2 enzymes featuring kinase-dead mutations (M978Y or M978F) in addition to an activating mutation (E957D) resulted in failure to transform.

[0011] Thus, selective inhibition of TYK2 has been suggested as a suitable 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 also been shown to mediate neuronal cell death caused by amyloid-P (A0) peptide. Decreased TYK2 phosphorylation of STAT3 following Ap administration led to decreased neuronal cell death, and increased phosphorylation of STAT3 has been observed in postmortem brains of Alzheimer's patients. Inhibition of JAK- STAT signaling pathways is also implicated in hair growth, and the reversal of the hair loss associated with alopecia areata.

[0012] Accordingly, there is a need to provide methods for inhibiting the activity ofTYK2 to treat one or more of the conditions described herein, without the side-effects associated with the inhibition of JAK2.SUMMARY

[0013] Described herein, in part, are methods and compositions that are useful in treating a TYK2 -mediated disorder. For example, disclosed herein is a method of treating a neuroinflammatory disease or a neurodegenerative disease in a patient in need thereof, comprising orally administering to the patient, once or twice daily, about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof.

[0014] Also disclosed herein is a method of treating a neuroinflammatory disease or a neurodegenerative disease in a patient in need thereof, comprising orally administering to the patient, once or twice daily, an oral composition comprising:IPTS / 128801445.1 3Attorney Docket No. ESK-033WO about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0015] Further disclosed herein, for example, is a method of treating multiple sclerosis in a patient in need thereof, comprising orally administering to patient, once or twice daily, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof.

[0016] In addition, disclosed here a is fixed unit dose pharmaceutical composition for oral administration comprising: about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:IPTS / 128801445 1 4Attorney Docket No. ESK-033WOor pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0017] For example, disclosed herein is an oral tablet composition comprising: about 5 mg, about 10 mg, about 20 mg, about 60 mg, or about 120 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0018] Also disclosed herein is a method for delivering a TK2 inhibitor to the brain tissue of a patient in need thereof, comprising orally administering to the patient an effective amount of a compound represented by:or pharmaceutically acceptable salt thereof.IPTS / 128801445 1 5Attorney Docket No. ESK-033WOBRIEF DESCRIPTION OF THE DRAWINGS

[0019] FIG. 1 depicts mean concentrations of Compound A in plasma (ng / mL) at various timepoints in healthy participants administered 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 120 mg, 240 mg, or 360 mg of Compound A.

[0020] FIG. 2 depicts total drug concentrations of Compound A in plasma (ng / mL) and free drug concentrations in plasma and cerebrospinal fluid (ng / mL) at various timepoints in healthy participants administered 120 mg of Compound A.

[0021] FIG. 3 depicts multiple ascending dose PK profiles (mean concentrations ofCompound A in plasma (ng / mL)) at 0 hours to 24 hours (Day 1) in healthy participants administered 10 mg QD, 30 mg QD, 60 mg QD, or 120 mg QD of Compound A.

[0022] FIG. 4 depicts multiple ascending dose PK profiles (mean concentrations of Compound A in plasma (ng / mL)) at 0 hours to 400 hours in healthy participants administered 10 mg QD, 30 mg QD, 60 mg QD, 120 mg QD, or 120 mg BID of Compound A.

[0023] FIG. 5 depicts multiple ascending dose PK profiles (mean concentrations ofCompound A in plasma (ng / mL)) at 312 hours to 336 hours (Day 14) in healthy participants administered 10 mg QD, 30 mg QD, 60 mg QD, or 120 mg QD of Compound A.

[0024] FIG. 6 depicts % pSTAT3 inhibition vs. concentration of Compound A (pM, log scale) in single ascending dose cohorts.

[0025] FIG. 7 depicts % pSTAT3 inhibition vs. concentration of Compound A (pM, log scale) in single ascending dose and multiple ascending dose cohorts.

[0026] FIG. 8 depicts inhibition of a Type I IFN gene signature in individuals administered Compound A at a dosing regimen of 10 mg once daily, 30 mg once daily, 60 mg once daily, 120 once daily, or 120 mg twice daily.

[0027] FIG. 9 depicts inhibition of SIGLEC1 expression in individuals administeredCompound A at a dosing regimen of 10 mg once daily, 30 mg once daily, 60 mg once daily, 120 once daily, or 120 mg twice daily.

[0028] FIG. 10 depicts mean clinical score of EAE pathology vs duration of treatment with Compound A in mouse model studies.DETAILED DESCRIPTION

[0029] The features and other details of the disclosure will now be more particularly described. Before further description of the present disclosure, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in theIPTS / 128801445 1 6Attorney Docket No. ESK-033WO art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.Definitions

[0030] 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.

[0031] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. For example, the term “about” when referring to a number or a numerical range means that the number or numerical range referred to will vary between 10% of the stated number or numerical range.

[0032] The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of” the described features.

[0033] The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect. In this respect, the disclosed methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal. For example, a disorder, including symptoms or conditions thereof, may be reduced by, for example, about 100%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10%. Furthermore, the treatment, prevention, amelioration, or inhibition provided by the methods disclosed herein can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer or an inflammatory disease. Also, for purposes herein, “treatment,” “prevention,” “amelioration,” or “inhibition” encompass delaying the onset of the disorder, or a symptom or condition thereof.IPTS / 128801445.1 7Attorney Docket No. ESK-033WO

[0034] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of a compound or composition (e.g., an oral tablet composition) disclosed herein being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated, e.g., a neuroinflammatory disease or a neurodegenerative disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound disclosed herein required to provide a clinically significant decrease in disease symptoms. In some embodiments, an appropriate “effective” amount in any individual case is determined using techniques, such as a dose escalation study.

[0035] As used herein, the term “TYK2-mediated” disorders, diseases, and / or conditions as used herein means any disease or other deleterious condition in which TYK2 or a mutant thereof is known to play a role. Accordingly, another embodiment relates 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 (e.g., neuroinflammatory diseases and disorders), neurodegenerative diseases or disorders, proliferative disorders, endocrine disorders, neurological disorders and disorders associated with transplantation.Methods and Compositions

[0036] Disclosed herein, is a method of treating a TYK2-mediated disease or disorder in a patient in need thereof, comprising orally administering to the patient, once or twice daily, about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof. For example, contemplated methods may include orally administering to a patient in need thereof a salt of the compound, in an amountIPTS / 128801445.1 8Attorney Docket No. ESK-033WO to deliver to the patient about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of the compound in free base form.

[0037] For example, disclosed herein is a method of treating a neuroinflammatory disease or a neurodegenerative disease in a patient in need thereof, comprising orally administering to the patient, once or twice daily, about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof.

[0038] Also disclosed herein is a method of treating a neuroinflammatory disease or a neurodegenerative disease in a patient in need thereof, comprising orally administering to the patient, once or twice daily, an oral composition comprising: about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof: and a pharmaceutically acceptable excipient.

[0039] In some embodiments, administering comprises, for example, once daily administering. In other embodiments, administering comprises, for example, twice daily administering. In still other embodiments, a contemplated method of the present disclosure comprises administering, for example, about 10 mg, about 15 mg, about 30 mg, about 60 mg,IPTS / 128801445.1 9Attorney Docket No. ESK-033WO about 120 mg, or about 240 mg of the compound. In further embodiments, the compound is administered to the patient in a fasted state. In certain embodiments, the methods described herein further comprise administering food to the patient before administration or upon administration of the compound.

[0040] In some embodiments, the TYK2-mediated disease or disorder is selected from the group consisting of, for example, multiple sclerosis, neuromyelitis optica (NMO), anti-myelin oligodendrocyte glycoprotein antibody disease (MOG), autoimmune encephalitis, transverse myelitis, optic neuritis, neurosarcoidosis, chronic meningitis, amyotrophic lateral sclerosis, neuroinflammation associated with traumatic brain injury, Lewy body dementia, Alzheimer's disease, and Parkinson’s disease. For example, in some embodiments a contemplated method comprises treating a patient suffering the TYK2-mediated disease or disorder, where the TYK2-mediated disorder is multiple sclerosis, comprising administering 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound to the patient once or twice daily.

[0041] In further embodiments, after administering, for example, about 120 mg of the compound to the patient, the ratio of cmaxof free drug in the cerebrospinal fluid to cmaxof free drug in the plasma of the patient is about 1.4 to about 1.0. In other embodiments, after administering for example, about 120 mg of the compound to the patient, the Cmax of free drug in the cerebrospinal fluid of the patient is from about 32 ng / mL to about 36 ng / mL. In still other embodiments, after administering, for example, about 120 mg of the compound to the patient, the cmax of free drug in the plasma of the patient is about from 27 ng / mL to about 31 ng / mL.

[0042] Also disclosed herein is a method of treating multiple sclerosis in a patient in need thereof, comprising orally administering to patient, once or twice daily, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof.IPTS / 128801445.1 10Attorney Docket No. ESK-033WO

[0043] Further disclosed herein is a method of treating multiple sclerosis in a patient in need thereof, comprising orally administering to patient, once or twice daily, an oral composition comprising: about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0044] In addition, disclosed herein is a fixed unit dose pharmaceutical composition for oral administration comprising: about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0045] In some embodiments, a contemplated fixed unit dose pharmaceutical composition for oral administration is formulated, for example as a fixed unit dose oral tablet composition, for example, a tablet.

[0046] For example, disclosed herein is an oral tablet composition comprising: about 5 mg, about 10 mg, about 20 mg, about 60 mg, or about 120 mg of a compound represented by:IPTS / 128801445.1 11Attorney Docket No. ESK-033WOor pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

[0047] Methods of treating a TYK2 -mediated disease or disorder contemplated herein, e.g., a neuroinflammatory disease (e.g., multiple sclerosis) or a neurodegenerative disease, in a patient in need thereof, may comprise, for example, administering to the patient an effective amount of the oral tablet composition contemplated herein. In some embodiments, the TYK2-mediated disease is, for example, a neuroinflammatory disease or a neurodegenerative disease. In other embodiments, for example, the TYK2-mediated disease is multiple sclerosis. In some embodiments, a method contemplated herein comprises administering, for example, about 10 mg, about 15 mg, about 30 mg, about 60 mg, or about 120 mg of the compound is administered one or twice daily.

[0048] Further disclosed herein is a method for delivering a TYK2 inhibitor to the brain tissue of a patient in need thereof, comprising orally administering to the patient an effective amount of a compound represented by:or pharmaceutically acceptable salt thereof. For example, contemplated methods may include administration of a TYK2 inhibitor orally to a patient who is in need of a TYK2 inhibitor that once administered crosses the patient’s blood brain barrier.

[0049] In some embodiments, such a patient is suffering from, for example, a neuroinflammatory disease or a neurodegenerative disease. In other embodiments, the patient is suffering from, for example, multiple sclerosis. In further embodiments, afterIPTS / 128801445.1 12Attorney Docket No. ESK-033WO administering the compound to the patient, the ratio of cmax of free drug in the cerebrospinal fluid to cmax of free drug in the plasma of the patient is from about 1.4 to about 1.0. In certain embodiments, about 10 mg, about 15 mg, about 30 mg, about 60 mg, or about 120 mg of the compound is administered one or twice daily.Pharmaceutical Compositions

[0050] In certain embodiments, the compound described herein is administered as a pure chemical. In some embodiments, the compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a 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, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0051] In certain embodiments, the compound provided herein is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0052] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient's disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition! s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome, such as more frequent complete or partial remissions, or longer disease-free and / or overall survival, or a lessening of symptom severity). Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0053] For example, in some embodiments a disclosed compound or composition (e.g., an oral tablet composition) may be administered once daily to the patient. In other embodiments, a disclosed compound or composition (e.g., an oral tablet composition) may be administered twice daily to the patient.

[0054] In some embodiments, a disclosed compound or pharmaceutical composition is formulated for oral, topical (including buccal and sublingual), rectal, vaginal, transdermal,IPTS / 128801445.1 13Attorney Docket No. ESK-033WO parenteral, intrapuhnonary, intradermal, intrathecal, and 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 as a tablet, a pill, a capsule, a liquid, an inhalant, a nasal spray solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment, a lotion, an eye drop, or an ear drop. In some embodiments, the pharmaceutical composition is formulated as a tablet.

[0055] In some embodiments, for example, a disclosed compound or pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as a tablet, a pill, a capsule, a liquid, a suspension, a dispersion, a solution, or an emulsion. In some embodiments, the pharmaceutical composition is formulated as a tablet, for example, a tablet formulated for oral administration.

[0056] Suitable doses and dosage regimens are determined by conventional rangefinding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound disclosed herein. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the present method involves the administration of about 0.1 pg to about 50 mg of at least one compound described herein per kg body weight of the subject. For a 70 kg patient, dosages of from about 10 pg to about 200 mg of the compound disclosed herein would be more commonly used, depending on a subject’s physiological response.

[0057] By way of example only, the dose of the compound described herein for methods of treating a disease as described herein is about 0.001 to about 1 mg / kg body weight of the subject per day, for example, 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 / kg body weight per day.

[0058] In some embodiments, the dose of compound described herein for the described methods is about 1 to about 1000 mg / kg body weight of the subject being treatedIPTS / 128801445.1 14Attorney Docket No. ESK-033WO per day, for example, about 1 mg, about 2 mg, about 4 mg, about 5 mg, about 8 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 240 mg, or about 360 mg,

[0059] Further, by way of example only, the dose of the compound for methods of treating a disease as described herein may be a fixed dose, e.g., 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, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, or 130 mg. Methods of Treatment

[0060] The methods described herein are useful for the inhibition of kinase activity of one or more enzymes. In some embodiments the kinase is TYK2.

[0061] Provided herein are methods for treating a TYK2-mediated disease or disorder in a patient in need thereof, comprising administering to the patient an effective amount of a compound or composition (e.g., an oral tablet composition) described herein.

[0062] In some embodiments, the disease or disorder is a disease or disorder of the central nervous system. For example, in some embodiments the disease or disorder is an immune-mediated inflammatory disease or disorder of the central nervous system.

[0063] For example, in some embodiments the disease or disorder is a neuroinflammatory or a neurodegenerative disease or disorder. In some embodiments, the disease or disorder is selected from the group consisting of, for example, multiple sclerosis, neuromyelitis optica (NMO), neuromyelitis optical spectrum disorder (NMOSD), anti-myelin oligodendrocyte glycoprotein antibody disease (MOG), autoimmune encephalitis, acute disseminated encephalomyelitis (ADEM), transverse myelitis, optic neuritis, neurosarcoidosis, chronic meningitis, central nervous system vasculitis, Hashimoto’s encephalitis, Rasmussen's syndrome, steroid responsive encephalopathy associated with autoimmune thyroiditis (SREAT), opsoclonus-myoclonus ataxia syndrome (OMAS), long COVID, amyotrophic lateral sclerosis, neuroinflammation associated with traumatic brain injury, Lewy body dementia, Alzheimer's disease, Parkinson’s disease, and Huntington disease. In some embodiments, the disease or disorder is, for example, multiple sclerosis. In other embodiments, the TYK2-mediated disease or disorder is, for example, Parkinson’s disease.IPTS / 128801445 1 15Attorney Docket No. ESK-033WO

[0064] In some embodiments, the disease or disorder is, for example, a neuroimmune disorder. In some embodiments, the disease or disorder is selected from the group consisting of, for example, Gulf War illness, myalgic encephalomyelitis, and chronic fatigue syndrome.

[0065] In some embodiments the disease or disorder is associated with type I interferon, IL-10, IL-12, or IL-23 signaling. In some embodiments the disease or disorder is associated with type I interferon signaling. In some embodiments the disease or disorder is associated with IL-10 signaling. In some embodiments the disorder is associated with IL-12 signaling. In some embodiments the disease or disorder is associated with IL-23 signaling.

[0066] In one 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 administration of either therapeutic agent alone.

[0067] 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.

[0068] In certain embodiments, different therapeutically-effective dosages of a compound disclosed herein will be utilized in formulating a pharmaceutical composition (e.g., an oral tablet composition and / or in treatment regimens when the compounds disclosed herein are administered in combination with a second therapeutic agent. Therapeutically- effective dosages of drugs and other agents for use in combination treatment regimens are optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention / treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a compound or composition is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a compound or composition and the second agent being used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment furtherIPTS / 128801445.1 16Attorney Docket No. ESK-033WO includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0069] It is understood that the dosage regimen to treat, prevent, or ameliorate the condition(s) for which relief is sought, is modified in accordance with a variety of factors (e.g., the disease, disorder or condition from which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and, in some embodiments, deviates from the dosage regimens set forth herein.

[0070] For combination therapies described herein, dosages of the co-administered compounds vary depending on the type of co-drug employed, on the specific drug employed, on the disease or condition being treated, and so forth. In additional embodiments, when coadministered with a second therapeutic agent, the compound provided herein is administered either simultaneously with the second therapeutic agent, or sequentially.

[0071] In combination therapies, the multiple therapeutic agents (one of which is one of the compounds described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0072] The compounds and compositions describe herein are administered before, during, or after the occurrence of a disease or condition, and the timing of administering the composition containing a compound varies. Thus, in one embodiment, the compounds and compositions described herein are used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the compounds and compositions are administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a compound or composition described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a compound described herein or a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.IPTS / 128801445.1 17Attorney Docket No. ESK-033WO

[0073] In some embodiments, a compound or composition described herein is administered in combination with an adjuvant. In one embodiment, the therapeutic effectiveness of one of the compounds or compositions described herein is enhanced by administration of an adjuvant (e.g., by itself the adjuvant has minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).EXAMPLES

[0074] The following examples are provided for illustrative purposes only and are not intended to limit the scope of the disclosure.

[0075] A-(4-((3-methoxy-4-( l-tmethyl-Aj-lH-l ,2,4-triazol-3-yl)pyridin-2- yl)amino)-5-propionylpyridin-2-yl)cyclopropanecarboxamide (Compound A) can be prepared according to the synthetic procedures described in WO 2020 / 086616, the entire content of which is incorporated by reference herein.Example 1:

[0076] A study to assess the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of Compound A in healthy adult subjects is conducted.Primary Endpoints:

[0077] Incidence, severity, and relationship of AEs (including withdrawals due to safety or tolerability reasons); change from baseline in physical examination findings; change from baseline in body weight; change from baseline in vital signs; change from baseline in ECG parameters; change from baseline in clinical laboratory parameters.Secondary Objectives:

[0078] To assess the PK of Compound A in plasma following single and multiple oral dose administration of Compound A in healthy adult subjects; to assess the rB A of the tablet formulation to liquid formulation in healthy adult subjects; to assess the effect of a high-fat / high-calorie breakfast on the plasma PK of a single oral dose administration of Compound A tablet in healthy adult subjects; to assess the PK of Compound A in urine following single and multiple oral dose administration of Compound A in healthy adult subjects; to evaluate the effect of Compound A on ECG intervals in healthy adult subjects.Secondary Endpoints:

[0079] Plasma PK endpoints include (but are not limited to):IPTS / 128801445.1 18Attorney Docket No. ESK-033WOPart A (SAD) and Part C ( Optional): AUCO-t, AUCO-inf, AUCO-12, AUCO-24, AUC%extrap, Cmax, Tmax, Tlag (rBA / FE Cohort only), Kel, t' / i, CL / F, and Vz / F.MP ration for metabolites;Part B (MAD) - Day 1: AUCO-12 (if BID dosing) or AUCO-24 (if QD dosing), Cmax, and Tmax.Part B (MAD) - Day 1 to Day 14: Ctrough.Part B (MAD) - Day 1 to Day 14: Ctrough.

[0080] The rBA are assessed by comparing Compound A PK parameters (mainlyAUCO-t, AUC0- inf, and Cmax) of the tablet formulation versus the liquid formulation using an ANOVA approach (Day 1 Period 2 versus Day 1 Period 1: rBA / FE Cohort).

[0081] The food effect are assessed by comparing Compound A PK parameters (mainly AUCO-t, AUCO-inf, and Cmax) of the tablet formulation under fed versus under fasting conditions using an ANOVA approach (Day 1 Period 3 versus Day 1 Period 2; rBA / FE Cohort).

[0082] Urine PK endpoints include (but are not limited to):Part A (SAD; Cohort S2, S5, S6, and S7): Ae, CumAe, CLr, and Fe.Part B (MAD; Cohorts M2, M3, M4, M5, andM6)\ Ae,ss, CumAe, ss, Fe,ss, and CLr,ss.

[0083] The potential relationship between AQTc (using the most appropriate HR correction factor) and plasma Compound A concentrations (C- QT relationship).Other Objectives / Endpoints:

[0084] To assess the PD of biomarker changes associated with single and multiple oral dose administration of Compound A in healthy adult subjects; to assess the metabolites PK characteristics, when possible, in plasma, urine, and possibly in CSF in healthy adult subjects; to assess Compound A penetration into the CSF following single oral dose administration of Compound A tablet in healthy adult subjects (Part C only).A number of PD parameters relating to the pharmacology of Compound A (e.g., biomarker profile, transcriptomics, and proteomics) are be evaluated at baseline and at several time points postdose; Measurement of up to three metabolites; Measurement of Compound A in CSF.

[0085] This is a 3-part study. Parts A and B are randomized, double-blind, placebo- controlled, multi cohort investigations to assess the safety, PK, and PD of SAD (Part A) and MAD (Part B) of orally-administered Compound A. Part C is optional and is an open-label,IPTS / 128801445.1 19Attorney Docket No. ESK-033WO one-cohort, single-dose study to assess the penetration of orally-administered Compound A into the CSF. Approximately 135 subjects participate in this study. Subjects will participate in only 1 cohort and in only 1 study part.Part A (SAD): Approximately 78 healthy adult subjects are enrolled in up to 9 cohorts, with Cohort S7, Cohort S8, and Cohort S9 being optional. Cohorts SI to S9 will each enroll 8 subjects (6 active and 2 placebo). The cohort chosen for the rBA / FE evaluation will enroll 14 subjects (12 active and 2 placebo in Period 1 and 14 active in Periods 2 and 3). Part B (MAD): Approximately 48 healthy adult subjects are planned to be enrolled in up to 6 cohorts (8 subjects in each cohort; 6 active and 2 placebo), with Cohort M5 and Cohort M6 being optional.Part C (Lumbar puncture; optional): 9 healthy adult subjects (all active) are enrolled in1 cohort, Cohort Cl.

[0086] Discontinued subjects may be replaced at the discretion of the Sponsor.Screening of subjects will occur within 28 days prior to the first dosing.

[0087] The details of each study part are as follows:Part A (SAD):

[0088] Up to 9 cohorts (SI to S9) are evaluated; Cohort S7, Cohort S8, and Cohort S9 are optional. In each cohort, subjects receive on Day 1 (Period 1) a single dose of Compound A as an oral liquid formulation or placebo, under fasting conditions. Cohort S5 are selected to be conducted as a 3-period, fixed sequence study (rBA / FE Cohort). On Day 1 of Period 1, subjects receive a single dose of Compound A or placebo as an oral liquid formulation, under fasting conditions. On Day 1 of Period 2, all subjects receive the same dose of Compound A but as a tablet formulation, under fasting conditions. On Day 1 of Period 3, all subjects will receive the same Compound A tablet formulation but under fed conditions. There is a washout period of at least 4 days between dosing in each period. Each cohort (SI to S9) will include a sentinel group (1 active and 1 placebo; rBA / FE Cohort Period2 and Period 3 - 2 active) which are dosed at least 24 hours before the remaining 6 subjects (5 active and 1 placebo) or 12 subjects (11 active and 1 placebo in Period 1 and 12 active in Periods 2 and 3). Dosing of the remaining subjects will be conducted following a safety evaluation of the sentinel group by the PI and the Sponsor. In Period 1 of each cohort, there will be at least a 30-minute interval between dosing of each subject. Safety (i.e., AEs, clinical laboratory tests, standard and orthostatic vital signs, 12-lead safety ECGs, telemetry, C-SSRS, and physical examinations) will be assessed throughout the study. Blood samplesIPTS / 128801445.1 20Attorney Docket No. ESK-033WO(all cohorts) will be collected predose through 72 hours postdose and urine samples (for Cohorts S2, S5, S6, and S7; in the rBA / FE Cohort this is to be collected in Period 1 only) will be collected predose through 72 hours postdose for PK assessments of Compound A and its metabolites. Blood samples (except in Period 2 and Period 3 of rBA / FE Cohort) will be collected predose and through 24 hours postdose for the PD assessment of Compound A. Cardiodynamic ECG (except in Period 2 and Period 3 of rBA / FE Cohort) sampling will be collected predose and up to 24 hours postdose. For Cohorts SI to S4, the decision to escalate will not take place until the SRC has determined that adequate safety, tolerability, and PK data have been demonstrated in previous cohort(s) to permit proceeding to the next cohort. For Cohorts 5 and beyond, the decision to escalate will not take place until the SRC has determined that adequate safety and tolerability data have been demonstrated in previous cohort(s) to permit proceeding to the next cohort. The decision to escalate within the rBA / FE Cohort (i.e., to Period 2 and to Period 3) will not take place until the PI and the Sponsor has determined that adequate safety and tolerability data have been demonstrated in previous periods to permit proceeding to the next period.Part B (MAD):

[0089] Part B (MAD) may start prior to completion of Part A (SAD), however not until completion of Period 2 of the rBA / FE cohort from Part A (SAD) and only after the SRC has determined that adequate safety, tolerability, and PK (if available) data have been demonstrated in Part A (SAD) for at least a higher dose than the planned starting dose level in Part B (MAD). In each cohort, subjects receive either QD or BID dose of Compound A oral liquid formulation or tablet or placebo for 14 days (Days 1 to 14; only morning dose on Day 14), under fasting conditions. Sentinel dosing may be employed in Part B following evaluation of safety data from Part A (SAD) by SRC. Safety (i.e., AEs, clinical laboratory tests, standard and orthostatic vital signs, 12-lead safety ECGs, telemetry, C-SSRS, and physical examinations) will be assessed throughout the study. Blood samples will be collected on Day 1, at predose through 12 (if BID dosing) or 24 hours (if QD dosing) postdose, and on Day 14, at predose through 72 hours postdose, for PK assessments of Compound A and its metabolites. Urine samples (except for Cohort Ml) will be collected at predose on Day 1 and will be collected on Day 14 for 72 hours postdose for PK assessments of Compound A and its metabolites. Blood samples will be collected throughout for the PD assessment of Compound A. Cardiodynamic ECG sampling will be collected on Day 1 and Day 14 and up to 24 hours post (morning) dosing on Day 1 and Day 14. Within Part BIPTS / 128801445.1 21Attorney Docket No. ESK-033WO(MAD), the decision to escalate to Cohorts M2, M3, M4, M5, and M6 will not take place until the SRC has determined that adequate safety and tolerability data have been demonstrated in previous cohort(s) to permit proceeding to the next cohort.Part C (Lumbar puncture; optional):

[0090] Part C is optional. Part A (SAD) Cohorts S1-S6 must be completed before Part C can start. Initiation of Part C will not take place until the SRC has determined that adequate safety, tolerability, and PK (if available) data have been demonstrated in Part A (SAD). The dose will be selected following review of safety and available PK data in Part A (SAD). If conducted, only 1 cohort (Cohort Cl) is planned for evaluation. Subjects will receive a single dose of Compound A oral liquid formulation or tablet. The safety and plasma PK study procedures and their timing will be the same as in Part A (SAD). There will be no urine PK, no PD assessment, and no cardiodynamic assessment in Part C. In addition, a CSF sample for Compound A levels will be collected on Day 1 through a lumbar puncture (spinal tap) procedure; the time points will be confirmed following review of Part A (SAD) data.

[0091] Cohorts SI to S9 in Part A (SAD; except the rBA EE Cohort) and Cohort Cl in Part C: The total planned study duration (from screening to follow-up) for each subject is approximately 5 weeks. This includes a screening period of up to 28 days, a treatment period of 4 days, and a follow-up period of 7 to 9 days.

[0092] rBA / FE Cohort in Part A (SAD): The total planned study duration (from screening to follow-up) for each subject is approximately 6.5 weeks. This includes a screening period of up to 28 days, a treatment period of approximately 12 days, and a followup period of 7 to 9 days.Part B (MAD):

[0093] The total planned study duration (from screening to follow-up) for each subject is approximately 7 weeks. This includes a screening period of up to 28 days, a treatment period of 17 days, and a follow-up period of 7 to 9 days.

[0094] Compound A will be supplied as a liquid formulation and as 5 mg and 20 mg tablet formulation. Placebo will be provided as visually matching placebo liquid formulation or tablet. All doses of Compound A / placebo will be administered orally. All study drugs administered as a liquid formulation will be administered orally with a total of approximately 240 mL of liquid (this includes dosing water + volume of liquid with the dose), as described in the pharmacy manual. All study drugs administered as a tablet formulation will be administered orally with approximately 240 mL of water. If the study drugs cannot all beIPTS / 128801445 1 22Attorney Docket No. ESK-033WO swallowed at the same time, up to a maximum of 50 mL of additional water may be administered as required by the subject, however, dosing should be completed within 10 minutes. Subjects will be instructed not to crush, split or chew the Compound A / placebo tablet.Part A (SAD):

[0095] Subjects will be blinded to the treatment they receive. Subjects in each cohort will receive a single oral dose of Compound A or placebo, as applicable.

[0096] Planned doses are as follows: Cohort SI: 1 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1; Cohort S2: 2 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1 ; Cohort S3: 4 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1 ; Cohort S4: 8 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1; Cohort S5*: 15 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1; Cohort S6: 30 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1 ; Cohort S7 (optional): 60 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1; Cohort S8 (optional): 120 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1; Cohort S9 (optional): 240 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1; Cohort S10 (optional): 360 mg Compound A oral liquid formulation or matching placebo, under fasting conditions, on Day 1.

[0097] Dose level in each cohort will be determined based on emerging data from previous cohorts. Dose increment between consecutive cohorts will not exceed 2-fold at any point.

[0098] * The rBA / FE Cohort will be chosen to be Cohort S5 and will be conducted as a 3-period study. Dose level of the Compound A oral tablet will be 15 mg; all subjects in Period 2 and Period 3 will receive active drug. Subjects will be administered 15 mg of Compound A oral tablet, under fasting conditions, on Day 1 of Period 2. Subjects will be administered 15 mg of Compound A oral tablet, under fed conditions, 30 minutes after the start of a high-fat / high-calorie breakfast meal, on Day 1 of Period 3.Part A (SAD):

[0099] Subjects are blinded to the treatment they receive. Subjects in each cohort will receive either QD or BID oral dose of Compound A or placebo for 14 days (Days 1 toIPTS / 128801445.1 23Attorney Docket No. ESK-033WO14), under fasting conditions. If BID dosing, dosing on Day 14 will occur only in the morning. After initial dosing on Day 1, each subsequent study drug dose will be administered within ± 1 hour of dosing time established on Day 1 . If BID dosing, each evening dose will be approximately 12 hours after the morning dose on that day.

[0100] Planned doses will be as follows: Cohort Ml : 10 mg Compound A tablet or matching placebo QD; Cohort M2: 30 mg Compound A tablet or matching placebo QD; Cohort M3: 60 mg Compound A oral liquid formulation or tablet or matching placebo QD; Cohort M4: 120 mg Compound A oral liquid formulation or tablet or matching placebo QD; Cohort M5: 120 mg Compound A oral liquid formulation or tablet or matching placebo BID. Part C (Lumbar puncture; optional):

[0101] Subjects are not blinded to the treatment they receive. All subjects will receive a single dose of A-005 oral liquid formulation or tablet on Day 1, under fasting conditions. The dose in Part C will be determined based on safety, tolerability, and available PK data review of Part A (SAD; Cohort S1-S6).All Parts:

[0102] The highest dose to be assessed in the study will not exceed or be predicted to exceed a mean plasma AUCO-24 of 28,000ng*h / mL; the exposure observed at the NOAEL in 28-day oral monkey toxicology study. In Parts A and B, unblinded pharmacy personnel will be responsible for providing A- 005 / placebo to the blinded study personnel for dosing as per the randomization schedule. The exact clock time of dosing will be recorded.2.4 Study Population:

[0103] Participants must fulfill all of the following inclusion criteria to be eligible for participation in the study:

[0104] Must have given written informed consent before any study-related activities are carried out and must be able to understand the full nature and purpose of the trial, including possible risks and adverse effects; Healthy, adult, male or female 19-55 years of age, inclusive, at the screening visit; Female and male subjects must follow protocol-specified contraception guidance; Body mass index (BMI) > 18.0 and < 32.0 kg / m2at the screening visit; Be a continuous nonsmoker (including tobacco, e-cigarettes, and marijuana) for at least 3 months prior to first dosing and have a negative test for cotinine at the screening visit and at first check-in (Day -1); Medically healthy with no clinically significant medical history, physical examination, clinical laboratory profiles, and vital signs, as deemed by the PI or designee, at the screening visit and at first check-in (Day -1), including the following: (a)IPTS / 128801445.1 24Attorney Docket No. ESK-033WOSystolic blood pressure in the range of 90 to 140 mmHg (inclusive) and diastolic blood pressure in the range of 50 to 90 mmHg (inclusive) after 5 minutes in supine position; (b) Body temperature (tympanic or oral), between 35.5°C and 37.7°C (inclusive) (may be repeated once, if abnormal values were recorded in the first instance, at the discretion of the PI or designee); (c) Estimated creatinine clearance > 80 niL / min; (d) Liver function test results < 1.5-fold above the upper limit of normal (ULN) for gamma glutamyl transferase [GGT], bilirubin (total, conjugated and unconjugated) or ALP or < 2.0-fold above ULN for AST or ALT. Subjects with ALP and / or ALT / AST above the limits specified may be included, at the discretion of the PI or designee, if the levels are unaccompanied by clinical signs and are detenuined to be normal variant; No ECG findings of clinical significance as judged by the PI or designee at the screening visit and at first check-in (Day -1), including each criterion as follows: (a) Normal sinus rhythm (HR between 55 and 100 bpm, inclusive); (b) QTcF interval < 440 msec (males) and < 440 msec (females); (c) QRS interval < 110 msec; if > 110 msec; (d) PR interval < 220 msec; and (e) Significant ST-T wave abnormalities or flat T waves that could interfere with QTc analysis; Able to swallow multiple tablets;Understands the study procedures in the informed consent form (ICF), and be willing and able to comply with the protocol.

[0105] Subjects must not be enrolled in the study if they meet any of the following criteria:

[0106] History or evidence of significant cardiovascular, pulmonary, hepatic, renal, hematological, gastrointestinal, endocrine, immunologic, dermatologic or neurological disease, including any acute illness or major surgery within the past 3 months determined by the PI or designee to be clinically relevant; History or evidence of any of the following: myocardial infarction; cardiac valvulopathy; cardiac surgery revascularization (coronary artery bypass grafting or percutaneous, transluminal coronary angioplasty); unstable angina; cerebrovascular accident, stroke, or transient ischemic attack; pacemaker; atrial fibrillation, flutter, or nonsustained or sustained VT; orthostatic hypotension or orthostatic dizziness or lightheadedness, pulmonary arterial hypertension; sick sinus syndrome, second- or third- degree atrioventricular block; long QT syndrome; uncontrolled hypertension; congestive heart failure; unexplained syncope or syncope within the last 3 years regardless of etiology; or history of hypokalemia; Current infection that requires systemically absorbed antibiotic, antifungal, antiparasitic or antiviral medications; Creatinine phosphokinase levels > ULN at the screening visit; Clinically significant laboratory abnormalities in white blood cell count,IPTS / 128801445.1 25Attorney Docket No. ESK-033WO absolute neutrophil count, or absolute lymphocyte count at the screening visit; Triglyceride levels > ULN at the screening visit; Clinically significant abnormalities on urinalysis at the screening visit; Any history of malignant disease excluding surgically resected skin squamous cell or basal cell carcinoma; Presence of clinically relevant immunosuppression from immunodeficiency conditions such as common variable hypogammaglobulinemia; Use of or plans to use systemic immunosuppressive (e.g., corticosteroids, methotrexate, azathioprine, cyclosporine) or immunomodulating medications (e.g., interferon) during the study or within 3 months, 5 half-lives, or for the duration of the anticipated PD effects of the drug, whichever of these is longest, prior to the first dosing; Presence or evidence of recent sunburn, scar tissue, tattoo (more than 25% of body area), open sore, or branding that, in the opinion of the PI or designee, would interfere with interpretation of skin adverse reaction assessments, and, for Part C only, with the lumbar puncture; History or presence of risk factors for Torsade de Pointes including family history of Long QT Syndrome or sudden unexpected cardiac death at a young age); Allergy to band aids, adhesive dressing, or medical tape; Positive test results for active human immunodeficiency vims (HIV-1 and HIV-2), hepatitis B surface antigen (HBsAg), hepatitis B vims core antibody (HBcAb), or hepatitis C vims (HCV) antibodies at the screening visit; History of active, latent or inadequately treated tuberculosis infection; positive QuantiFERON®-TB test at the screening visit; Any positive responses within the past 12 months and in the opinion of the PI or designee on the C-SSRS at the screening visit or at first check-in (Day -1); Presence or having sequelae of gastrointestinal, liver (including Gilbert's syndrome), kidney, or other conditions known to interfere with the absorption, distribution, metabolism, or excretion of drugs. Exception: cholecystectomy is allowed;History or presence of alcohol or drug abuse within the past 2 years prior to the first dosing; Positive drug or alcohol test results at the screening visit or at first check-in (Day -1); Unable to refrain from or anticipates the use of: (a) Any drugs, including prescription and nonprescription medications, herbal remedies, or vitamin supplements beginning 14 days or 5 half-lives, whichever is longer, prior to the first dosing (b) St. John's Wort, beginning 28 days prior to the first dosing; Demonstrated clinically significant (required intervention, e.g., emergency room visit, epinephrine administration) allergic reactions (e.g., food, dmg, or atopic reactions, asthmatic episodes) which, in the opinion of the PI or designee, would interfere with the subject's ability to participate in the trial; Known hypersensitivity to any of the study dmg ingredients or related compounds; Positive COVID-19 results at first check-in (Day -1); Use of any vaccinations, other than the COVID-19 vaccination, within 30 days priorIPTS / 128801445 1 26Attorney Docket No. ESK-033WO to the first dosing. For the CO VID-19 vaccination, the first or second vaccination must be received at least 15 days prior to the dosing; Positive serum pregnancy test at the screening visit or at first check-in (Day -1); Female subject who is breast feeding or planning to breast feed within 30 days after the last dosing; Donation of blood or within 56 days prior to first study drug administration, or loss of whole blood of more than 500 inL within 56 days prior to randomization, or receipt of a blood transfusion within 1 year of first dosing; Plasma donation within 7 days prior to the first dosing; Participation in another investigational clinical trial within 30 days (or 5 half-lives of the investigational agent) (whichever is longer) for small molecules and within 60 days for biologic compounds (or for the anticipated duration of the biologic compound’s PD effects, whichever is longer), prior to the first dosing; Any other condition or prior therapy that in the opinion of the PI or designee would make the subject unsuitable for this study, including inability to cooperate fully with the requirements of the study protocol or likelihood of noncompliance with any study requirements; For rBA / FE Cohort in Part A; Is lactose intolerant; For Part C only: Subjects with bleeding disorders, relevant lab abnormalities (Screening international normalized ratio greater than 1.4, platelets less than 50), prior intolerance of lumbar puncture, anatomical reasons preventing safe or successful collection of fluid (skin infection at site of puncture, relevant spine surgery, spinal deformity, etc.), known intracranial space-occupying lesions with mass effect, posterior fossa masses, or relevant brain malformations (Arnold-Chiari malformation, etc.), exam findings suggestive of increased intracranial pressure, or known allergy / sensitivity to lidocaine or its derivatives will not be eligible.Example 2: Single Ascending Dose (SAD) Pharmacokinetic Studies

[0107] Healthy subjects were administered 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 120 mg, 240 mg, or 360 mg of Compound A. Pharmacokinetic parameters were measured upon administration and periodically for up to 24 hours. The results are shown in FIG. 1 , which depicts mean concentrations of Compound A in plasma (ng / mL) at various timepoints in healthy participants administered 1 mg, 2 mg, 4 mg, 8 mg, 15 mg, 30 mg, 60 mg, 120 mg, 240 mg, or 360 mg of Compound A.

[0108] As shown in FIG. 1, Compound A demonstrated a dose linear PK profile, rapid adsorption, a dose -proportional plasma exposure. For example, Compound A demonstrated a TIII;IXof about 1.5 hours, a ti / 2 which increased from about 6 hours to about 12 hours with dose escalation, while cmax increased proportionally with low PK variability.Example 3: Compound A Effectively Penetrates the Blood-Brain BarrierIPTS / 128801445.1 27Attorney Docket No. ESK-033WO

[0109] A 120 mg single dose of Compound A (liquid formulation) was orally administered to 9 healthy subjects. Cerebrospinal fluid samples (one per subject) were collected at 1, 2, and 9 h (n = 3 at each time point). Plasma PK samples were also collected to obtain a complete PK profile. The results are shown in Table 1 and FIG. 2. As shown in Table 1 and FIG. 2, cerebrospinal fluid exposures at all timepoints were similar to free drug exposures in plasma (CSF:Plasma ratio of ~1).Table 1 .Example 4: Multiple Ascending Dose (MAD) Pharmacokinetic Studies

[0110] Multiple ascending dose studies of Compound A were conducted in healthy subjects using 10 mg QD, 30 mg QD, 60 mg QD, 120 mg QD, and 120 mg BID.Pharmacokinetic parameters were measured at various timepoints. The results are shown in FIG. 3, FIG. 4, and FIG. 5. FIG. 3 depicts multiple ascending dose PK profiles (mean concentrations of Compound A in plasma (ng / mL)) at 0 hours to 24 hours (Day 1) in healthy participants administered 10 mg QD, 30 mg QD, 60 mg QD, or 120 mg QD of Compound A. FIG. 4 depicts multiple ascending dose PK profiles (mean concentrations of Compound A in plasma (ng / mL)) at 0 hours to 400 hours in healthy participants administered 10 mg QD, 30 mg QD, 60 mg QD, 120 mg QD, or 120 mg BID of Compound A. FIG. 5 depicts multiple ascending dose PK profiles (mean concentrations of Compound A in plasma (ng / mL)) at 312 hours to 336 hours (Day 14) in healthy participants administered 10 mg QD, 30 mg QD, 60 mg QD, or 120 mg QD of Compound A.Example 5: pSTAT3 Inhibition Studies in Single and Multiple Ascending Doses

[0111] From the single ascending dose studies dosing up to 120 mg of Compound A, and multiple ascending dosing studies up to 60 mg QD of Compound A, pSTAT3 inhibition was measured. The results are shown in FIG. 6 and FIG. 7. FIG. 6 depicts % pSTAT3 inhibition vs. concentration of Compound A (pM, log scale) in single ascending dose cohorts. FIG. 7 depicts % pSTAT3 inhibition vs. concentration of Compound A (pM,IPTS / 128801445.1 28Attorney Docket No. ESK-033WO log scale) in single ascending dose and multiple ascending dose cohorts. As shown in FIG. 6 and FIG. 7, a strong PK / PD correlation was observed (R2= 0.89) was observed.Example 6: Compound A Achieves Maximal Inhibition of Type I IFN Gene Signature

[0112] Healthy volunteers were administered Compound A at a dosing regimen of 10 mg once daily, 30 mg once daily, 60 mg once daily, 120 once daily, or 120 mg twice daily, or were administered a placebo. Blood samples were collected at baseline on day 1, and pre-dose on day 2, day 7, and day 14. The samples were analyzed by bulk-RNA sequencing and normalized gene expression of a Type I IFN gene signature composed of composed of HERC5, IFI27, RSAD2, and IFIT1 was assessed. The results are shown in FIG. 8. As shown in FIG. 8, Compound A reduces expression of the Type I IFN gene signature in a dose dependent manner.Example 7: Compound A Achieves Maximal Inhibition of SIGLEC1

[0113] Healthy volunteers were administered Compound A at a dosing regimen of 10 mg once daily, 30 mg once daily, 60 mg once daily, 120 once daily, or 120 mg twice daily, or were administered a placebo. Blood samples were collected at baseline on day 1, and pre-dose on day 2, day 7, and day 14. The samples were analyzed by bulk-RNA sequencing and normalized gene expression of SIGEEC1 was assessed. The results are shown in FIG. 9. As shown in FIG. 9, Compound A reduces expression of SIGEEC1 in a dose dependent manner.Example 8: Compound A Suppresses TYK2 Pathway Activation in iPSC Astrocytes and Microglia, as well as Peripheral B Cells, with Nanomolar Potency

[0114] The aim of this study was to evaluate the in vitro activity and pharmacology of Compound A in CNS cells, for example induced pluripotent stem cell (iPSC)-derived astrocytes and microglia, as well as in peripheral B cells. Without wishing to be bound by any particular theory, it is contemplated that TYK2 is expressed by CNS-resident astrocytes and microglia, and that pathogenic TYK2 signaling is associated with immune -mediated diseases in both the periphery and CNS. Astrocyte and microglial activation is contemplated to contribute to the inflammation associated with progressive forms of multiple sclerosis. Therefore, TYK2 inhibition may be useful in treating CNS inflammation associated with neurodegeneration and disability in MS.

[0115] In this study, for example, human induced pluripotent stem cell (iPSC)- derived astrocytes and microglia were stimulated in vitro with IFNa in the absence or presence of a concentration range of Compound A. In addition, purified human B cells wereIPTS / 128801445.1 29Attorney Docket No. ESK-033WO stimulated with CpG-B + IFNa in the absence or presence of a concentration range of Compound A. Levels of phosphorylated STAT (pSTAT3 and pSTAT 5) proteins were measured by Alpha-LISA. Levels of secreted Interferon Gamma-induced Protein 10 (IP- 10) were measured by MSD (Meso Scale Discovery) Assay Kit.

[0116] The results are show in Table 2. Numbers represent the mean IC50 value for the indicated readout. As shown in Table 2, Compound A limits TYK2 pathway activation in astrocytes, microglia, and B cells. For example, in iPSC astrocytes and microglia, Compound A suppresses TYK2 pathway activation as evidenced by suppressed IFNa-induced STAT phosphorylation and IP-10 secretion. In glial cells, Compound A suppresses CpG-B + IFNa- stimulated IP- 10 production. These data demonstrate that Compound A potently targets microglia and astrocytes, key drivers of chronic neuroinflammation, as well as TYK2 signaling and effector readouts within peripheral B cells.Table 2.Example 9: Compound A Exhibits Suppression of Clinical Signs in a B Cell-Dependent Model of EAE

[0117] In this study, the clinical efficacy of Compound A was determined in experimental autoimmune encephalomyelitis (EAE), a mechanistic model of neuroinflammation. For example, C57BL / 6 mice were immunized with full length MOG protein (MOG1-125), an EAE model with pathology that is dependent on B cells. Once daily oral dosing of Compound A was initiated one day prior to EAE induction.

[0118] The results are shown in FIG. 10, which depicts mean clinical score of EAE pathology vs duration of treatment with Compound A (Mann-Whitney U test vs vehicle: p<0.05 for 3 mg / kg (day 15-22); p<0.05 for 10 mg / kg (day 14-28); and p<0.05 for 30 mg / kg (day 13-28)). As shown in FIG. 10, Compound A exhibits robust efficacy in a B celldependent model of EAE, achieves complete or near complete suppression of clinical signs of EAE at 10 mg / kg and 30 mg / kg.IPTS / 128801445.1 30Attorney Docket No. ESK-033WOINCORPORATION BY REFERENCE

[0119] All publications and patents mentioned herein, including those items listed below, are hereby incorporated by reference in their entirety for all purposes as if each individual publication or patent was specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.EQUIVALENTS AND SCOPE

[0120] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[0121] Furthermore, the invention 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 is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is / are referred to as comprising particular elements and / or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and / or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permit the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value orIPTS / 128801445.1 31Attorney Docket No. ESK-033WO sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[0122] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

[0123] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.IPTS / 128801445.1 32

Claims

Attorney Docket No. ESK-033WOCLAIMSWhat is claimed is:

1. A method of treating a neuroinflammatory disease or a neurodegenerative disease in a patient in need thereof, comprising orally administering to the patient, once or twice daily, about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof.

2. A method of treating a neuroinflammatory disease or a neurodegenerative disease in a patient in need thereof, comprising orally administering to the patient, once or twice daily, an oral composition comprising: about 1 mg, about 2 mg, about 4 mg, about 8 mg, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

3. The method of claim 1 or 2, wherein the administrating is once daily administering.

4. The method of claim 1 or 2, wherein administering is twice daily administering.IPTS / 128801445 1 33Attorney Docket No. ESK-033WO5. The method of any one of claims 1-4, comprising administering about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about of the compound.

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

7. The method of any one of claims 1-6, further comprising administering food to the patient before administration or upon administration of the compound.

8. The method of any one of claims 1 -7, wherein the TYK2 -mediated disease or disorder is selected from the group consisting of multiple sclerosis, neuromyelitis optica (NMO), antimyelin oligodendrocyte glycoprotein antibody disease (MOG), autoimmune encephalitis, transverse myelitis, optic neuritis, neurosarcoidosis, chronic meningitis, amyotrophic lateral sclerosis, neuroinflammation associated with traumatic brain injury, Lewy body dementia, Alzheimer’s disease, and Parkinson’s disease.

9. The method of any one of claims 1-8, wherein the TYK2 -mediated disease or disorder is multiple sclerosis.

10. The method of any one of claims 1-8, wherein the TYK2-mediated disease or disorder is Parkinson’s disease.

11. The method of any one of claims 1-10, wherein after administering about 120 mg of the compound to the patient, the ratio of Cmax of free drug in the cerebrospinal fluid to cmax of free drug in the plasma of the patient is about 1.4 to about 1.0.

12. The method of any one of claims 1-11, wherein after administering about 120 mg of the compound to the patient, the cma.x of free drug in the cerebrospinal fluid of the patient is from about 32 ng / mL to about 36 ng / mL.

13. The method of any one of claims 1-12, wherein after administering about 120 mg of the compound to the patient, the cmax of free drug in the plasma of the patient is about from 27 ng / mL to about 31 ng / mL.

14. A method of treating multiple sclerosis in a patient in need thereof, comprising orally administering to patient, once or twice daily, about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:IPTS / 128801445.1 34Attorney Docket No. ESK-033WOor pharmaceutically acceptable salt thereof.

15. A method of treating multiple sclerosis in a patient in need thereof, comprising orally administering to patient, once or twice daily, an oral composition comprising: about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

16. A fixed unit dose pharmaceutical composition for oral administration comprising: about 10 mg, about 15 mg, about 30 mg, about 60 mg, about 120 mg, about 240 mg, or about 360 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.IPTS / 128801445.1 35Attorney Docket No. ESK-033WO17. The pharmaceutical composition of claim 16, wherein the composition is formulated as a tablet.

18. An oral tablet composition comprising: about 5 mg, about 10 mg, about 20 mg, about 60 mg, or about 120 mg of a compound represented by:or pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

19. A method of treating a TYK2 -mediated disease or disorder in a patient in need thereof, comprising administering to the patient an effective amount of the oral tablet composition of claim 18.

20. The method of claim 19, wherein the TYK2-mediated disease or disorder is treating a neuroinflammatory disease or a neurodegenerative disease.

21. The method of claim 19 or 20, wherein the TYK2-mediated disease is multiple sclerosis.

22. The method of any one of claims 19-21, wherein about 10 mg, about 15 mg, about 30 mg, about 60 mg, or about 120 mg of the compound is administered one or twice daily.

23. A method for delivering a TYK2 inhibitor to the brain tissue of a patient in need thereof, comprising orally administering to the patient an effective amount of a compound represented by:IPTS / 128801445.1 36Attorney Docket No. ESK-033WO or pharmaceutically acceptable salt thereof.

24. The method of claim 23, wherein the patient is suffering from a neuroinflammatory disease or a neurodegenerative disease.

25. The method of claim 23 or 24, wherein the patient is suffering from multiple sclerosis.

26. The method of any one of claims 23-25, wherein after administering the compound to the patient, the ratio of cmax of free drug in the cerebrospinal fluid to Cmax of free drug in the plasma of the patient is from about 1.4 to about 1.0.

27. The method of any one of claims 23-26, wherein about 10 mg, about 15 mg, about 30 mg, about 60 mg, or about 120 mg of the compound is administered one or twice daily.IPTS / 128801445.1 37

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