Methods for treating dermatological disorders

Abstract

The present disclosure is directed, in part, to a method of treating a patient suffering from a TYK2-mediated disorder, such as an autoimmune skin disease or dermatological disorder disclosed herein, comprising administering to the patient an effective amount of a TYK2 inhibitor.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 485,409, filed February 16, 2023, the contents of which are incorporated herein by reference in their entirety. [Background technology]

[0002]

[0002] 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 these receptors in response to 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 limitin)) and interleukins (e.g., IL-4, IL-6, IL-10, IL-11, IL-12, IL-13, IL-22, IL-23, IL-27, IL-31, oncostatin M, ciliary neurotrophic factor, cardiotrophin 1, cardiotrophin-like cytokine, and LIF). Activated TYK2 then phosphorylates additional signaling proteins, such as members of the STAT family, including STAT1, STAT2, STAT4, and STAT6.

[0003] TYK2 activation by IL-23 has been implicated in 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 of TYK2 or inhibition with tyrphostins significantly reduced both IL-23- and IL-22-induced dermatitis.

[0004] TYK2 is the only signaling messenger common to both IL-12 and IL-23. TYK2 knockout reduced footpad thickening induced by methylated BSA injection, psoriasis-like skin inflammation induced by imiquimod, and colitis induced by dextran sulfate sodium or 2,4,6-trinitrobenzenesulfonic acid in mice.

[0005]

[0005] Combined linkage and association studies of various type I IFN signaling genes and systemic lupus erythematosus (SLE, an autoimmune disorder) demonstrated a strong and significant correlation between loss-of-function mutations in TYK2 and reduced prevalence of SLE in affected families. Genome-wide association studies comparing SLE-affected and unaffected cohorts demonstrated a highly significant correlation between the TYK2 locus and SLE. Summary of the Invention [Problem to be solved by the invention]

[0006]

[0006] Therefore, there is a need to provide a method for inhibiting the activity of TYK2 to treat one or more of the conditions described herein without causing the side effects associated with inhibition of JAK2. [Means for solving the problem]

[0007]

[0007] This disclosure is directed, in part, to methods of treating a TYK2-mediated disorder, e.g., an autoimmune skin disease or dermatological disorder. For example, provided herein is a method of treating a patient suffering from an autoimmune skin disease and having elevated levels of type I IFN-induced sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1), in need of treatment, comprising administering to the patient an effective amount of a TYK2 inhibitor.

[0008]

[0008] Also disclosed herein is a method for treating a dermatological disorder in a patient having high sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression induced by type I IFN and in need of treatment, comprising administering to the patient an effective amount of a TYK2 inhibitor, thereby reducing the expression of SIGLEC1 in the patient in response to administration.

[0009]

[0009] Further described herein is, for example, a method for reducing expression of a SIGLEC1 protein or gene in a cell, the method comprising contacting the cell with an agent that reduces TYK2 gene expression or reduces TYK2 in the cell, thereby reducing the expression of SIGLEC1.

[0010]

[0010] Additionally, the present specification provides a method for treating a subject suffering from an autoimmune skin disease and in need of treatment, the method comprising: providing a biological sample from the subject; assaying gene expression of one or more IFN-1 genes in the biological sample; determining an expression value of the IFN-1 genes; and, if the expression value exceeds a threshold value, administering a TYK2 inhibitor to the patient. [Brief explanation of the drawings]

[0011] [Figure 1]

[0011] Figure 1 shows IFN signature median violin plot of median IFN gene expression in disease (HS) and control states. [Figure 2]

[0012] FIG. 1 shows IFN signature median density plots of median IFN gene expression in disease (HS) and control states. [Figure 3]

[0013] FIG. 1 shows density plots of SIGLEC1 gene expression in disease (HS) and control conditions. [Figure 4]

[0014] FIG. 1 shows dose-dependent median IFN gene expression levels over time for HERC5, IFI27, IFIT1, RSAD2 in healthy volunteers after 14 days of Compound A compared to placebo. [Figure 5]

[0015] FIG. 1 shows dose-dependent median IFN gene expression levels (log scale) over time for HERC5, IFI27, IFIT1, RSAD2 in healthy volunteers after 14 days of Compound A compared to placebo. [Figure 6]

[0016] FIG. 1 shows dose-dependent median IFN gene expression levels over time for SIGLEC1 in healthy volunteers after 14 days of Compound A compared to placebo. [Figure 7]

[0017] FIG. 1 shows dose-dependent median IFN gene expression levels (log scale) over time for SIGLEC1 in healthy volunteers after 14 days of Compound A compared to placebo. [Figure 8]

[0018] FIG. 1 shows percent change in PASI score as a function of baseline SIGLEC1 gene expression (log10 scale) in psoriasis patients after 12 weeks of treatment with placebo. [Figure 9]

[0019] FIG. 1 shows percent change in PASI score as a function of baseline SIGLEC1 gene expression (log10 scale) in psoriasis patients after 12 weeks of treatment with Compound A, 10 mg, once daily. [Figure 10]

[0020] FIG. 1 shows percent change in PASI score as a function of baseline SIGLEC1 gene expression (log10 scale) in psoriasis patients after 12 weeks of treatment with Compound A, 20 mg, once daily. [Figure 11]

[0021] FIG. 1 shows percent change in PASI score as a function of baseline SIGLEC1 gene expression (log10 scale) in psoriasis patients after 12 weeks of treatment with Compound A, 40 mg, once daily. [Figure 12]

[0022] FIG. 1 shows percent change in PASI score as a function of baseline SIGLEC1 gene expression (log10 scale) in psoriasis patients after 12 weeks of treatment with Compound A, 20 mg, twice daily. [Figure 13]

[0023] FIG. 1 shows percent change in PASI score as a function of baseline SIGLEC1 gene expression (log10 scale) in psoriasis patients after 12 weeks of treatment with Compound A, 40 mg, twice daily. DETAILED DESCRIPTION OF THE INVENTION

[0012]

[0024] The features and other details of the present disclosure will now be described in more detail.Before further describing the present disclosure, the specific terms used in this specification, examples and appended claims will be listed here.These definitions should be interpreted in light of the remainder of this disclosure and should be understood by those skilled in the art.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art.

[0013] definition

[0025] As used in this specification and 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 multiple agents and equivalents thereof known to those of skill in the art. When ranges are used herein, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term "about," when referring to a number or numerical range, means that the stated number or numerical range is approximate within experimental variation (or within statistical experimental error), and therefore, the number or numerical range may, in some cases, vary by 1% to 15% from the stated number or numerical range. The term "comprising" (and related terms such as "comprise," "comprises," "having," or "including") is not intended to exclude that, in other specific embodiments, any compositional embodiment, e.g., of the substances, compositions, methods, or processes described herein, "consists of" or "consists essentially of" the described features.

[0014]

[0026] As used herein, the terms "treat," "prevent," "ameliorate," and "inhibit," as well as derivatives thereof, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are various degrees of treatment, prevention, amelioration, and inhibition that one of skill in the art would recognize as having a potential benefit or therapeutic effect. In this regard, the disclosed methods may result in treatment, prevention, amelioration, or inhibition of a disorder in a mammal at any level and in any amount. For example, a disorder, including its symptoms or condition, 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 may include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of a disorder, e.g., cancer or inflammatory disease. As used herein, "treating," "preventing," "ameliorating," or "inhibiting" also includes delaying the onset of a disorder or a symptom or condition thereof.

[0015]

[0027] The terms "effective amount" or "therapeutically effective amount," as used herein, refer to an administration of a compound or composition disclosed herein sufficient to alleviate to some extent one or more of the symptoms of the disease or condition being treated, e.g., cancer or inflammatory disease. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or some other desired change in a biological system. For example, in therapeutic applications, an "effective amount" is the amount of a composition comprising a compound disclosed herein required to result in a clinically significant reduction in a disease symptom. In some embodiments, an appropriate "effective" amount in a particular case is determined using techniques such as a dose escalation study.

[0016]

[0028] As used herein, the term "TYK2-mediated" disorder, disease, and / or condition refers to any disease or other deleterious condition in which TYK2 or a variant 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 variant 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 transplant-related disorders.

[0017] method

[0029] Disclosed herein, for example, is a method for treating a patient suffering from an autoimmune skin disease and having high levels of sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) induced by type I IFN, and in need of treatment, comprising administering to the patient an effective amount of a TYK2 inhibitor.

[0018]

[0030] In some embodiments, a lesional skin sample from a patient before administration of a TYK2 inhibitor has elevated sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression induced by type I IFN. In certain embodiments, the elevated sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression induced by type I IFN is elevated compared to SIGLEC1 expression in the patient's whole blood or compared to patients not suffering from an autoimmune skin disease. In further embodiments, a biological sample from a patient before administration of a TYK2 inhibitor has increased IFN-1 gene expression. For example, in certain embodiments, the increased IFN-1 gene expression is increased gene expression of one or more of OAS3, OAS2, CD8A, EPSTI1, BST2, RNF213, EIF2AK2, IFIT2, IFIT3, SP100, SP110, LY6E, MX1, IFI6, RTP4, XAF1, PATL2, STAT1, and SIGLEC1.

[0019]

[0031] Also disclosed herein is a method for treating a dermatological disorder in a patient having type I IFN-induced elevated sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression and in need of treatment, comprising administering to the patient an effective amount of a TYK2 inhibitor, thereby reducing the expression of SIGLEC1 in the patient in response to administration.

[0020]

[0032] Further disclosed herein is a method of reducing SIGLECl protein or gene expression in a cell, comprising contacting the cell with an agent that reduces TYK2 gene expression or reduces TYK2 in the cell, thereby reducing SIGLECl expression. In some embodiments, the cell is, for example, a skin cell.

[0021]

[0033] Additionally, disclosed herein is a method for treating a subject suffering from an autoimmune skin disease and in need of treatment, comprising: providing a biological sample from the subject; assaying the gene expression of one or more IFN-1 genes in the biological sample; determining the expression level of the IFN-1 genes; and administering a TYK2 inhibitor to the patient if the expression level exceeds a threshold. For example, in some embodiments, the IFN-1 genes are one or more of OAS3, OAS2, CD8A, EPSTI1, BST2, RNF213, EIF2AK2, IFIT2, IFI6, and SIGLEC1. In certain embodiments, the biological sample is, for example, the subject's blood or tissue.

[0022]

[0034] Additionally, disclosed herein is a method of treating a subject suffering from an autoimmune skin disease and in need of treatment, comprising providing a biological sample from the subject, assaying protein expression of one or more IFN-1 proteins in the biological sample, determining an expression level of the IFN-1 proteins, and administering a TYK2 inhibitor to the patient if the expression level exceeds a threshold value.

[0023]

[0035] In some embodiments, the TYK2 inhibitor is, for example, GLPG3121, GLPG3667, VTX-958, ICP-332, BGB-23339,

[0024] [ka] and the like.

[0025]

[0036] In other embodiments, the TYK2 inhibitor is

[0026] [ka] (wherein X is CH or N, and R 1 and R 2 are each independently selected from CH3 and CD3 in terms of expression, or a pharmaceutically acceptable salt thereof. In certain embodiments, the methods described herein include orally or topically administering the compound to a patient.

[0027]

[0037] For example, in some embodiments, the disclosed TYK2 inhibitors include, for example:

[0028] [ka] or a pharmaceutically acceptable salt thereof.

[0029]

[0038] In further embodiments, the autoimmune skin disease or dermatological disorder is, for example, one or more of systemic sclerosis, Sjogren's syndrome, cutaneous lupus erythematosus, systemic lupus erythematosus with cutaneous manifestations, psoriasis, dermatomyositis, hidradenitis suppurativa, vitiligo, and Behcet's disease. In other embodiments, the autoimmune skin disease or dermatological disorder is, for example, one or more of systemic sclerosis, Sjogren's syndrome, cutaneous lupus erythematosus, systemic lupus erythematosus with cutaneous manifestations, psoriasis, dermatomyositis, hidradenitis suppurativa, vitiligo, and Behcet's disease.

[0030]

[0039] For example, 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, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0031]

[0040] In some embodiments, the methods described herein include orally or topically administering a compound to a patient, e.g., orally administering 10 mg to 80 mg of the compound once or twice daily, e.g., orally administering 40 mg or 60 mg of the compound once or twice daily. In other embodiments, the methods described herein further include administering an antibiotic to the patient.

[0032]

[0041] In certain embodiments, the compounds described herein are administered as pure chemicals. In some embodiments, the compounds described herein are administered according to a selected route of administration (e.g., oral administration) and the dosage regimen described in, for example, Remington: The Science and Practice of Pharmacy (Gennaro, 2011). stThe compound is 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 on the basis of standard pharmaceutical practice, such as that described in Ed. Mack Pub. Co., Easton, PA (2005).

[0033]

[0042] In certain embodiments, the compounds provided herein are substantially pure, in the sense 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 synthetic by-products, e.g., arising in one or more of the steps of the synthetic method.

[0034]

[0043] The pharmaceutical composition is administered in a manner appropriate for the disease to be treated (or prevented).The appropriate dosage and the suitable duration and frequency of administration are 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 the composition in an amount sufficient to bring about therapeutic and / or preventive benefits (for example, increasing the frequency of complete or partial remission, or extending disease-free survival and / or overall survival, or improving clinical outcomes such as reducing the severity of symptoms).The optimal dosage is generally determined using experimental models and / or clinical trials.The optimal dosage depends on the patient's size, weight, or blood volume.

[0035]

[0044] For example, in some embodiments, the disclosed compounds or compositions can be administered to a patient once daily. In other embodiments, the disclosed compounds or compositions can be administered to a patient twice daily.

[0036]

[0045] In some embodiments, the disclosed compounds or pharmaceutical compositions are formulated for oral administration. In some embodiments, the pharmaceutical compositions are formulated as tablets, pills, capsules, liquids, suspensions, dispersions, solutions, or emulsions. In some embodiments, the pharmaceutical compositions are formulated as tablets, for example, tablets formulated for oral administration.

[0037]

[0046] Suitable doses and administration regimens can be determined by conventional range-finding techniques known to those skilled in the art. Generally, treatment is initiated with a low dose that is less than the optimal dose of the compounds disclosed herein. Thereafter, the dosage is increased by small increments until the optimal effect for the situation is achieved. In some embodiments, the subject method involves administering about 0.1 μg to about 50 mg of at least one compound described herein per kg of subject body weight. For a 70 kg patient, a dose of about 10 μg to about 200 mg of the compounds disclosed herein will be more commonly used, depending on the subject's physiological response.

[0038]

[0047] By way of example only, the dose of a compound described herein for a method of treating a disease described herein is about 0.001 to about 1 mg / kg of the subject's body weight 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 of body weight per day. In some embodiments, the dose of a compound described herein for the described methods is about 1 to about 1000 mg / kg of the body weight of the subject being treated per day, e.g., 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 100 mg, about 150 mg, about 200 mg, about 250 mg, about 500 mg, about 750 mg, or about 1000 mg per day.

[0039]

[0048] Further, by way of example only, the dose of the compound for the methods of treating the diseases 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.

[0040]

[0049] In certain cases, the compounds described herein are administered in combination with a second therapeutic agent. In some embodiments, the benefit experienced by the patient is increased by administering the compounds described herein with a second therapeutic agent that also has a therapeutic benefit. In a specific embodiment, the compounds described herein are co-administered with a second therapeutic agent, and the compounds described herein and the second therapeutic agent regulate different aspects of the disease, disorder, or condition being treated, thereby resulting in a greater overall benefit than administering either therapeutic agent alone. The overall benefit experienced by the patient is simply the addition of the two therapeutic agents, or the patient experiences a synergistic benefit.

[0041]

[0050] It is understood that the dosage regimen for treating, preventing, or ameliorating the condition for which relief is sought will be modified according to various factors (e.g., the disease, disorder, or condition from which the subject suffers, the age, weight, sex, diet, and medical condition of the subject). As such, in some cases, the dosage regimen actually employed will differ from, and in some embodiments deviate from, the dosage regimens described herein.

[0042]

[0051] The compounds described herein may be administered before, during, or after the onset of a disease or condition, and the timing of administering a composition containing the compound may vary. Thus, in one embodiment, the compounds and compositions described herein are used as prophylactics and administered continuously to subjects prone to developing a condition or disease to prevent the onset of the disease or condition. In another embodiment, the compounds are administered to a subject during or as soon as possible after the onset of symptoms. In certain embodiments, the compounds described herein are administered as soon as possible after the onset of a disease or condition is detected or suspected, for the length of time required to treat the disease. In some embodiments, the length of treatment required may vary, and the length of treatment may be tailored to suit the unique needs of each subject. For example, in certain embodiments, the compounds or formulations containing the compounds described herein are administered for at least two weeks, from about one month to about five years. [Example]

[0043]

[0052] The following examples are offered for illustrative purposes only and are not intended to limit the scope of the present disclosure.

[0044] Example 1: Differential Gene Expression (DGE) Analysis in a Case-Control HS Dataset Analysis method

[0053] A differential gene expression (DGE) analysis was performed on a case-control HS dataset. The dataset used in this analysis was imported from the NCBI BioProject, accession number PRJNA647407. This dataset was contributed by "Prens EP, Gudjonsson JE, Tsoi LC" for hidradenitis suppurativa. This dataset was a case-control set consisting of transcriptome profiling of lesional tissue and whole blood. The analyzed dataset was raw counts at the gene level. Custom quantification was performed using STAR→Salmon→RSEM. Differential expression analysis was performed comparing cases with controls using the DESeq2 program for normalization, visualization, and analysis of RNA-seq data. The geometric mean was calculated for each gene across all samples. The gene counts in each sample were then divided by this mean, and the median of these ratios across samples was used as the size factor for that sample. Genes with a total count of fewer than 20 across all individuals were excluded.

[0045] result

[0054] Differential gene expression analysis was also performed on interferon type 1 (IFN-1) cytokine genes. Table 1 shows the top differentially expressed IFN-1 genes in lesional tissue and whole blood samples obtained from patients with hidradenitis suppurativa. As shown in Table 1, type I IFN-induced sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression is elevated in patients with hidradenitis suppurativa compared to basal levels.

[0046]

[0055] Figure 1 shows an IFN signature median violin plot of median IFN gene expression in disease and control states. As shown in Figure 1, subjects with hidradenitis suppurativa exhibited increased IFN gene expression (shown as median values) compared to non-disease states. Figure 2 shows an IFN signature median density plot of median IFN gene expression in disease and control states. Similar to Figure 1, Figure 2 also shows that subjects with hidradenitis suppurativa exhibited increased IFN expression (shown as median values) compared to non-disease states. Figure 3 shows a density plot of SIGLEC1 gene expression in disease and control states. As shown in Figure 3, subjects with hidradenitis suppurativa exhibited increased median SIGLEC1 expression compared to non-disease states.

[0047] [Table 1-1]

[0048] [Table 1-2]

[0049] Example 2: Gene expression analysis in healthy volunteers

[0056] A study was conducted to evaluate IFN1 gene expression in healthy volunteers receiving a Compound A regimen. The dataset consisted of 48 subjects, and transcriptome-wide RNA sequencing data was collected for each subject at separate time points. For each subject, time points included pre-dose on Day 1, pre-dose on Day 14, and 4 hours post-dose on Day 14. Wald tests were used to assess the association of various doses post-dose on Day 14 relative to placebo. A secondary transcriptome-wide analysis was performed to assess potential off-target effects. Multiple testing correction was performed using a Benjamini-Hochberg cutoff of 0.05 in the primary and secondary analyses separately.

[0050]

[0057] For example, Figures 4 and 5 show the dose-dependent median IFN gene expression levels over time for HERC5, IFI27, IFIT1, and RSAD2. As shown in Figures 4 and 5, a significant decrease in IFN expression was observed 14 days after treatment with Compound A. Figures 6 and 7 show the dose-dependent median IFN gene expression levels over time for SIGLEC1. As shown in Figures 6 and 7, SIGLEC1 was decreased after a 14-day treatment regimen with Compound A.

[0051]

[0058] Table 2, for example, shows the results of the IFN gene set after 14 days of treatment with Compound A compared to placebo (P values ​​based on Wald test). As shown in Table 2, a significant association of Compound A with SIGLEC1 gene expression was observed.

[0052] [Table 2]

[0053]

[0059] Table 3 shows the changes in IFN gene expression in healthy volunteers after 7 days of treatment with 40 mg of Compound A twice daily compared to placebo. As shown in Table 3, SIGLEC1 was found to be the top differentially expressed gene in the treatment group compared to placebo.

[0054] [Table 3]

[0055]

[0060] Table 4 shows the results of a secondary analysis to assess possible off-target effects (4 hours after treatment on day 14 versus placebo). As shown in Table 4, no significant off-target associations were observed after correction for multiple testing.

[0056] [Table 4]

[0057] Example 3: SIGLEC1 whole blood gene expression at baseline predicts PASI response in psoriasis patients after 12 weeks of treatment with Compound A

[0061] Psoriasis patients were treated with placebo or Compound A and underwent assessment of the Psoriasis Area and Severity Index (PASI) after 12 weeks of treatment. Percent change in PASI score was plotted against baseline SIGLEC1 whole blood gene expression.

[0058]

[0062] Figures 8, 9, 10, 11, 12, and 13 show the percent change in PASI score as a function of baseline SIGLEC1 gene expression (log10 scale) in psoriasis patients after 12 weeks of treatment with placebo, Compound A (10 mg qd), Compound A (20 mg qd), Compound A (40 mg qd), Compound A (20 mg bid), and Compound A (40 mg bid), respectively. As shown in Figures 8-13, higher baseline SIGLEC1 gene expression can be correlated with a greater change in PASI response.

[0059] Example 4: SIGLEC1 expression in patients with skin disorders and healthy subjects

[0063] Publicly available gene expression datasets were analyzed to test for statistically significant upregulation of SIGLEC1 in skin disorder patients compared to healthy subjects, and the results are shown in Table 5. As shown in Table 5, changes in SIGLEC1 were significant with a p-value adjusted for multiple testing of less than 0.1 and were enriched in skin disorder patients compared to healthy subjects.

[0060] [Table 5]

[0061] Incorporation by Reference

[0064] All publications and patents mentioned herein, including those 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 specifically and individually incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0062] Equivalence and Scope

[0065] In the claims, articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or clearly indicated otherwise from the context. A claim or statement including "or" between one or more members of a group is deemed valid if one, more than one, or all of the members of the group are present in, employed in, or otherwise relevant to a given result or process, unless indicated to the contrary or clearly indicated otherwise from the context. The invention includes embodiments in which only one member of a group is present in, employed in, or otherwise relevant to a given result or process. The invention includes embodiments in which more than one or all of the members of a group are present in, employed in, or otherwise relevant to a given result or process.

[0063]

[0066] Furthermore, the present invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the enumerated claims are introduced into another claim. For example, any claim that depends on another claim can be modified to include one or more limitations found in any other claim that depends from the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of those elements is also disclosed, and any element may be removed from the group. In general, when the invention or aspects of the invention are referred to as comprising particular elements and / or features, it is to be understood that a particular embodiment of the invention or aspect of the invention consists of or consists essentially of such elements and / or features. For purposes of brevity, such embodiments have not been specifically described herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of additional elements or steps. Where ranges are given, both endpoints are included. Furthermore, unless otherwise stated or apparent from the context and the understanding of one of ordinary skill in the art, values ​​expressed as ranges can, in different embodiments of the invention, take any specific value or subrange within the range provided, to one-tenth of the unit of the lower limit of that range, unless the context clearly dictates otherwise.

[0064]

[0067] This application references various issued patents, published patent applications, journal articles, and other published documents, all of which are incorporated herein by reference. In the event of a conflict between any of the incorporated references and this application, this specification shall control. Additionally, certain embodiments of the present invention that fall within the prior art may be specifically excluded from one or more of the claims. Because such embodiments are deemed known to those of ordinary skill in the art, they may be excluded even if not expressly set forth herein. Certain embodiments of the present invention may be excluded from any claim for any reason, whether or not related to the existence of prior art.

[0065]

[0068] 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 is instead defined in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this description without departing from the spirit or scope of the invention, as defined in the following claims.

[0066]

[0069] The subject matter claimed is as follows:

Claims

1. A method for treating a patient suffering from an autoimmune skin disease and having high levels of sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) induced by type I IFN, and in need of treatment, comprising administering to the patient an effective amount of a TYK2 inhibitor.

2. 2. The method of claim 1, wherein the lesional skin sample from the patient prior to administration of the TYK2 inhibitor has high type I IFN-induced sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression.

3. The method of claim 2, wherein the high level of sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression induced by type I IFN is higher than the SIGLEC1 expression in the whole blood of the patient or is higher than the level in a patient not suffering from the autoimmune skin disease.

4. 2. The method of claim 1, wherein the biological sample from the patient prior to administration of the TYK2 inhibitor has increased IFN-1 gene expression.

5. 5. The method of claim 4, wherein the increased IFN-I gene expression is increased gene expression of one or more of OAS3, OAS2, CD8A, EPSTI1, BST2, RNF213, EIF2AK2, IFIT2, IFIT3, SP100, SP110, LY6E, MX1, IFI6, RTP4, XAF1, PATL2, STAT1, and SIGLEC1.

6. A method for treating a dermatological disorder in a patient having high sialic acid-binding immunoglobulin-like lectin 1 (SIGLEC1) expression induced by type I IFN and in need of treatment, comprising administering to the patient an effective amount of a TYK2 inhibitor, thereby reducing the expression of SIGLEC1 in the patient in response to administration.

7. A method for reducing the expression of SIGLEC1 protein or gene in a cell, comprising contacting the cell with an agent that reduces TYK2 gene expression or reduces TYK2 in the cell, thereby reducing the expression of SIGLEC1.

8. The method of claim 7 , wherein the cells are skin cells.

9. 1. A method of treating a subject suffering from an autoimmune skin disease and in need thereof, comprising: providing a biological sample from said subject; assaying gene expression of one or more IFN-I genes in said biological sample; determining the expression level of the IFN-1 gene; if the expression value exceeds a threshold, administering a TYK2 inhibitor to the patient; A method comprising:

10. 10. The method of claim 9, wherein the IFN-I gene is one or more of OAS3, OAS2, CD8A, EPSTI1, BST2, RNF213, EIF2AK2, IFIT2, IFI6, and SIGLEC1.

11. 11. The method of claim 9 or 10, wherein the biological sample is blood or tissue of the subject.

12. The TYK2 inhibitor is GLPG3121, GLPG3667, VTX-958, ICP-332, BGB-23339, 【Chemistry 1】 12. The method of any one of claims 1 to 11, selected from the group consisting of:

13. The TYK2 inhibitor is 【Chemistry 2】 (In the formula, X is CH or N; R １ and R ２ are independently CH ３ and CDs ３ 13. The method of claim 1, wherein the compound is selected from the group consisting of:

14. 14. The method of claim 12 or 13, comprising administering the compound orally or topically to the patient.

15. 15. The method of any one of claims 1 to 14, wherein the autoimmune skin disease or dermatological disorder is one or more of systemic sclerosis, Sjogren's syndrome, cutaneous lupus erythematosus, systemic lupus erythematosus with cutaneous manifestations, psoriasis, dermatomyositis, hidradenitis suppurativa, vitiligo, and Behcet's disease.

16. 15. The method of any one of claims 1 to 14, wherein the autoimmune skin disease or dermatological disorder is one or more of vasculitis, pemphigus disease, alopecia, atopic dermatitis, epidermolysis bullosa, bullous pemphigoid, and dermatitis herpetiformis.

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