Interleukin-23 receptor antagonist peptide for use in the treatment of psoriasis

Abstract

The present invention relates to a method of administering a cyclic peptide inhibitor of the interleukin-23 receptor (IL-23R) or a pharmaceutically acceptable salt or solvate thereof, a corresponding composition, assay, method and / or use for the treatment of psoriasis.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 488,419 filed 3 March 2023, U.S. Provisional Patent Application No. 63 / 511,837 filed 3 July 2023, and U.S. Provisional Patent Application No. 63 / 589,553 filed 11 October 2023, all of which are incorporated herein by reference in their entirety.

[0002] (Reference to sequence listings submitted as XML files) This application includes a sequence listing submitted electronically as an XML file named "PRD4263WOPCT1_Sequencelisting.xml", created on February 27, 2024, and having a size of 6,202 bytes. The sequence listing is part of this specification and is incorporated herein by reference in its entirety.

[0003] The present invention relates to interleukin-23 receptor (IL-23R) peptide inhibitors, or methods for administering pharmaceutically acceptable salts or solvates thereof, as well as other corresponding assays, methods, and / or uses for the treatment of psoriasis.

[0004] (background) Psoriasis, a chronic skin disease affecting approximately 2-3% of the general population, has been shown to be mediated by the body's T-cell inflammatory response mechanisms. IL-23 is one of several interleukins reportedly involved as a key player in the pathogenesis of psoriasis by maintaining chronic autoimmune inflammation through the induction of interleukin-17, regulation of T memory cells, and activation of macrophages. Expression of IL-23 and the IL-23 receptor (IL-23R) has been shown to be increased in the tissues of patients with psoriasis, and antibodies that neutralize IL-23 have shown IL-23-dependent inhibition of psoriasis development in animal models of psoriasis.

[0005] IL-23 has a unique p19 subunit and interferon-γ (IFN-γ) producing T helper 1 (T Helper 1, T H 1) It is a heterodimer composed of a p40 subunit shared with IL-12, a cytokine involved in cell development. Although both IL-23 and IL-12 contain the p40 subunit, they have different phenotypic characteristics. For example, animals lacking IL-12 are prone to inflammatory autoimmune diseases, while IL-23-deficient animals have a reduced number of CD4 cells that produce IL-6, IL-17, and TNF in the CNS of IL-23-deficient animals. + Resistance to such diseases is attributed to T cells. IL-23 binds to IL-23R. IL-23 binding to IL-23R activates Jak-Stat signaling molecules, Jak2, Tyk2, and Stat1, Stat3, Stat4, and Stat5, although Stat4 activation is substantially weaker. In addition, different DNA-binding Stat complexes are formed in response to IL-23 compared to IL-12. IL-23R constitutively associates with Jak2 and associates with Stat3 in a ligand-dependent manner. In contrast to IL-12, which primarily acts on naive CD4(+) T cells, IL-23 preferentially acts on memory CD4(+) T cells.

[0006] According to the World Psoriasis Day Consortium, approximately 125 million people worldwide, or about 2-3 percent of the total population, suffer from psoriasis. In the United States, it is estimated that more than 8 million Americans have the disease. Effective treatments for psoriasis patients, especially oral therapies, are needed.

[0007] (overview) The present invention addresses these needs by providing a peptide inhibitor suitable for oral administration, or a pharmaceutically acceptable salt or solvate form thereof, that binds to IL-23R and inhibits IL-23 binding and signal transduction. Some embodiments relate to a method for treating psoriasis in a subject requiring treatment for psoriasis, comprising administering an IL-23 receptor antagonist peptide, wherein, after treatment with the IL-23 receptor antagonist peptide, the subject is a responder to treatment by at least one measure of response to treatment, selected from the group consisting of: (i) a reduction of 75% or more in the Psoriasis Area and Severity Index (PASI) compared to the baseline PASI (PASI75); (ii) an Investigator's Global Assessment (IGA) score of 2 or less after treatment; (iii) a reduction of 1 or more in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score from baseline; and (iv) a reduction in the Dermatological Life Quality Index (DLQI) score.

[0008] Some embodiments are methods for treating psoriasis in subjects requiring treatment for psoriasis, wherein the patient requiring administration is given formula (I):

[0009] [ka] compounds or The present invention relates to a method of treatment in which, after treatment with an IL-23 receptor antagonist peptide, the subject is a responder to treatment, selected from the following groups: (i) a reduction of 75% or more in the Psoriasis Area and Severity Index (PASI) compared to baseline PASI; (ii) an Investigator's Global Assessment (IGA) score of 2 or less after treatment; (iii) a reduction of 1 or more in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score from baseline; and (iv) a reduction in the Dermatological Quality of Life Index (DLQI) score.

[0010] Some embodiments relate to a method for treating psoriasis in a subject in need of treatment for psoriasis, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient in need of administration, wherein, after treatment with the IL-23 receptor antagonist peptide, the subject is a responder to treatment, achieving a reduction of 90% or more in the Area and Severity Index (PASI) of psoriasis compared to baseline PASI (PASI90).

[0011] Some embodiments relate to a method for treating psoriasis in a subject in need of treatment for psoriasis, comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof to a patient in need of administration, wherein, after treatment with the IL-23 receptor antagonist peptide, the subject is a responder to treatment, achieving a reduction of 90% or more in the Area and Severity Index (PASI) of psoriasis compared to baseline PASI (PASI90).

[0012] Some embodiments relate to a method for treating psoriasis in a subject requiring treatment for psoriasis, comprising orally administering to the subject about 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the subject is a human being diagnosed with moderate to severe psoriasis vulgaris.

[0013] Some embodiments are methods for treating psoriasis in subjects requiring treatment for psoriasis, wherein the patient requiring administration is given formula (I):

[0014] [ka] compounds or The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate thereof, wherein, after treatment with an IL-23 receptor antagonist peptide, the subject is a responder to treatment, selected from the following groups: (i) a reduction of 90% or more in the Psoriasis Area and Severity Index (PASI) compared to baseline PASI (PASI90), and (ii) an investigator's global assessment (IGA) score of 1 or less after treatment, with an improvement of ≥2 grades from baseline IGA.

[0015] Some embodiments are methods for treating psoriasis in subjects requiring treatment for psoriasis, wherein the patient requiring administration is given formula (I):

[0016] [ka] compounds or The present invention relates to a method comprising administering a pharmaceutically acceptable salt or solvate thereof, wherein, after treatment with an IL-23 receptor antagonist peptide, the subject is a responder to treatment, selected from the following groups: (i) a reduction of 90% or more in the Psoriasis Area and Severity Index (PASI) compared to baseline PASI (PASI90), and (ii) an investigator's global assessment (IGA) score of 1 or less after treatment, with an improvement of ≥2 grades from baseline IGA.

[0017] Some embodiments relate to a method for treating psoriasis in a subject in need of treatment for psoriasis, comprising administering a compound of (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the subject achieves a reduction of 75% or more in the Area and Severity Index (PASI) score compared to the baseline PASI score (PASI75).

[0018] In some embodiments, the subject records a scalp-specific IGA (ss-IGA) score of 0 or 1. In some embodiments, the subject records a scalp-specific IGA (ss-IGA) score of 0. In some embodiments, the subject records an improvement of ≥2 grades from baseline ss-IGA. In some embodiments, the subject achieves a PASI score reduction of at least approximately 90% compared to the baseline PASI score. In some embodiments, the subject achieves a PASI score reduction of approximately 100% compared to the baseline PASI score. In some embodiments, the subject achieves an Investigator's Global Assessment (IGA) score of 2 or less. In some embodiments, the subject achieves an IGA score of 1 or less. In some embodiments, the subject achieves an IGA score of 0. In some embodiments, the patient achieves an Investigator's Global Assessment (IGA) score of 2 or less after treatment. In some embodiments, the patient achieves an IGA score of 1 or less after treatment. In some embodiments, the patient achieves an IGA score of 0 after treatment. In some embodiments, the reduction in PASI score is measured at least two weeks after the initiation of treatment. In some embodiments, the clinical endpoint for psoriasis is measured at least four weeks after the initiation of treatment. In some embodiments, the clinical endpoint for psoriasis is measured at least eight weeks after the initiation of treatment. In some embodiments, the clinical endpoint for psoriasis is measured at least sixteen weeks after the initiation of treatment. In some embodiments, the clinical endpoint for psoriasis is measured at least twenty-four weeks after the initiation of treatment.

[0019] In some embodiments, measures of response to treatment include one or more selected from the group consisting of scalp-specific IGA (ss-IGA), s-PGA (physician's static global assessment of the genitals), hand and / or foot (hf-PGA), fingernail physician's global assessment (f-PGA), and the Nail Psoriasis Area and Severity Index (NAPSI). In some embodiments, measures of response to treatment include scalp-specific IGA.

[0020] In some embodiments, the psoriasis is psoriasis vulgaris. In some embodiments, the psoriasis is moderate to severe psoriasis vulgaris. In some embodiments, the subject is a candidate for phototherapy or systemic therapy.

[0021] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is the hydrochloride salt of the compound of formula (I) or its solvate. In some embodiments, treatment comprises oral administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, treatment comprises daily administration of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0022] In some embodiments, the treatment involves administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 5 mg to about 800 mg per day. In some embodiments, the treatment involves administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 25 mg to about 500 mg per day. In some embodiments, the treatment involves administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 50 mg to about 500 mg per day. In some embodiments, the treatment involves administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 25 mg per day. In some embodiments, the treatment involves administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 50 mg per day. In some embodiments, the treatment involves administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 100 mg per day. In some embodiments, the treatment involves administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof at a dose of approximately 200 mg per day.

[0023] In some embodiments, the patient has at least 10% Body Surface Area (BSA) prior to treatment. In some embodiments, the patient has a PASI score of approximately 12–72 prior to treatment. In some embodiments, the subject has at least 3 Investigator General Assessments (IGA) prior to treatment. In some embodiments, the subject has at least 1 Psoriasis Symptom and Signs Diary (PSSD) symptom score prior to treatment. In some embodiments, the subject has a Dermatological Quality of Life Index (DLQI) score greater than 1 prior to treatment. In some embodiments, the subject has never been treated with a biological agent for psoriasis prior to initiation of treatment with the compound of formula (I) or its pharmaceutically acceptable salt or solvate. In some embodiments, the subject has never been treated with any IL-23 receptor antagonist prior to initiation of treatment with the compound of formula (I) or its pharmaceutically acceptable salt or solvate.

[0024] Some embodiments describe a method for treating a patient population diagnosed with psoriasis, wherein the patient population is given formula (I):

[0025] [ka] compounds or The present invention relates to a method of treatment in which a proportion of the patient population responds to treatment by at least one measure of response to treatment, selected from the following groups: (i) a reduction of 75% or more in the Psoriasis Area and Severity Index (PASI) compared to baseline PASI (PASI75); (ii) an Investigator's Global Assessment (IGA) score of 2 or less after treatment; (iii) a reduction of 1 or more in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score from baseline; and (iv) a reduction in the Dermatological Quality of Life Index (DLQI) score.

[0026] Some embodiments describe a method for treating a patient population diagnosed with psoriasis, wherein the patient population is given formula (I):

[0027] [ka] compounds or This includes administering a pharmaceutically acceptable salt or solvate thereof, This invention relates to a method for enabling patients in a population of approximately 50% or more to respond to treatment when their Psoriasis Area and Severity Index (PASI) shows a reduction of 75% or more compared to baseline PASI (PASI75).

[0028] In some embodiments, administration of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof results in a reduction in the area and severity index score of psoriasis compared to baseline in a patient population administered placebo. In some embodiments, the patient population has an average response rate of approximately 25% or higher to treatment, measured by a 90% reduction in the PASI score compared to the baseline PASI score (PASI90). In some embodiments, the patient population has an average response rate of approximately 10% or higher to treatment, measured by a 100% reduction in the PASI score compared to the baseline PASI score (PASI100). In some embodiments, the patient population has an average response rate of approximately 39% or higher to treatment, measured by achieving an Investigator Global Assessment (IGA) score of 1 or less after treatment. In some embodiments, the patient population has an average response rate of approximately 15% or higher to treatment, measured by achieving an Investigator Global Assessment (IGA) score of 0 after treatment. In some embodiments, the clinical endpoint for psoriasis is measured at least 16 weeks after the initiation of treatment.

[0029] In some embodiments, more than 25% of the patient population responds to treatment when measured by a 90% reduction in the PASI score compared to the baseline PASI score. In some embodiments, more than 10% of the patient population responds to treatment when measured by a 100% reduction in the PASI score compared to the baseline PASI score. In some embodiments, more than 39% of the patient population responds to treatment when measured by achieving an Investigator Global Assessment (IGA) score of 1 or less after treatment. In some embodiments, more than 15% of the patient population responds to treatment when measured by achieving an Investigator Global Assessment (IGA) score of 0 after treatment.

[0030] Some embodiments are pharmaceuticals for treating subjects diagnosed with psoriasis, and formula (I):

[0031] [ka] compounds or The present invention relates to a pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which, when administered to a subject in an amount of at least 50 mg, causes an average reduction of at least 75% in the Area and Severity Index (PASI) of psoriasis, as measured from the baseline PASI score.

[0032] In some embodiments, subjects achieve a reduction of at least about 90% in the area and severity index of psoriasis compared to baseline. In some embodiments, subjects achieve a reduction of about 100% in the area and severity index of psoriasis compared to baseline. In some embodiments, patients achieve an Investigator Global Assessment (IGA) score of 2 or less after treatment. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 5 mg to about 800 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 25 mg to about 500 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 50 mg to about 500 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 25 mg. In some embodiments, the amount of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is about 50 mg. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 100 mg.

[0033] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered in an amount of about 5 mg to about 800 mg per day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered in an amount of about 25 mg to about 500 mg per day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered in an amount of about 50 mg to about 500 mg per day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered in an amount of about 25 mg per day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered in an amount of about 50 mg per day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered in an amount of about 100 mg per day. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is administered once daily. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered twice daily. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to an empty stomach.

[0034] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, to a subject requiring administration, (a) Equation (I):

[0035] [ka] compounds or With the pharmaceutically acceptable salt or solvate thereof, (b) administering a composition comprising one or more pharmaceutically acceptable excipients, The present invention relates to a method and / or use in which a composition is administered to a subject for at least 16 weeks.

[0036] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, to a subject requiring administration, (a) Equation (I):

[0037] [ka] compounds or With the pharmaceutically acceptable salt or solvate thereof, (b) administering a composition comprising one or more pharmaceutically acceptable excipients, The present invention relates to a method and / or use in which the composition is administered to a subject for at least 52 weeks.

[0038] In some embodiments, the present invention relates to a method and / or use for treating moderate to severe psoriasis vulgaris, comprising orally administering to a subject in need of administration (a) about 25 mg to about 500 mg of a hydrochloride of a compound of formula (I) or a solvate thereof, and (b) one or more pharmaceutically acceptable excipients, wherein the subject is a candidate for phototherapy or systemic therapy, and the compound of formula (I) or a solvate thereof is administered to the subject daily for at least 16 weeks.

[0039] In some embodiments, the present invention relates to a method and / or use for treating moderate to severe psoriasis vulgaris, comprising orally administering to a subject in need of administration (a) about 25 mg to about 500 mg of a hydrochloride of a compound of formula (I) or a solvate thereof, and (b) one or more pharmaceutically acceptable excipients, wherein the subject is a candidate for phototherapy or systemic therapy, and the compound of formula (I) or a solvate thereof is administered to the subject daily for at least 52 weeks. [Brief explanation of the drawing]

[0040] [Figure 1]A schematic diagram of the study protocol described in Example 1 is shown. R = randomization, BID = twice daily, QD = once daily, LTEa = long-term extension, all subjects ineligible for bLTE, those chosen not to enroll in LTE, and all subjects eligible for LTW will complete a 4-week safety follow-up to complete the study, and final safety follow-up for subjects not enrolled in cLTE. [Figure 2] The results for patients who achieved a PASI75 response at week 16 are shown. [Figure 3A] The results for patients who achieved a PASI90 response at week 16 are shown. [Figure 3B] The results for patients who achieved a PASI100 response at week 16 are shown. [Figure 3C] The results for patients who achieved an IGA0 / 1 response at week 16 are shown. [Figure 3D] The results for patients who achieved an IGA0 response at week 16 are shown. [Figure 4] The PASI response is shown over a 16-week period. [Figure 5] The median trough plasma concentration (ng / mL) of IL-23 receptor antagonist peptide up to week 16 is shown. [Figure 6A] This shows the median trough plasma concentration (ng / mL) up to week 16 for subjects receiving different doses of IL-23 receptor antagonist peptide, based on baseline weight (baseline weight ≤ median). [Figure 6B] This shows the median trough plasma concentration (ng / mL) up to week 16 for subjects receiving different doses of IL-23 receptor antagonist peptide, based on baseline weight > median. [Figure 7] This shows the percentage of subjects that achieved PASI 75, 90, and 100 responses at week 16, which varied depending on the trough plasma concentration (ng / mL) of the IL-23 receptor antagonist peptide. [Figure 8]This shows the percentage of subjects who achieved an IGA score of 0 or 1 and 0 at week 16, which varies depending on the trough plasma concentration (ng / mL) of IL-23 receptor antagonist peptide. [Figure 9] This shows the percentage of subjects that achieved PASI 75, 90, and 100 responses at week 16, which varied depending on the intermediate plasma concentration (ng / mL) of the IL-23 receptor antagonist peptide. [Figure 10] This shows the percentage of subjects who achieved an IGA score of 0 or 1, and IGA0, at week 16, which varied depending on the intermediate plasma concentration (ng / mL) of the IL-23 receptor antagonist peptide. [Figure 11] The percentage of subjects achieving PASI 75, 90, and 100 responses at week 16 is shown, varying depending on the peak plasma concentration (ng / mL) of the IL-23 receptor antagonist peptide. [Figure 12] This shows the percentage of subjects who achieved an IGA score of 0 or 1 and 0 at week 16, which varies depending on the peak plasma concentration (ng / mL) of the IL-23 receptor antagonist peptide. [Figure 13] This shows the decrease in serum BD-2 levels over time as the dose of IL-23 receptor antagonist peptide is varied. *: p<0.05 for all doses vs. placebo at all time points, † 100 mg BID vs. other active dose arms at that time point, p<0.05. [Figure 14] This shows the time course of decrease in serum IL-22 levels when the dose of IL-23 receptor antagonist peptide is varied. *: p<0.05 for all doses vs. placebo at all time points, † 100 mg BID vs. other active dose arms at that time point, p<0.05. [Figure 15] This shows the time course of decrease in serum IL-17A levels when the dose of IL-23 receptor antagonist peptide is varied. *: p<0.05 for all doses vs. placebo at all time points. [Figure 16]This shows the decrease in serum IL-17F levels over time as the dose of IL-23 receptor antagonist peptide is varied. *: p<0.05 for all doses vs. placebo at all time points. [Figure 17] At week 16, the response rate for scalp psoriasis was higher than placebo for all doses. Scalp psoriasis response was defined as at least two grades improvement from baseline and an ss-IGA score of 0 or 1 (left), or at least two grades improvement from baseline and an ss-IGA score of 0 (right). [Figure 18] The following shows the BD-2 serum level response across various dose groups. *: p<0.05 for all doses versus placebo at all time points, † 100 mg BID versus other active dose arms at that time point, p<0.05. [Figure 19] The following shows the response to IL22 serum levels in various dose groups. *: p<0.05 for all doses vs. placebo at all time points, † 100 mg BID vs. other active dose arms at that time point, p<0.05. [Figure 20A] This shows the IL-17A serum level response in various dose groups. *: p<0.05 for all doses vs. placebo at all time points. [Figure 20B] Shows IL-17F serum level responses in various dose groups. *: p<0.05 for all doses vs. placebo at all time points. [Figure 21] A schematic diagram of the trial protocol for Example 2 is shown. Subjects who completed Example 1 (weeks 0-16) continued treatment for an additional 36 weeks, followed by a 4-week safety follow-up. Subjects who were randomized to receive placebo in Example 1 were switched to 100 mg QD at week 16. BID = twice daily, QD = once daily. [Figure 22A] This shows a representative percentage of subjects who achieved a time-series PASI75 response by week 52. [Figure 22B] This shows a representative percentage of patients who achieved a time-series PASI90 response by week 52 of treatment. [Figure 22C]This shows a representative percentage of patients who achieved a time-series PASI100 response by week 52 of treatment. [Figure 22D] This shows a representative percentage of subjects who achieved a longitudinal IGA score of 1 or 0 by week 52 of treatment. [Figure 22E] This shows a representative percentage of patients who achieved a longitudinal IGA score of 0 by week 52 of treatment. [Figure 23A] The left image shows representative percentages of patients who achieved PASI90 after 16 weeks of treatment and after 52 weeks of treatment. [Figure 23B] The left image shows representative percentages of patients who achieved PASI100 after 16 weeks of treatment and after 52 weeks of treatment. [Figure 23C] The left and right images show representative percentages of subjects who achieved an IGA score of 1 or 0 after 16 weeks of treatment and 52 weeks of treatment, respectively. [Figure 23D] The left and right images show representative percentages of patients who achieved an IGA score of 0 after 16 weeks of treatment and 52 weeks of treatment, respectively. [Figure 24] This shows representative changes in PASI scores from baseline over 52 weeks of treatment. [Figure 25A] This shows a representative percentage of patients who achieved a PSSD symptom score of 0 over 52 weeks of treatment. [Figure 25B] This shows a representative percentage of subjects who achieved a PSSD sign score of 0 over 52 weeks of treatment. [Figure 26A] This shows a representative reduction in PSSD symptom scores from baseline over 52 weeks of treatment. [Figure 26B] This shows a representative decrease from baseline in PSSD sign scores over 52 weeks of treatment. [Figure 27A] The left image shows a representative decrease from baseline in PSSD symptom scores at 16 weeks of treatment and at 52 weeks of treatment (right image). [Figure 27B]The left image shows a representative decrease from baseline in PSSD sign scores at 16 weeks of treatment and at 52 weeks of treatment (right image). [Figure 28] A schematic diagram of the trial protocol described in Example 3 is shown. R = Randomization, PE = Primary endpoint, Q12w = Every 12 weeks, SE = Secondary endpoint, SFU = Safety follow-up visit. [Figure 29] This chart shows the PASI75 response rate versus a representative exposure-response model of Ctrough at week 16. Ctr is the steady-state serum trough concentration. The solid line represents the model-predicted response rate, and the dashed line represents the predicted median exposure metric for 200 mg QD (Ctr = 0.469 ng / mL) based on a model from 1,000 simulated subjects similar to that of Example 1. The horizontal bars represent the 25th to 75th percentiles of the pharmacokinetic (PK) post-exposure metrics for each dosing regimen. The box plots represent the observed placebo-adjusted response rates and their corresponding 95% confidence intervals. [Figure 30] This shows a representative exposure-response model of PASI75 response rate versus Cavg at week 16. Cavg is the steady-state serum trough concentration. The solid line represents the model-predicted response rate, and the dashed line represents the predicted median exposure metric (Ctr = 1.36 ng / mL) for 200 mg QD based on a model from 1,000 simulated subjects similar to that of Example 1. Horizontal bars represent the 25th to 75th percentiles of the pharmacokinetic (PK) post-exposure metrics for each dosing regimen. The box plots represent the observed placebo-adjusted response rates and their corresponding 95% confidence intervals. [Figure 31]This chart shows the IGA0 / 1 response rate versus Ctrough's representative exposure-response model at week 16. The solid line represents the model-predicted response rate, and the dashed line represents the predicted median exposure metric for 200 mg QD (Ctr=0.469 ng / mL) based on a model from 1,000 simulated subjects similar to that in Example 1. The horizontal bars represent the 25th to 75th percentiles of the pharmacokinetic (PK) post-exposure metrics for each dosing regimen. The box plots represent the observed placebo-adjusted response rates and their corresponding 95% confidence intervals. [Figure 32] This chart shows a representative exposure-response model of IGA0 / 1 response rate versus Cavg at week 16. The solid line represents the model-predicted response rate, and the dashed line represents the predicted median exposure metric (Ctr=1.36 ng / mL) for 200 mg QD based on a model from 1,000 simulated subjects similar to that in Example 1. The horizontal bars represent the 25th to 75th percentiles of the pharmacokinetic (PK) post-exposure metric for each dosing regimen. The box plots represent the observed placebo-adjusted response rates and their corresponding 95% confidence intervals. [Figure 33] The XRPD pattern of the crystalline form of the hydrochloride salt of the compound of formula (I) is shown.

[0041] (Detailed description) The present invention provides an effective treatment for psoriasis using an oral IL-23 receptor antagonist. The IL-23 receptor antagonist, as described below and supported by clinical trial studies, provides a novel and effective therapy for patients with psoriasis, possessing both superior efficacy, ease of administration, improved patient adherence, low anti-drug antibody (ADA) risk, and a better safety profile.

[0042] "A," "an," or "a(n)" are indefinite articles meaning at least one when used herein in reference to a group of substituents or "substituents."

[0043] When referring to a value, "approximately" includes the stated value plus or minus 10% of the stated value. For example, approximately 50% includes the range of 45% to 55%, and approximately 20 molar equivalents includes the range of 18 to 22 molar equivalents. Therefore, when referring to a range, "approximately" refers to each upper and lower limit of the stated range, plus or minus 10% of the stated value. For example, the ratio of approximately 1 to approximately 3 (weight / weight) includes the range of 0.9 to 3.3.

[0044] "Administering" refers to administering the composition of the present invention to a subject.

[0045] As used herein, “composition” is intended to encompass products obtained from specific combinations of components, including specific active product ingredients (APIs) (i.e., as defined herein as compounds of formula (I) or pharmaceutically acceptable salts or solvates thereof) and pharmaceutically acceptable excipients, carriers, or diluents, as described herein.

[0046] A state of "fasting" or "abstaining from food" refers to refraining from food intake for at least two hours before administering the composition of the present invention, and refraining from food and liquid intake for at least 30 minutes after administering the composition of the present invention.

[0047] The "PASI score" refers to a numerical value obtained from an assessment using the Area and Severity Index (PASI) of psoriasis. PASI is a system used to assess and rate the severity of psoriatic lesions and their response to therapy.

[0048] As used herein, "PASI xx response" refers to a reduction of xx% or more in the Psoriasis Area and Severity Index (PASI) score after treatment compared to before treatment. In an exemplary example, a PASI50 response in a subject treated with the composition of the present invention is a subject that has a reduction of 50% or more in the PASI score after treatment. Thus, a subject that had a PASI72 score before treatment and has a PASI36 score or less after treatment is said to achieve a PASI50 response.

[0049] "Patient" or "Subject" means a living organism, which includes, but is not limited to, a human subject suffering from or susceptible to a disease or condition that can be treated by administration of a pharmaceutical composition such as those provided herein. Further non-limiting examples include, but are not limited to, humans or other mammals. In some embodiments, the subject is human.

[0050] "Medically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow enhancers, sweeteners, diluents, preservatives, pigments / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are approved by the U.S. Food and Drug Administration as acceptable for use in humans or livestock, or that are understood by or to those skilled in the art working in the field of formularies.

[0051] The pharmaceutically acceptable salts of the compounds of the present invention are salts formed with acids such as mineral acids, organic carboxylic acids and organic sulfonic acids, hydrochloric acid, methanesulfonic acid, and maleic acid, provided that a basic group such as an amine constitutes part of the structure.

[0052] As used herein, “salt” refers to an acid or base salt of a compound used in the method of the present invention. Exemplary examples of pharmaceutically acceptable salts include mineral acid salts (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid), organic acid salts (e.g., acetic acid, propionic acid, glutamic acid, citrate), and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide). It is understood that pharmaceutically acceptable salts are non-toxic.

[0053] The compounds of the present invention may form solvates with, for example, water (i.e., hydrates) or common organic solvents. As used herein, the term “solvate” means the physical association of the compound of the present invention with one or more solvent molecules. This physical association involves changes in the degree of ionic and covalent bonding, such as hydrogen bonding. In certain cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be isolated. The term “solvate” shall encompass both solution-phase solvates and isolateable solvates. Non-limiting examples of suitable solvates include the compounds of the present invention in combination with water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, or ethanolamine. The compounds of this specification may exert their biological effects while they are in solution. Solvates are well known in the pharmaceutical industry. Solvates can be important in the process of preparing substances (e.g., in relation to their purification), in terms of the storage of substances (e.g., their stability), and the ease of handling of substances, and are often formed as part of the isolation or purification steps of chemical synthesis. Those skilled in the art can use techniques such as thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), X-ray crystallography (e.g., single X-ray crystallography or X-ray powder diffraction), and solid-state NMR (SS-NMR, also known as magic-angle rotation NMR or MAS-NMR) to determine whether a hydrate or other solvate was formed by the isolation or purification conditions used to prepare a given compound.

[0054] "Therapeutic dose" refers to the amount of compound or pharmaceutical composition useful for treating or relieving an identified disease or condition, or for exhibiting a detectable therapeutic or inhibitory effect. Within the scope of the meaning of therapeutic dose, "therapeutic dose" further includes a non-toxic but sufficient amount of a particular drug, and the therapeutic dose refers to the amount sufficient to provide the desired therapeutic effect. The exact amount required varies from subject to subject, depending on factors such as the patient's overall health and age. The exact amount depends on the therapeutic purpose and can be determined by those skilled in the art using known techniques (see, for example, Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992), Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999), Pickar, Dosage Calculations (1999), and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0055] The term “safe and effective dose” as used herein in the context of dose, administration regimen, treatment, or method refers to the effectiveness of a particular dose, administration, or treatment regimen. Effectiveness can be measured based on changes in the course of the disease in response to the agent of the present invention. For example, the IL-23 receptor antagonist of the present invention (e.g., a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof) is administered to a subject in an amount and time sufficient to produce improvement, preferably sustained improvement, in at least one index reflecting the severity of the disorder being treated. Various indices reflecting the extent of the disease, disorder, or condition in the subject may be evaluated to determine whether the amount and time of treatment are sufficient. Such indices include, for example, clinically recognized indices of disease severity, symptoms, or the manifestation of the disorder in question. The degree of improvement is determined overall by a physician, who may make this determination based on signs, symptoms, biopsy, or other test results, or by employing questionnaires administered to the subject, such as quality of life questionnaires developed in relation to a given disease. For example, the IL-23 receptor antagonist of the present invention can be administered to achieve improvement in the condition of a subject associated with psoriasis.

[0056] This improvement can be indicated by an improvement in the disease activity index, remission of clinical symptoms, or any other measure of disease activity. Once such a disease index is the Area and Severity Index of Psoriasis (PASI), which is a system used to assess and rate the severity of psoriatic lesions and their response to therapy. Other indicators may include the Investigator's Global Assessment (IGA) score, the Psoriasis Symptoms and Signs Diary (PSSD) symptom score, and the Dermatology Quality of Life Index (DLQI) score.

[0057] With respect to the doses, administration regimens, treatments, or methods using the IL-23 receptor antagonist of the present invention (e.g., a compound of formula I or a pharmaceutically acceptable salt or solvate thereof), the term “clinically safe” means a favorable risk-benefit ratio with an acceptable frequency and / or acceptable severity of adverse events (referred to as adverse events, AEs, or treatment-emergent adverse events, TEAEs) compared to standard treatment or another comparator. As used herein, “adverse event,” “treatment-emergent adverse event,” and “adverse reaction” mean any harmful, undesirable, unintended, or unwanted sign or result associated with or caused by the administration of a pharmaceutical composition or therapeutic agent. This is an undesirable medical event in a subject to which the drug has been administered. However, abnormal values ​​or observations are not reported as adverse events unless they are considered clinically significant by the principal investigator. Where used herein, “clinically apparent” when referring to an adverse event means clinically significant as determined by a physician or principal investigator using criteria acceptable to those skilled in the art. If the adverse or undesirable consequences of an adverse event reach such severity, regulatory authorities may consider the pharmaceutical composition or therapeutic agent unacceptable for the proposed use. In particular, “safety” in relation to the dose, administration regimen, or treatment of the IL-23 receptor antagonist of the present invention means an acceptable frequency and / or acceptable severity of treatment-related adverse events where the adverse event is considered likely, probable, or very likely to be due to the use of the IL-23 receptor antagonist.

[0058] "To treat," "to treat," and "treatment" mean any sign of treatment success or remission of injury, condition, or state, including any objective or subjective parameters such as remission, relief, reduction of symptoms or making the injury, condition, or state more tolerable to the patient, slowing the rate of degeneration or decline, making the final point of degeneration less debilitating, or improving the patient's physical or mental health. Treatment or remission of symptoms may be based on objective or subjective parameters, including the results of physical examination, neuropsychiatric examination, and / or psychiatric evaluation.

[0059] The term "pharmaceutical" refers to a product containing an active pharmaceutical ingredient that has been shown to be a safe and effective treatment for one or more indications, as supported by findings from clinical trials regulated by government authorities, such as the Food and Drug Administration or similar authorities in other countries.

[0060] The term "subject" or "subjects" refers to human patients. Examples of human patients include, but are not limited to, adult (≥18 years) and adolescent (≥12 and <18 years) human patients.

[0061] In describing the present invention, the abbreviations and symbols used herein follow the common use of such abbreviations and symbols by those skilled in the art of chemistry and biology. Specifically, the following abbreviations may be used in the examples and throughout this specification.

[0062] [Table 1]

[0063] compound The present invention relates to IL-23 receptor antagonists useful for the treatment of psoriasis. In some embodiments, the IL-23 receptor antagonist is a peptide. In some embodiments, the IL-23 receptor antagonist is a cyclic peptide.

[0064] The present invention relates to a compound of formula (I), Ac-[Pen] * -N-T-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-E-N-[3-Pal]-Sarc-NH2( * Pen-Pen form disulfide bond) (SEQ ID NO: 1):

[0065]

Chemical formula

[0066] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be present in any form, such as a pharmaceutically acceptable salt, hydrate, or other solvate. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof may be provided in a crystalline form, an amorphous form, or a semi-crystalline form.

[0067] ​In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is a salt. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is an acetate. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is a bisacetate. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is an acetate. In some embodiments, the acetate of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is in an amorphous form. In some embodiments, the acetate of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is an acetate. In some embodiments, the acetate of the compound of formula (I) or its pharmaceutically acceptable salt or solvate is a bisacetate. In some embodiments, the acetate of the composition of the present invention is in an amorphous form. In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is a solvate. In some embodiments, the acetate form of the compound of formula (I) is an acetate solvate.

[0068] The present invention also provides the peptide of SEQ ID NO: 1, or pharmaceutically acceptable salts thereof, or crystalline forms of solvates thereof. Pharmacologically acceptable salts of the peptide of SEQ ID NO: 1 provided herein include hydrochloride, bishydrochloride, acetate, fumarate, glutarate, glycolate, mesylate, sulfate, and citrate.

[0069] The present invention also provides compounds of formula (I), or pharmaceutically acceptable salts thereof, or crystalline forms of solvates thereof. Pharmacologically acceptable salts of compounds of formula (I) provided herein include hydrochlorides, bishydrochlorides, acetates, fumarates, glutarates, glycolates, mesylates, sulfates, and citrates.

[0070] In particular, the present invention has the following structure:

[0071] [ka] A compound of formula (I) having, or This relates to the crystalline form of the hydrochloride salt of the solvate.

[0072] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt or solvate form thereof is the hydrochloride salt of the compound of formula (I) or its solvate.

[0073] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of the peptide of SEQ ID NO: 1. In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is the hydrochloride salt form of the peptide of SEQ ID NO: 1, substantially characterized by the XRPD pattern shown in Figure 22.

[0074] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt or solvate is crystalline and in the form of a solvate.

[0075] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at two-theta angles selected from 4.2, 6.9, 7.6, and 9.2+ / -0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at two-theta angles selected from 4.2, 6.9, 7.6, and 9.2+ / -0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at two-theta angles selected from 4.2, 6.9, 7.6, and 9.2+ / -0.4 degrees 2-theta.

[0076] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.7, or 17.1+ / -0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of sequence number 1 or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 13.9, 15.8, or 17.1+ / -0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 10.0, 10.7, 12.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1+ / -0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.2, 10.0, 10.7, 12.1, 13.9, 15.8, or 17.1+ / -0.4 degrees 2-theta.

[0077] In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.2 degrees 2-theta. In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.3 degrees two-theta. In other embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.4 degrees two-theta.

[0078] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having diffraction peaks at 2-theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having diffraction peaks at 2-theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having diffraction peaks at 2-theta angles of at least 4.3, 6.9, 7.7, 8.6, 9.3, 10.0, 10.7, 11.5, 12.0, 13.1, 13.3, 14.0, 14.8, 15.8, 17.1, 17.6, 18.1, 18.6, 19.3, 20.5, 20.7, or 21.8 + / - 0.4 degrees 2-theta.

[0079] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees two-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a 2-theta angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having two or more diffraction peaks at a two-theta angle selected from 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees 2-theta.

[0080] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having diffraction peaks at at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.2 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having diffraction peaks at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.3 degrees 2-theta. In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an XRPD pattern having diffraction peaks at least 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.5, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 + / - 0.4 degrees 2-theta.

[0081] In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having an endothermic peak at about 81.4°C, as determined by differential scanning calorimetry (DSC). In some embodiments, the crystalline hydrochloride salt of the compound of formula (I) or its solvate is characterized by having a weight loss of about 5.6% between about 26.5°C and about 160.0°C, as determined by thermogravimetric analysis (TGA).

[0082] In one embodiment, the hydrochloride salt of the compound of formula (I) or its solvate is a hemi hydrochloride. In some embodiments, the hemi hydrochloride has about 0.1 to about 0.9, for example, about 0.2 to about 0.8, or about 0.3 to about 0.7 molar equivalents of hydrogen chloride compared to the compound of formula (I). In some embodiments, the hemi hydrochloride has about 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, or about 0.9 molar equivalents of hydrogen chloride compared to the compound of formula (I). In some embodiments, the hemi hydrochloride has about 0.5 molar equivalents of hydrogen chloride compared to the compound of formula (I).

[0083] In some embodiments, the molar equivalent of the chloride anion of the crystalline hydrochloride of the compound of formula (I) per mole of the compound of formula (I) is about 0.2 to about 2.0. In some embodiments, the molar equivalent of the chloride anion of the crystalline hydrochloride of the compound of formula (I) per mole of the compound of formula (I) is about 0.4 to about 1.5. In other embodiments, the molar equivalent of the chloride anion of the crystalline hydrochloride of the compound of formula (I) per mole of the compound of formula (I) is about 0.5 to about 1.0. In a particular embodiment, the molar equivalent of the chloride anion of the crystalline hydrochloride of the compound of formula (I) per mole of the compound of formula (I) is about 0.6 to about 0.7.

[0084] In some embodiments, the hydrochloride salt of the compound of formula (I) or its solvate may be a hydrate. In some embodiments, the hydrate of the hydrochloride salt of the compound of formula (I) has about 0.2 to about 10 molar equivalents of water compared to the compound of formula (I).

[0085] Alternatively, a person skilled in the art can intentionally form a solvate using crystallization conditions that include the required amount of solvent for a particular solvate. The formation of the solvate can then be confirmed using the method described above.

[0086] composition The present invention also relates to compositions of compounds of formula (I). Preferred compositions of the present invention may be in different forms, which include, but are not limited to, liquid compositions, such as solution compositions, or tablet compositions. When the composition is a tablet, the tablet may contain two or more different phases, which may include an inner phase and an outer phase that may contain a core. The tablet composition may also contain one or more coatings.

[0087] Compositions intended for oral use may contain one or more excipients, including sweeteners, flavoring agents, coloring agents, and preservatives, to provide a palatable formulation. Tablets containing the active ingredient mixed with non-toxic, pharmaceutically acceptable excipients suitable for tablet production are acceptable. These excipients may include, for example, inert diluents such as calcium carbonate or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as cellulose, microcrystalline cellulose, starch, gelatin, or gum arabic; and lubricants such as magnesium stearate, stearic acid, or talc.

[0088] In some embodiments, the composition comprises about 5 mg to about 600 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 5 mg to about 600 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 5 mg to about 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 10 mg to about 500 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 10 mg to about 300 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 10 mg to about 250 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 50 mg to about 250 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 100 mg to about 250 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition comprises about 150 mg to about 250 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0089] In some embodiments, the composition comprises 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments, the tablet is film-coated. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0090] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0091] In some embodiments, the composition comprises 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments, the tablet is film-coated. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0092] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0093] In some embodiments, the composition comprises 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments, the tablet is coated. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0094] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0095] In some embodiments, the composition comprises 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients. In some embodiments, the composition is a tablet. In some embodiments, the tablet is coated. In some embodiments, the tablet is an immediate-release tablet. In some embodiments, the tablet is an immediate-release film-coated tablet. In some embodiments, the composition is a solution.

[0096] In some embodiments, the composition is an oral immediate-release film-coated tablet containing 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0097] Methods of administration, treatment, assay, and / or use In some embodiments, the present invention relates to methods and / or uses for administering the compositions disclosed herein to a subject.

[0098] In some embodiments, the present invention relates to a method for administering a composition to a subject requiring administration, (a) Equation (I):

[0099] [ka] compounds or Its pharmaceutically acceptable salt or solvate form, (b) A method comprising administering a composition comprising one or more pharmaceutically acceptable excipients.

[0100] In some embodiments, the present invention relates to a method and / or use for treating psoriasis by administering a composition to a subject requiring administration, (a) Equation (I):

[0101] [ka] compounds or Its pharmaceutically acceptable salt or solvate form, (b) A method comprising administering a composition comprising one or more pharmaceutically acceptable excipients.

[0102] In some embodiments, the present invention relates to a method and / or use comprising multiple doses of the composition of the present invention.

[0103] In some embodiments, the present invention relates to a method and / or use for treating psoriasis by administering a composition to a subject requiring administration, (a) Equation (I):

[0104] [ka] compounds or Its pharmaceutically acceptable salt or solvate form, (b) administering a composition comprising one or more pharmaceutically acceptable excipients, The present invention relates to a method and / or use in which a composition is administered to a subject for at least 16 weeks.

[0105] In some embodiments, the present invention relates to methods and / or uses comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which is a hydrochloride salt of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0106] In some embodiments, the present invention relates to methods and / or uses for the treatment of psoriasis vulgaris, onychopsoriasis, and reverse psoriasis.

[0107] Some embodiments relate to methods and / or uses for treating psoriasis vulgaris, comprising administering an IL-23 receptor antagonist peptide, wherein, after treatment with the IL-23 receptor antagonist peptide, the subject is a responder to treatment by at least one measure of response to treatment, selected from the group consisting of (i) a decrease in serum levels of the psoriasis-related biomarker BD-2, (ii) a decrease in serum levels of the psoriasis-related biomarker IL-22, (iii) a decrease in serum levels of the psoriasis-related biomarker IL-17A, and (iv) a decrease in serum levels of the psoriasis-related biomarker IL-17F.

[0108] In some embodiments, the present invention relates to a method and / or use for the treatment of psoriasis vulgaris. In some embodiments, the psoriasis is moderate to severe psoriasis vulgaris.

[0109] The compositions of the present invention may be administered to a subject or patient by any means in accordance with a therapeutic administration to achieve the intended purpose or pharmaceutically effectiveness. Examples include oral, parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, buccal, or ocular administration. In some embodiments, the administration of the compositions of the present invention is adapted for oral administration.

[0110] In some embodiments of the present invention, the method and / or use includes administering the composition orally.

[0111] In some embodiments of the present invention, the method and / or use comprises administering the composition daily.

[0112] In some embodiments of the methods and / or uses of the present invention, the composition is a tablet, or the composition is formulated into a tablet comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof and at least one pharmaceutically acceptable excipient. In some embodiments of the methods and / or uses of the present invention, the composition is a tablet.

[0113] In some embodiments, the IL-23 receptor antagonist (e.g., the compound of formula (I) or a pharmaceutically acceptable salt or solvate) is systemically active. In some embodiments, the IL-23 receptor antagonist (the compound of formula (I) or a pharmaceutically acceptable salt or solvate) is administered orally once daily. In some embodiments, the IL-23 receptor antagonist (the compound of formula (I) or a pharmaceutically acceptable salt or solvate) is administered orally twice daily.

[0114] In some embodiments, the present invention relates to methods and / or uses comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present invention relates to methods and / or uses comprising orally administering a composition or a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof under fasting conditions.

[0115] In some embodiments, the present invention relates to methods and / or uses, which include administering a composition or compound orally in a ingested state.

[0116] In some embodiments, the subject is administered the composition in simultaneous or sequential treatment periods. In some embodiments, the subject is administered the composition in a simultaneous treatment period. In some embodiments, the subject is administered the composition in sequential treatment periods.

[0117] In some embodiments, the present invention relates to a method and / or use in which a subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for about 12 to about 52 weeks, for example, about 12 to about 48 weeks, about 12 to about 44 weeks, about 12 to about 40 weeks, about 12 to about 36 weeks, about 12 to about 32 weeks, about 12 to about 28 weeks, about 12 to about 24 weeks, about 12 to about 20 weeks, or about 14 to about 18 weeks. In some embodiments, the present invention relates to a method and / or use in which a subject is administered a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof for about 12 weeks, about 13 weeks, about 14 weeks, about 15 weeks, about 16 weeks, about 17 weeks, about 18 weeks, about 19 weeks, or about 20 weeks. In some embodiments, the present invention relates to a method and / or use in which a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a subject for about 14 weeks. In some embodiments, the present invention relates to a method and / or use in which a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a subject for about 15 weeks. In some embodiments, the present invention relates to a method and / or use in which a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a subject for about 16 weeks. In some embodiments, the present invention relates to a method and / or use in which a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a subject for about 17 weeks. In some embodiments, the present invention relates to a method and / or use in which a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a subject for about 18 weeks.

[0118] In some embodiments, the present invention relates to a method and / or use in which a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is administered to a subject daily for 16 weeks.

[0119] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, comprising (a) 25 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and (b) one or more pharmaceutically acceptable excipients.

[0120] In some embodiments, the methods and / or uses described herein are administered to subjects requiring administration. (a) Formula (I) of 25 mg:

[0121] [ka] compounds or Its pharmaceutically acceptable salt or solvate form, (b) Methods and / or uses comprising administering a composition comprising one or more pharmaceutically acceptable excipients.

[0122] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, comprising (a) 50 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and (b) one or more pharmaceutically acceptable excipients.

[0123] In some embodiments, the methods and / or uses described herein are administered to subjects requiring administration. (a) 50 mg, formula (I):

[0124] [ka] compounds or Its pharmaceutically acceptable salt or solvate form, (b) Methods and / or uses comprising administering a composition comprising one or more pharmaceutically acceptable excipients.

[0125] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, comprising (a) 100 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and (b) one or more pharmaceutically acceptable excipients.

[0126] In some embodiments, the methods and / or uses described herein are administered to subjects requiring administration. (a) 100 mg, formula (I):

[0127] [ka] compounds or Its pharmaceutically acceptable salt or solvate form, (b) Methods and / or uses comprising administering a composition comprising one or more pharmaceutically acceptable excipients.

[0128] In some embodiments, the present invention relates to a method and / or use for treating psoriasis by administering a composition comprising (a) 200 mg of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, and (b) one or more pharmaceutically acceptable excipients.

[0129] In some embodiments, the methods and / or uses described herein are administered to subjects requiring administration. (a) 200 mg, formula (I):

[0130] [ka] compounds or Its pharmaceutically acceptable salt or solvate form, (b) Methods and / or uses comprising administering a composition comprising one or more pharmaceutically acceptable excipients.

[0131] In some embodiments, the present invention relates to a method and / or use comprising administering once daily a composition comprising about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0132] In some embodiments, the present invention relates to a method and / or use comprising administering once daily a composition comprising about 50 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0133] In some embodiments, the present invention relates to a method and / or use comprising administering once daily a composition comprising about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0134] In some embodiments, the present invention relates to a method and / or use comprising administering once daily a composition comprising about 200 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0135] In some embodiments, the present invention relates to a method and / or use comprising administering a composition containing about 25 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof twice daily.

[0136] In some embodiments, the present invention relates to a method and / or use comprising administering a composition containing about 100 mg of the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof twice daily.

[0137] In some embodiments, the present invention relates to methods and / or uses in which the subject is a candidate for phototherapy or systemic therapy.

[0138] Subjects suitable for the methods of the present invention satisfy one or more inclusion criteria, as described below. In some embodiments, the present invention relates to methods and / or uses in which subjects have at least 10% psoriasis-affected body surface area (BSA) prior to the initiation of treatment. In this specification, the term BSA means a measure of the percentage of the total body surface area affected by psoriasis.

[0139] The Area and Severity Index of Psoriasis (PASI) is a system used to assess and rate the severity of psoriatic lesions and their response to treatment. In the PASI system, the body is divided into four regions: head, torso, upper extremities, and lower extremities. Each of these regions is separately assessed and scored for erythema, induration, and scaling, each on a scale from 0 to 4, and the degree of involvement on a scale from 0 to 6. PASI generates a numerical score ("PASI score") that can range from 0 to 72. A higher score indicates a more severe disease.

[0140] In some embodiments, the present invention relates to a method and / or use in which the subject has a Psoriasis Area and Severity Index (PASI) score of 12 to 72 prior to the initiation of treatment.

[0141] The Investigator's Global Assessment (IGA) records the investigator's assessment of the participant's psoriasis at a given point in time. The overall lesions are graded for induration, erythema, and scaling. The patient's psoriasis is assessed as clear (0), minimal (1), mild (2), moderate (3), or severe (4).

[0142] In some embodiments, the present invention relates to a method and / or use in which the subject has at least three Investigator General Assessments (IGAs) prior to the initiation of treatment.

[0143] The Psoriasis Symptoms and Signs Diary (PSSD) includes a patient-reported outcome (PRO) questionnaire designed to measure the severity of psoriasis symptoms and signs for evaluation of treatment effectiveness. This trial uses a 7-day recall version of the PSSD, in which participants are asked to answer questions recalling the past 7 days. The PSSD is a self-administered PRO scale with 11 items covering symptoms (itching, pain, tingling, burning, and skin tightness) and patient-observable signs (such as dry skin, cracking, scaling, desquamation or peeling, redness, and bleeding), using a numerical rating scale of 0 to 10 for severity. Two subscores are divided into the Psoriasis Symptoms Score and the Psoriasis Signs Score, each ranging from 0 to 100. Higher scores indicate a more severe disease.

[0144] In some embodiments, the present invention relates to a method and / or use in which the subject has at least one Psoriasis Symptoms and Signs Diary (PSSD) symptom score before initiating treatment.

[0145] In some embodiments, the present invention relates to a method and / or use in which the subject has at least one Psoriasis Symptoms and Signs Diary (PSSD) sign score before initiating treatment.

[0146] The Dermatology Quality of Life Index (DLQI), designed to assess the impact of disease on participants' health-related quality of life (HRQoL), is a dermatology-specific measure of quality of life. It is a 10-item questionnaire that assesses HRQoL over the past week. In addition to assessing overall HRQoL, it can be used to evaluate six different aspects that may influence quality of life: symptoms and emotions, daily activities, leisure, work or school outcomes, relationships, and treatment. The total score ranges from 0 to 30, with higher scores indicating a greater impact on quality of life (QoL).

[0147] In some embodiments, the present invention relates to methods and / or uses in which the subject has a dermatological quality of life index (DLQI) score greater than 1 prior to the initiation of treatment.

[0148] In some embodiments, anchor-based methods can link scores for patient-reported outcomes to external criteria for identifying participants who have experienced a significant change in their condition. Patient Global Impression-Severity (PGI-S) and Patient Global Impression-Change (PGI-C) can be used as anchors, external criteria for determining significant changes in scores for other PROs in this population. PGI-S includes one question about how participants rate the severity of their illness over the past 7 days, with responses ranging from 1 = "none" to 5 = "very severe." PGI-C includes one question about how participants rate the change from their initial treatment in this trial. Response options are presented on a 7-point scale from 1 = "fairly good now" to 7 = "fairly bad now."

[0149] In some embodiments, the present invention relates to a method and / or use in which a subject has not been treated with a biological agent for psoriasis prior to the initiation of treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present invention relates to a method and / or use in which the biological agent for psoriasis is an anti-IL-23 antibody, an anti-IL-17 or anti-IL-12 / 23 antibody, an anti-TNFα antibody, a B cell modulator, or a T cell modulator.

[0150] In some embodiments, the present invention relates to a method and / or use in which a subject has not been treated with a JAK inhibitor or a PDE4 inhibitor prior to the initiation of treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

[0151] In some embodiments, the present invention relates to a method and / or use in which a subject has not been treated with an immunosuppressant prior to the initiation of treatment with a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the present invention relates to a method and / or use in which the immunosuppressant is methotrexate, azathioprine, cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, or tacrolimus.

[0152] The effectiveness of the methods and / or uses of the present invention can be evaluated by several methods or criteria, as described above and below. In some embodiments, the response of a subject to the methods and / or uses of the present disclosure can be measured by the PASI response.

[0153] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI75 response. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI75 response at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI75 response at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI75 response at 16 weeks of treatment and maintain that PASI75 response until 52 weeks of treatment.

[0154] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI90 response. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI90 response at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI90 response at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI90 response at 16 weeks of treatment and maintain that PASI90 response until 52 weeks of treatment.

[0155] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI100 response. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI100 response at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI100 response at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a PASI100 response at 16 weeks of treatment and maintain a PASI100 response up to 52 weeks of treatment.

[0156] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in PASI score from baseline. In some embodiments, the subject achieves a reduction of at least 14 points in the PASI score. In some embodiments, the subject achieves a reduction of at least 15 points in the PASI score. In some embodiments, the subject achieves a reduction of at least 16 points in the PASI score. In some embodiments, the subject achieves a reduction of at least 17 points in the PASI score. In some embodiments, the subject achieves a reduction of at least 18 points in the PASI score. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in PASI score at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in PASI score at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in PASI score at 16 weeks of treatment and maintain that reduction until 52 weeks of treatment.

[0157] In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0 or 1. In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0 or 1 at week 52 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0 or 1 at week 16 of treatment and maintain an IGA score of 0 or 1 until week 52 of treatment.

[0158] In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0. In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0 at week 16 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0 at week 52 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve an Investigator's Global Assessment (IGA) score of 0 at week 16 of treatment and maintain an IGA score of 0 until week 52 of treatment.

[0159] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) symptom score of 0. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) symptom score of 0 at week 16 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) symptom score of 0 at week 52 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) symptom score of 0 at week 16 of treatment and maintain a PSSD symptom score of 0 up to week 52 of treatment.

[0160] In some embodiments, the present invention relates to methods and / or uses for subjects to achieve a reduction in their PSSD symptom score from baseline. In some embodiments, subjects achieve a reduction of at least 30 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 35 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 40 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 45 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 46 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 47 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 48 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 49 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 50 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 51 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 52 points in their PSSD symptom score. In some embodiments, subjects achieve a reduction of at least 53 points in their PSSD symptom score. In some embodiments, the present invention relates to a method and / or use in which a subject achieves a reduction in PSSD symptom scores at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use in which a subject achieves a reduction in PSSD symptom scores at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use in which a subject achieves a reduction in PSSD symptom scores at 16 weeks of treatment and maintains that reduction up to 52 weeks of treatment.

[0161] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) sign score of 0. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) sign score of 0 at week 16 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) sign score of 0 at week 52 of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Psoriasis Symptom and Signs Diary (PSSD) sign score of 0 at week 16 and maintain a PSSD sign score of 0 up to week 52 of treatment.

[0162] In some embodiments, the present invention relates to methods and / or uses for subjects to achieve a reduction in their PSSD sign score from baseline. In some embodiments, subjects achieve a reduction of at least 40 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 41 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 42 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 43 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 44 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 45 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 46 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 47 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 48 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 49 points in their PSSD sign score. In some embodiments, subjects achieve a reduction of at least 50 points in their PSSD sign score. In some embodiments, the subject achieves a reduction of at least 51 points in the PSSD sign score. In some embodiments, the subject achieves a reduction of at least 52 points in the PSSD sign score. In some embodiments, the subject achieves a reduction of at least 53 points in the PSSD sign score. In some embodiments, the subject achieves a reduction of at least 54 points in the PSSD sign score. In some embodiments, the subject achieves a reduction of at least 55 points in the PSSD sign score. In some embodiments, the present invention relates to a method and / or use by which the subject achieves a reduction in the PSSD sign score at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use by which the subject achieves a reduction in the PSSD sign score at 52 weeks of treatment.In some embodiments, the present invention relates to a method and / or use in which a subject achieves a reduction in PSSD sign score at 16 weeks of treatment and maintains that reduction in PSSD sign score up to 52 weeks of treatment.

[0163] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Dermatological Quality of Life Index (DLQI) score of 0 or 1. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Dermatological Quality of Life Index (DLQI) score of 0 or 1 at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Dermatological Quality of Life Index (DLQI) score of 0 or 1 at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a Dermatological Quality of Life Index (DLQI) score of 0 or 1 at 16 weeks of treatment and maintain a DLQI score of 0 or 1 up to 52 weeks of treatment.

[0164] The Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29) is a 29-item general health-related quality of life (HRQoL) survey that assesses each of the seven PROMIS domains (depression, anxiety; physical functioning, pain interference, fatigue, sleep disturbances, and ability to participate in social roles and activities) using four questions. The questions are ranked on a 5-point Likert scale. There is also one 11-point rating scale for pain intensity.

[0165] In some embodiments, the present invention relates to a method and / or use in which a subject achieves a reduction of at least 5 points in the Patient Reported Outcome Measurement Information System-29 (PROMIS-29) domain. In some embodiments, the present invention relates to a method and / or use in which a subject achieves a reduction of at least 5 points in the Patient Reported Outcome Measurement Information System-29 (PROMIS-29) domain at 16 weeks of treatment.

[0166] In some embodiments, the present invention relates to a method and / or use in which the pharmacodynamic and pharmacokinetic relationships of a compound of formula (I) are determined for biomarkers, efficacy, and / or safety in a subject. In some embodiments, one or more of IL-22, IL-17A, IL-17F, and / or beta-defensin-2 (BD-2) are evaluated to assess the effect of the composition of the present invention on inflammatory proteins in serum.

[0167] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in BD-2 serum levels from baseline. In some embodiments, the reduction in BD-2 serum levels is at least a 50% reduction from baseline. In some embodiments, the reduction in BD-2 serum levels is at least a 75% reduction from baseline. In some embodiments, the reduction in BD-2 serum levels is at least an 87.5% reduction from baseline. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in BD-2 serum levels from baseline at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to have a reduction in BD-2 serum levels from baseline at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in BD-2 serum levels from baseline at 16 weeks of treatment and maintain that reduction until 52 weeks of treatment.

[0168] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in serum IL-22 levels from baseline. In some embodiments, the reduction in serum IL-22 levels is at least 30% from baseline. In some embodiments, the reduction in serum IL-22 levels is at least 50% from baseline. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in serum IL-22 levels from baseline at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in serum IL-22 levels from baseline at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in serum IL-22 levels from baseline at 16 weeks of treatment and maintain that reduction up to 52 weeks of treatment.

[0169] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17A serum levels from baseline. In some embodiments, the reduction in IL-17A serum levels is at least 30% from baseline. In some embodiments, the reduction in IL-17A serum levels is at least 50% from baseline. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17A serum levels from baseline at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17A serum levels from baseline at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17A serum levels from baseline at 16 weeks of treatment and maintain that reduction until 52 weeks of treatment.

[0170] In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17F serum levels from baseline. In some embodiments, the reduction in IL-17F serum levels is at least 30% from baseline. In some embodiments, the reduction in IL-17F serum levels is at least 50% from baseline. In some embodiments, the reduction in IL-17F serum levels is at least 60% from baseline. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17F serum levels from baseline at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17F serum levels from baseline at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject to achieve a reduction in IL-17F serum levels from baseline at 16 weeks of treatment and maintain that reduction until 52 weeks of treatment.

[0171] In some embodiments, the present invention relates to a method and / or use in which the plasma concentration of the compound of formula (I) is determined immediately before the start or at the end of the administration interval. In some embodiments, the present invention relates to a method and / or use in which the plasma concentration of the compound of formula (I) is determined by C trough , C max , C avg The present invention relates to a method and / or use in which the relationship between pharmacokinetic parameters and pharmacodynamics is determined by measuring and / or AUC. In some embodiments, the present invention relates to a method and / or use in which the relationship between pharmacokinetic parameters and pharmacodynamics is determined, comprising determining skin, blood cell, and molecular biomarker activity, clinical endpoints, and / or safety parameters. In some embodiments, the present invention relates to a method and / or use in which the incidence of anti-drug antibodies against compounds of formula (I) is determined.

[0172] In some embodiments, the present invention relates to methods and / or uses, including the treatment of topical psoriasis.

[0173] To assess the severity of scalp psoriasis, the Scalp-Specific Principal Investigator Global Assessment (ss-IGA) scale is used. Lesions are evaluated based on clinical signs of redness, thickening, and scaling, and scored as no disease (0), very mild disease (1), mild disease (2), moderate disease (3), and severe disease (4).

[0174] In some embodiments, the present invention relates to a method and / or use for a subject to achieve an ss-IGA score of 0 or 1. In some embodiments, the present invention relates to a method and / or use for a subject to achieve an improvement of at least 2 in the ss-IGA score. In some embodiments, the present invention relates to a method and / or use for a subject having scalp psoriasis to achieve an ss-IGA score of 0 or 1 and an improvement of at least 2 in the ss-IGA score. In some embodiments, the present invention relates to a method and / or use for a subject having scalp psoriasis to achieve an ss-IGA score of 0 or 1 and an improvement of at least 2 in the ss-IGA score at 16 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject having scalp psoriasis to achieve an ss-IGA score of 0 or 1 and an improvement of at least 2 in the ss-IGA score at 52 weeks of treatment. In some embodiments, the present invention relates to a method and / or use for a subject having scalp psoriasis who achieves an ss-IGA score of 0 or 1 at week 16 of treatment and an improvement of at least 2 in the ss-IGA score, and maintains an ss-IGA score of 0 or 1 until week 52 of treatment.

[0175] The Nail Psoriasis Area and Severity Index (NAPSI) is an index used to assess and rate the severity of nail psoriasis. Each of the 20 nails (fingernails and toenails) of a participant is divided into quarters and assessed for any presence of nail psoriasis in the nail matrix (punctate pitting, leukoplakia, red patches on the lunula, and nail collapse) and any presence of nail psoriasis in the nail bed (onycholysis, linear hemorrhage, oily discoloration, and nail bed hyperkeratosis). Both the nail matrix (score 0-4) and nail bed (score 0-4) scores are equal to the number of quarters affected by nail / nail bed psoriasis. The sum of the individual nail scores is the sum of the nail matrix and nail bed scores, ranging from 0 to 8. The sum of the scores for the 20 individual nails is the total NAPSI score (0-160).

[0176] In some embodiments, the present invention relates to a method and / or use for achieving improvement in NAPSI. In some embodiments, the present invention relates to a method and / or use for achieving improvement in NAPSI at 16 weeks of treatment.

[0177] The current status of participants' fingernail psoriasis is assessed using the Fingernail Physician's Global Assessment (f-PGA) on a scale of 0 to 4 (clear [0], minimal [1], mild [2], moderate [3], or severe [4]), similar to the IGA.

[0178] In some embodiments, the present invention relates to a method and / or use for a subject to achieve an f-PGA score of 0 or 1. In some embodiments, the present invention relates to a method and / or use for a subject having an f-PGA score ≥ 2 at week 0 to achieve an f-PGA score of 0 or 1 at week 16 of treatment.

[0179] The severity of hand and foot psoriasis has been assessed in various clinical trials using the Physician's Global Assessment of Hands and / or Feet (hf-PGA) scale. Plaque on the hands and feet is scored on a 5-point scale as clear[0], nearly clear[1], mild[2], moderate[3], and severe[4].

[0180] In some embodiments, the present invention relates to a method and / or use for a subject to achieve an hf-PGA score of 0 or 1. In some embodiments, the present invention relates to a method and / or use for a subject having an hf-PGA score ≥ 2 at week 0 to achieve an hf-PGA score of 0 or 1 and a reduction of at least 2 in the hf-PGA score at week 16 of treatment.

[0181] The Static Physician's Global Assessment of Genitalia (s-PGA-G) is a 6-point numerical rating scale for assessing the severity of genital psoriasis at a given point in time. The s-PGA-G scales erythema, plaque elevation, and genital psoriatic lesions. The severity of genital psoriasis is assessed as clear [0], minimal [1], mild [2], moderate [3], severe [4], and very severe [5].

[0182] In some embodiments, the present invention relates to a method and / or use for a subject to achieve an s-PGA-G score of 0 or 1. In some embodiments, the present invention relates to a method and / or use for a subject having an s-PGA-G score ≥ 3 at week 0 to achieve an s-PGA-G score of 0 or 1 at week 16 of treatment.

[0183] The Genital Psoriasis Sexual Frequency Questionnaire (GenPs-SFQ) is a two-item patient-reported survey used to assess the impact of genital psoriasis on the frequency of sexual activity in the last 7 days. Item 1 assesses the overall frequency of sexual activity in the last 7 days (none / zero, once, or twice or more), and item 2 assesses the extent to which genital psoriasis symptoms have limited the frequency of sexual activity in the last 7 days (not at all [0], rarely [1], sometimes [2], often [3], or always [4]).

[0184] In some embodiments, the invention relates to a method and / or use in which a subject achieves a GenPs-SFQ score of 0 or 1. In some embodiments, the invention relates to a method and / or use in which a subject having a GenPs-SFQ score ≥2 at week 0 achieves a GenPs-SFQ score of 0 or 1 at week 16 of treatment.

[0185] In some embodiments, the invention relates to a method and / or use that includes determining the frequency and type of related adverse events. In some embodiments, the invention relates to a method and / or use that includes determining the frequency and type of adverse events that lead to discontinuation of administration of the composition of the invention.

[0186] In some embodiments, the invention relates to a method and / or use that includes determining experimental parameters in a subject and the change over time of the experimental parameters.In some embodiments, the invention relates to a method and / or use that includes determining systolic and diastolic blood pressure over time in a subject.

[0187] In some embodiments, the invention relates to a method and / or use that includes determining the change over time in the levels of skin and blood biomarkers in a subject.

[0188] In some embodiments, the present invention relates to a method and / or use comprising evaluating the treatment satisfaction domain using the Treatment Satisfaction Questionnaire for Medications-9 items (TSQM-9). In some embodiments, the present invention relates to a method and / or use comprising evaluating the treatment satisfaction domain using the Treatment Satisfaction Questionnaire for Medications-9 items (TSQM-9) at week 16.

[0189] In some embodiments, the present invention relates to a method and / or use for treating moderate to severe psoriasis vulgaris, for adult human subjects requiring administration, (a) Formula (I) of approximately 25 mg to 100 mg:

[0190] [ka] compounds or The hydrochloride salt of that solvate, (b) administering a composition comprising one or more pharmaceutically acceptable excipients orally on a daily basis, The present invention relates to a method and / or use in which an adult human subject is a candidate for phototherapy or systemic therapy, and the compound of formula (I) or its solvate is administered to the adult human subject daily for at least 16 weeks.

[0191] In some embodiments, the present invention relates to a method and / or use for treating moderate to severe psoriasis vulgaris, for adult human subjects requiring administration, (a) Formula (I) of approximately 25 mg to 100 mg:

[0192] [ka] compounds or The hydrochloride salt of that solvate, (b) administering a composition comprising one or more pharmaceutically acceptable excipients orally on a daily basis, Relates to a method and / or use in which an adult human subject is a candidate for phototherapy or systemic therapy, and the hydrochloride salt of a compound of formula (I) or a solvate thereof is administered daily to the adult human subject for at least 52 weeks.

[0193] In some embodiments, the invention is a method and / or use for treating moderate to severe plaque psoriasis, comprising orally administering daily to an adult human subject in need of administration, (a) from about 25 mg to about 200 mg of a compound of formula (I):

[0194] [Chemical formula] or the hydrochloride salt of a solvate thereof, (b) one or more pharmaceutically acceptable excipients, Relates to a method and / or use in which an adult human subject is a candidate for phototherapy or systemic therapy, and the hydrochloride salt of a compound of formula (I) or a solvate thereof is administered daily to the adult human subject for at least 16 weeks.

[0195] In some embodiments, the invention is a method and / or use for treating moderate to severe plaque psoriasis, comprising orally administering daily to an adult human subject in need of administration, (a) from about 25 mg to about 200 mg of a compound of formula (I):

[0196] [Chemical formula] or the hydrochloride salt of a solvate thereof, (b) one or more pharmaceutically acceptable excipients, Relates to a method and / or use in which an adult human subject is a candidate for phototherapy or systemic therapy, and the hydrochloride salt of a compound of formula (I) or a solvate thereof is administered daily to the adult human subject for at least 52 weeks.

[0197] In some embodiments, the present invention relates to a method and / or use for treating psoriasis, for adult human subjects requiring administration,

[0198] (a) (i) Formula (I) of approximately 25 mg to 200 mg:

[0199] [ka] compounds or The hydrochloride salt of that solvate, (ii) Orally administering daily a composition comprising one or more pharmaceutically acceptable excipients, (b) (i) A reduction of 75% or more in the Area and Severity Index of Psoriasis (PASI) compared to baseline PASI. (ii) Investigator's Global Assessment (IGA) score of 2 or less after treatment, (iii) A decrease of 1 or more from baseline in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score, and The present invention relates to methods and / or uses, including achieving at least one psoriasis clinical endpoint selected from the group consisting of (iv) a reduction in the Dermatological Quality of Life Index (DLQI) score.

[0200] In some embodiments, step (b) includes achieving at least one psoriasis clinical endpoint after daily oral administration of a compound of formula (I) or its solvate for at least 16 weeks. In some embodiments, step (b) includes achieving at least one psoriasis clinical endpoint after daily oral administration of a compound of formula (I) or its solvate for at least 52 weeks. In some embodiments, step (b) includes achieving at least one psoriasis clinical endpoint after daily oral administration of a compound of formula (I) or its solvate for at least 16 weeks and maintaining at least one psoriasis clinical endpoint for at least 52 weeks.

[0201] In another aspect, the present invention relates to an assay method for evaluating the dose-response of a compound of formula (I) to a placebo in the treatment of moderate to severe psoriasis vulgaris, i) The step of orally administering a pharmaceutical composition to a patient or subject requiring administration, Here, Pharmaceutical compositions, Formula (I) for amounts ranging from approximately 25 mg to approximately 100 mg:

[0202] [ka] compounds or The present invention relates to an assay method comprising a pharmaceutically acceptable salt or solvate and one or more pharmaceutically acceptable excipients.

[0203] In another aspect, the present invention relates to an assay method for evaluating the dose-response of a compound of formula (I) to a placebo in the treatment of moderate to severe psoriasis vulgaris, [A] A step of orally administering a pharmaceutical composition to a patient or subject requiring administration, Here, Pharmaceutical compositions, (1) For amounts of approximately 25 mg to 200 mg, formula (I):

[0204] [ka] compounds or With the pharmaceutically acceptable salt or solvate thereof, (2) A step of orally administering a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, [B] A step of orally administering a placebo to a patient or subject in need of administration, wherein the patient or subject is different from the patient or subject in step [A], [C] A step of collecting biological samples and vital signs from patients or subjects requiring collection from steps [A] and [B] in order to measure laboratory parameters over a period of at least 16 weeks, Here, Laboratory parameters, A plasma concentration parameter [C] selected from immediately before or after the start of the administration interval of the compound of formula (I). trough , C max , C avg , and / or AUC], Activity and levels of skin, blood cells, DNA, or molecular biomarkers, Corresponding clinical endpoints and safety parameters, The incidence of antidrug antibodies against the compound of formula (I) or its pharmaceutically acceptable salt, Vital signs selected from heart rate, and blood pressure including systolic and diastolic blood pressure as determined by physical examination, and / or The steps include, optionally, collecting any sub-test collections from the lesion or the lesion and whole body, selected from pharmacological genomic blood samples, ex vivo cytokine-releasing blood samples, skin biopsy samples, and photographic collection samples, [D] A step in which laboratory parameters from step [C] are used to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) relationships of the compound of formula (I) or a pharmaceutically acceptable salt thereof to placebo for efficacy, safety, immunogenicity, and biomarkers, [E] A step of characterizing the additional efficacy of the compound of formula (I) or a pharmaceutically acceptable salt thereof compared to a placebo, [F] The present invention relates to an assay method comprising steps [A] to [E], each of which provides an endpoint used to analyze and determine the dose-response of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a placebo used for the treatment of localized, moderate to severe psoriasis, by measuring the endpoint determination after administration of the pharmaceutical composition.

[0205] In another embodiment, the present invention relates to an assay method for evaluating the dose-response of a compound of formula (I) to a placebo in the treatment of moderate to severe psoriasis vulgaris, wherein the assay method is characterized in that the compound of formula (I) or a pharmaceutically acceptable salt is the hydrochloride salt of the compound of formula (I).

[0206] Embodiment 1. A method for treating psoriasis in subjects requiring treatment for psoriasis, wherein the patient requiring administration is given formula (I):

[0207] [ka] compounds or This includes administering a pharmaceutically acceptable salt or solvate form thereof, After treatment with the compound of formula (I) or its pharmaceutically acceptable salt or solvation, the subject, (i) A reduction of 75% or more in the Area and Severity Index of Psoriasis (PASI) compared to baseline PASI. (ii) A global investigator assessment (IGA) score of 2 or less after treatment, (iii) A decrease of 1 or more from baseline in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score, and (iv) A response to treatment by at least one measure of psoriasis response to treatment, selected from the group consisting of (iv) a decrease in the Dermatological Quality of Life Index (DLQI) score. 2. A method for treating psoriasis in a person in need of treatment for psoriasis, wherein formula (I):

[0208] [ka] compounds or This includes administering a pharmaceutically acceptable salt or solvate thereof, A method for achieving a measure of psoriasis response, which is a reduction of 75% or more in the Area and Severity Index (PASI) score compared to the baseline PASI score. 3. The method according to any one of Embodiments 1-2, wherein the subject achieves a measure of psoriasis response which is a reduction of at least about 90% in the PASI score compared to the baseline PASI score. 4. The method according to any one of Embodiments 1 to 3, wherein the subject achieves a measure of psoriasis response which is a reduction of approximately 100% in the PASI score compared to the baseline PASI score. 5. The method according to any one of Embodiments 1 to 4, wherein the subject achieves a measure of psoriasis response which is an Investigator Global Assessment (IGA) score of 2 or less. 6. The method according to any one of Embodiments 1 to 5, wherein the subject achieves a measure of psoriasis response which is a decrease of at least 2 points in the IGA score. 7. The method according to any one of Embodiments 1 to 6, wherein the subject achieves a measure of psoriasis response, which is an IGA score of 1 or less. 8. The method according to any one of Embodiments 1 to 7, wherein the subject achieves a measure of psoriasis response which is an IGA score of 0. 9. The method according to any one of Embodiments 1 to 8, wherein the subject achieves a measure of psoriasis response, which is an Investigator Global Assessment (IGA) score of 2 or less after treatment. 10. The method according to any one of Embodiments 1 to 9, wherein the patient achieves a measure of psoriasis response which is an IGA score of 1 or less after treatment. 11. The method according to any one of Embodiments 1 to 10, wherein the patient achieves a measure of psoriasis response which is an IGA score of 0 after treatment. 12. The method according to any one of Embodiments 1 to 11, wherein a measure of the response to psoriasis is measured at least two weeks after the initiation of treatment. 13. The method according to any one of Embodiments 1 to 12, wherein a measure of the response to psoriasis is measured at least four weeks after the start of treatment. 14. The method according to any one of Embodiments 1 to 13, wherein a measure of the response to psoriasis is measured at least 8 weeks after the start of treatment. 15. The method according to any one of Embodiments 1 to 14, wherein a measure of the response to psoriasis is measured at least 16 weeks after the initiation of treatment. 16. The method according to any one of Embodiments 1 to 15, wherein a measure of the response to psoriasis is measured at least 20 weeks after the initiation of treatment. 17. The method according to any one of Embodiments 1 to 16, wherein a measure of the response to psoriasis is measured at least 24 weeks after the initiation of treatment. 18. The method according to any one of Embodiments 1 to 17, wherein a measure of the response to psoriasis is measured at least 28 weeks after the initiation of treatment. 19. The method according to any one of Embodiments 1 to 18, wherein a measure of the psoriasis response is measured at least 32 weeks after the initiation of treatment. 20. The method according to any one of Embodiments 1 to 19, wherein a measure of the response to psoriasis is measured at least 40 weeks after the initiation of treatment. 21. The method according to any one of Embodiments 1 to 20, wherein a measure of the response to psoriasis is measured at least 52 weeks after the initiation of treatment. 22. The method according to any one of Embodiments 1 to 21, wherein the psoriasis is psoriasis vulgaris. 23. The method according to Embodiment 22, wherein the psoriasis is moderate to severe plaque psoriasis. 24. The method according to any one of Embodiments 1 to 23, wherein the subject is a candidate for phototherapy or systemic therapy. 25. The method according to any one of Embodiments 1 to 24, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is the hydrochloride salt of the compound of formula (I) or its solvate. 26. The method according to any one of Embodiments 1 to 25, comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 27. The method according to any one of Embodiments 1 to 26, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof on a daily basis. 28. The method according to any one of Embodiments 1 to 27, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 5 mg to about 800 mg. 29. The method according to any one of Embodiments 1 to 28, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 25 mg to about 500 mg. 30. The method according to any one of Embodiments 1 to 29, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 50 mg to about 500 mg. 31. The method according to any one of Embodiments 1 to 29, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 25 mg. 32. The method according to any one of Embodiments 1 to 30, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 50 mg. 33. The method according to any one of Embodiments 1 to 30, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 100 mg. 34. The method according to any one of Embodiments 1 to 30, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg. 35. The method according to any one of Embodiments 1 to 34, wherein the patient has at least 10% body surface area (BSA) prior to treatment. 36. The method according to any one of Embodiments 1 to 35, wherein the patient has a PASI score of approximately 12 to 72 prior to treatment. 37. The method according to any one of Embodiments 1 to 36, wherein the subject has at least three Investigator General Assessments (IGAs) prior to treatment. 38. The method according to any one of Embodiments 1 to 37, wherein the subject has at least one Psoriasis Symptoms and Signs Diary (PSSD) symptom score prior to treatment. 39. The method according to any one of Embodiments 1 to 38, wherein the subject has a dermatological quality of life index (DLQI) score greater than 1 prior to treatment. 40. The method according to any one of Embodiments 1 to 39, wherein the subject has not been treated with a biological agent for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 41. The method according to any one of Embodiments 1 to 40, wherein the subject has not been treated with any IL-23 receptor antagonist for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 42. A pharmaceutical product for treating subjects diagnosed with psoriasis, formula (I):

[0209] [ka] compounds or A pharmaceutical product comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which, when administered to a subject in an amount of at least 25 mg, causes an average reduction of approximately 75% or more in the Area and Severity Index (PASI) of psoriasis, as measured from the baseline PASI score, or an average reduction of 90% or more in the PASI. 43. The medicinal product according to Embodiment 42, wherein the subject achieves at least a 90% reduction in the area and severity index score of psoriasis compared to baseline. 44. The medicinal product according to Embodiment 42 or 43, wherein the subject achieves approximately 100% reduction in the area and severity index score of psoriasis compared to baseline. 45. A medicinal product according to any one of embodiments 42 to 44, wherein the patient achieves an Investigator's Global Assessment (IGA) score of 2 or less after treatment. 46. ​​A pharmaceutical product according to any one of Embodiments 42 to 45, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 25 mg to about 800 mg. 47. A pharmaceutical product according to any one of Embodiments 42 to 46, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 50 mg to about 800 mg. 48. A pharmaceutical product according to any one of Embodiments 42 to 47, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 50 mg to about 500 mg. 49. A pharmaceutical product according to any one of Embodiments 42 to 46, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 25 mg. 50. A pharmaceutical product according to any one of Embodiments 42 to 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 50 mg. 51. A pharmaceutical product according to any one of Embodiments 42 to 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 100 mg. 52. A pharmaceutical product according to any one of Embodiments 42 to 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of approximately 200 mg. 53. A method for treating psoriasis in a person in need of treatment for psoriasis, wherein the patient in need of administration is given formula (I):

[0210] [ka] compounds or A method comprising administering a pharmaceutically acceptable salt or solvate thereof in an amount of approximately 200 mg. 54. The method according to Embodiment 53, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg once daily. 55. The method is (i) A reduction of 75% or more in the Area and Severity Index of Psoriasis (PASI) compared to baseline PASI. (ii) A global investigator assessment (IGA) score of 2 or less after treatment, (iii) A decrease of 1 or more from baseline in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score, and The method according to Embodiment 53 or 54, further comprising the step of achieving one or more selected from the group consisting of (iv) a reduction in the Dermatological Quality of Life Index (DLQI) score. 56. The method according to embodiments 53 to 55, wherein the psoriasis is psoriasis vulgaris. 57. The method according to embodiment 56, wherein the psoriasis is moderate to severe psoriasis vulgaris. 58. The method according to any one of Embodiments 53 to 57, wherein the subject is a candidate for phototherapy or systemic therapy. 59. The method according to any one of Embodiments 53 to 58, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is the hydrochloride salt of the compound of formula (I) or its solvate. 60. The method according to any one of Embodiments 53 to 59, comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 61. The method according to any one of Embodiments 53 to 60, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof on a daily basis. 62. The method according to any one of embodiments 53 to 61, wherein the patient has at least 10% of body surface area (BSA) prior to treatment. 63. The method according to any one of embodiments 53 to 62, wherein the patient has a PASI score of approximately 12 to 72 prior to treatment. 64. The method according to any one of embodiments 53 to 63, wherein the subject has at least three Investigator General Assessments (IGAs) prior to treatment. 65. The method according to any one of embodiments 53 to 64, wherein the subject has at least one Psoriasis Symptoms and Signs Diary (PSSD) symptom score prior to treatment. 66. The method according to any one of embodiments 53 to 65, wherein the subject has a PSSD sign score of at least 1 prior to treatment. 67. The method according to any one of embodiments 53 to 66, wherein the subject has a dermatological quality of life index (DLQI) score greater than 1 prior to treatment. 68. The method according to any one of Embodiments 53 to 67, wherein the subject has not been treated with a biological agent for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 69. The method according to any one of embodiments 53 to 68, wherein the subject has not been treated with any IL-23 receptor antagonist for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 70. A method for treating a patient population diagnosed with psoriasis, wherein the patient population is given formula (I):

[0211] [ka] compounds or A method comprising administering a pharmaceutically acceptable salt or solvate thereof in an amount of approximately 200 mg. 71. The method according to Embodiment 66, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg daily. 72. The method shall (i) achieve a reduction of at least approximately 75% in the area and severity index of psoriasis (PASI) from baseline in at least approximately 70% of the patient population, (ii) achieve a reduction of at least approximately 90% in the area and severity index of psoriasis (PASI) from baseline in at least approximately 60% of the patient population, (iii) achieve a reduction of approximately 100% in the area and severity index of psoriasis (PASI) from baseline in at least approximately 40% of the patient population, and (iv) achieve a reduction in the PASI score from baseline in at least half of the patient population. The method according to Embodiment 70 or 71, further comprising the step of achieving one or more selected from the group consisting of: (v) achieving an average reduction of at least approximately 14 points; (vi) achieving an average reduction of at least approximately 40 points in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score; (vi) achieving an average reduction of at least approximately 50 points in the PSSD sign score of score 0; (vii) achieving an Investigator's Global Assessment (IGA) score of 0 or 1 in at least approximately 60% of the patient population; and (viii) achieving an IGA score of 0 in at least approximately 40% of the patient population. 73. The method according to embodiments 70-72, wherein the psoriasis is psoriasis vulgaris. 74. The method according to embodiment 73, wherein the psoriasis is moderate to severe plaque psoriasis. 75. The method according to any one of Embodiments 70 to 74, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is the hydrochloride salt of the compound of formula (I) or its solvate. 76. The method according to any one of Embodiments 70 to 75, comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof. 77. The method according to any one of Embodiments 70 to 76, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof on a daily basis. 78. The method according to any one of embodiments 70 to 77, wherein the patients in the patient population have at least 10% body surface area (BSA) before treatment. 79. The method according to any one of embodiments 70 to 78, wherein the patients in the patient population have a PASI score of approximately 12 to 72 prior to treatment. 80. The method according to any one of embodiments 70 to 79, wherein the patients in the patient population have at least three Investigator General Assessments (IGAs) prior to treatment. 81. The method according to any one of Embodiments 70 to 80, wherein the patient population has at least one Psoriasis Symptom and Signs Diary (PSSD) symptom score. 82. The method according to any one of Embodiments 70 to 81, wherein, prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, patients in the patient population have not been treated with a biological agent for psoriasis. 83. The method according to any one of Embodiments 70 to 82, wherein, prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, patients in the patient population have not been treated with any IL-23 receptor antagonist for psoriasis. 84. The method according to any one of embodiments 70 to 83, wherein the subject is a patient. 85. The method of Embodiment 84, wherein the subject is an adult or adolescent patient. 86. The method according to Embodiments 70 to 85, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is a hydrochloride salt. 87. The method according to Embodiments 70 to 86, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is a hydrochloride salt in a crystalline form. 88. A pharmaceutical product for treating subjects diagnosed with psoriasis, formula (I):

[0212] [ka] compounds or A pharmaceutical product comprising a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (I) or its pharmaceutically acceptable salt or solvate is present in an amount of approximately 200 mg. [Examples]

[0213] Example 1. Daily administration for 16 weeks in adult human subjects with moderate to severe psoriasis vulgaris. The IL-23 receptor antagonist peptide used in this embodiment refers to the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, specifically the hydrochloride salt of the compound of formula (I) in crystalline form.

[0214] The following describes a multicenter, randomized, placebo-controlled dose-range study evaluating the efficacy and safety of the hydrochloride of compound (I) for the treatment of moderate to severe plaque psoriasis.

[0215] Interleukin-23 is responsible for the activation and maintenance of T helper 17 (Th17) to secrete pro-inflammatory cytokines involved in the progression of psoriasis. Due to its high potency, IL-23 receptor antagonist peptides can systemically antagonist IL-23R, providing activity to the skin and / or joint tissues, and addressing unmet needs for a wide range of diseases.

[0216] [Table 2-1]

[0217] [Table 2-2]

[0218] Overall design This was a randomized, double-blind, placebo-controlled, dose-range, parallel-group, multicenter intervention trial in subjects with moderate to severe psoriasis vulgaris. 240 target subjects were enrolled in the trial, with 40 subjects planned for each intervention group. A schematic diagram of the trial is shown in Figure 1.

[0219] Participants were instructed to undergo the study intervention at approximately the same time each day, in the morning (AM) and afternoon (PM), using approximately 240 mL of non-carbonated water on an empty stomach. Fasting was defined as refraining from food intake for at least two hours before the study intervention and refraining from food and liquid intake for at least 30 minutes after the study intervention.

[0220] Group 1: 25 mg once daily: Participants received 25 mg of IL-23 receptor antagonist peptide once daily (QD) from week 0 to week 16.

[0221] Group 2: 50 mg once daily: Participants receive IL-23 receptor antagonist peptide 50 mg QD from week 0 to week 16.

[0222] Group 3: 100 mg once daily: Participants receive IL-23 receptor antagonist peptide 100 mg QD from week 0 to week 16.

[0223] Group 4: 25 mg twice daily: Participants received 25 mg of IL-23 receptor antagonist peptide twice daily (BID) from week 0 to week 16.

[0224] Group 5: 100 mg twice daily: Participants receive IL-23 receptor antagonist peptide 100 mg BID from week 0 to week 16.

[0225] Group 6: Placebo: Participants receive placebo BID from week 0 to week 16.

[0226] At week 16, eligible subjects will have the option to enroll in a 36-week long-term extension (LTE) trial of the treatment. All subjects will be treated with an active trial intervention in the LTE.

[0227] The total duration of this trial was 24 weeks: a screening period of ≤4 weeks, a treatment period of 16 weeks, and a 4-week safety follow-up period after the last trial intervention dose for subjects who were deemed ineligible for the LTE trial or were not enrolled at week 16. All eligible subjects enrolled in the LTE will continue treatment after their week 16 visit under the LTE protocol.

[0228] Efficacy, safety, PK, immunogenicity, and biomarkers were evaluated. In addition, (where local regulations permitted) four optional sub-study collections were available for consenting subjects: pharmacological genomic blood samples, ex vivo cytokine-releasing blood samples, skin biopsies, and photographic collections (lesions or lesions and whole body).

[0229] Inclusion Criteria Each participant was 18 years of age or older and met all of the following criteria. (a) Having had a diagnosis of psoriasis vulgaris with or without PsA for at least 6 weeks prior to the first dose of the study intervention, (b) Patients who had a total BSA of ≥ 10% at screening and baseline, (c) Patients who had a total PASI ≥ 12 at the time of screening and at baseline, (d) Patients who had a total IGA ≥ 3 at the time of screening and at baseline, (e) For psoriasis vulgaris, phototherapy or systemic treatment was a candidate, (f) During the test, I agree to avoid prolonged sun exposure and to avoid using tanning rooms or other sources of ultraviolet (UV) light. (g) Otherwise healthy, based on health examination, medical history, vital signs, and a 12-lead triplicate electrocardiogram (ECG) performed at the time of screening.

[0230] Exclusion criteria Potential subjects were excluded if they possessed any of the following disease characteristics. (a) Having had a non-plaque form of psoriasis (e.g., erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis), or (b) Having current drug-induced psoriasis (e.g., new onset or exacerbation of psoriasis from beta-blockers, calcium channel blockers, or lithium).

[0231] The target cases are those in which the subjects are (a) If you have previously received any other treatment that directly targets IL-23, (b) If, within 12 weeks of the first dose of the study intervention or within 5 half-lives, whichever is longer, you have received any treatment that directly targets IL-17 or IL-12 / 23, or have received anti-TNFα biological therapy, (c) If you have received any B-cell depleting agent (including, but not limited to, rituximab or alemtuzumab) within 26 weeks of the first dose of the trial intervention, (d) If you have previously received natalizumab, belimumab, or a T-cell modulating agent (including, but not limited to, abatacept or vizilizumab) within 12 weeks of the first dose of the study intervention or within 5 half-lives, whichever is longer, (e) If you have received a JAK inhibitor within 4 weeks of the first dose of the trial intervention, (f) If you have received phosphodiesterase 4 (PDE4) inhibitor therapy (including, but not limited to, apremilast) within 4 weeks of the first dose of the trial intervention, (g) If you have received any systemic immunosuppressant (including, but not limited to, methotrexate (MTX), azathioprine, cyclosporine, 6-thioguanine, mercaptopurine, mycophenolate mofetil, and tacrolimus) within four weeks of the first dose of the study intervention, (h) Except for the Bacille Calmette Guerin (BCG) vaccine listed below, if you have received or are expected to receive any live viral or bacterial vaccine within 12 weeks prior to the first dose of the trial intervention, (i) If you have received the BCG vaccine within 12 months of the first dose of the trial intervention, (j) If, within four weeks of the first dose of the study intervention, you have received any phototherapy or any systemic drug administration that may affect psoriasis or PASI or IGA assessment (including, but not limited to, oral or injectable corticosteroids, acitretin, retinoids, 1,25-dihydroxyvitamin D3 and analogues, herbal remedies or traditional Taiwanese, Korean or Chinese medicines), (k) If a participant had received any topical therapy that could affect psoriasis or PASI or IGA assessment within two weeks of the first dose of the study intervention, they were excluded (including, but not limited to, corticosteroids, tar, anthraline, calcipotriene, tazarotene, methoxsalen, pimecrolimus, tacrolimus, and traditional Taiwanese, Korean, or Chinese medicines).

[0232] Intervention group Each participant in the group received a film-coated tablet containing either an IL-23 receptor antagonist peptide or a placebo twice daily, as described in Table 1. Participants took the tablet with approximately 240 mL of non-carbonated water and remained consistently fasted throughout the study (including the day of facility visit). Fasting was defined as refraining from food intake for at least two hours before the study intervention and refraining from food and liquid intake for at least 30 minutes after the study intervention.

[0233] [Table 3]

[0234] Test evaluation During treatment, criteria for efficacy, PK, immunogenicity, biomarkers, pharmacogenomics, and safety were measured. Participants were provided with an electronic device to input patient-reported outcome (PRO) data at each trial visit. All visit-specific PRO assessments, with the exception of urine pregnancy tests and urinalysis, were performed / completed before any other tests, procedures, or clinical assessments to prevent interference with participants' perception.

[0235] An electrocardiogram (ECG) was performed before vital signs were recorded, and both procedures were completed before any invasive procedures. Vital signs were recorded from the arm opposite to the one from which the blood sample was taken.

[0236] All samples (including safety, efficacy, PK, and biomarkers) were obtained after PRO and ECG evaluation.

[0237] Clinician-reported outcomes, including the Area and Severity Index of Psoriasis (PASI), Body Surface Area (BSA), Investigator's Global Assessment (IGA), Nail Psoriasis Area and Severity Index (NAPSI), Fingernail Investigator's Global Assessment (f-PGA), Genital Investigator's Static Global Assessment (s-PGA-G), Hand and / or Foot Investigator's Global Assessment (hf-PGA), and Scalp-Specific Investigator's Global Assessment (ss-IGA), were obtained at weeks 0, 8, and 16. PASI and IGA were also obtained at weeks 1, 2, 4, and 12, and at week 20, four weeks after discontinuation of tablet administration.

[0238] Adverse events were reported and followed up by the investigator. Clinically relevant changes that occurred during the study were recorded. Any clinically significant abnormalities that persisted at the end of the study / at early withdrawal were followed up by the investigator, if possible, until improvement or clinical stability was achieved. Safety and tolerability assessments included physical examination, vital signs, electrocardiogram, clinical safety laboratory assessment, review of concomitant medications, pregnancy testing, assessment of suicidal ideation using the Columbia Suicide Severity Scale, and tuberculosis assessment.

[0239] Summary of Results A total of 337 participants were screened, and 255 of them were randomized into six treatment groups: placebo (n=43), 25 mg QD (n=43), 50 mg QD (n=43), 25 mg BID (n=41), 100 mg QD (n=43), and 100 mg BID (n=43)). The trial was conducted at 65 sites across 10 countries, with 49.4% of participants from Europe and the remainder distributed across Asia (17.3%) and North America (33.3%). Most participants were Caucasian (74.5%) and male (69.0%). The mean age (SD) was 44.3 (12.65) years, and the mean baseline weight was 88.9 (20.87) kg.

[0240] Disposition and baseline characteristics of the primary efficacy analysis set (n=255): In total, 24 participants (9.4%) discontinued the study drug by week 16. The proportion of participants discontinuing the study drug was highest in the placebo group and the 25 mg QD group (16.3% each [n=7]). A total of 17 participants (8.0%) in the composite group discontinued the study drug, with some variability across dose groups. No dose-dependent trends were observed for any reason for discontinuation.

[0241] Baseline disease characteristics were generally similar across treatment groups. Overall, the mean psoriasis disease duration (SD) was 18.2 (12.79) years. The mean PASI total score (SD) was 19.05 (5.831). Compared to placebo (11.6% with an IGA score of 4) and other treatment arms (range 16.3–19.5%), a higher proportion of patients in the 25 mg QD group (30.2%) and the 100 mg BID dose (28.6%) had severe psoriasis based on an IGA score of 4 at baseline. While some variability in baseline data was observed across treatment groups, the arms were largely balanced.

[0242] The proportion of participants with prior treatment experience was similar across treatment groups. Overall, 43.1% had previously received phototherapy, 47.8% had previously received conventional non-biological systemic therapy, 7.1% had previously received novel non-biological systemic therapy, and 22.0% had previously received biological therapy.

[0243] Analysis of test results The primary efficacy endpoint was the proportion of participants who achieved a PASI75 response at week 16, defined as a reduction of at least 75% from baseline in the total PASI score.

[0244] For the primary analysis, a combined strategy (non-responder complementation) was applied to address intermediate events #1 (discontinuation of the study intervention due to AEs such as lack of efficacy or worsening of psoriasis) and #2 (initiation of protocol-prohibited medication or therapy that could improve psoriasis). A treatment strategy (observational data) was applied to intermediate event #3 (discontinuation of the study intervention for other reasons). Participants for whom data were missing after the application of ICE were also considered non-responders.

[0245] Using MCP Mod, we tested for a positive overall therapeutic effect based on a candidate response model. A response signal was detected for the primary endpoint (p < 0.001).

[0246] In addition to response analysis, pairwise comparisons of each treatment group versus placebo group were performed for the primary endpoint, PASI75, at week 16. Pairwise comparisons were not adjusted for multiplicity. Cochrane-Mantel-Henzel-Chi-squared statistics were used, stratified by baseline weight categories (≤90kg, >90kg) at a two-sided significance level of 0.05 (Table 2). PASI75 responses at week 16 are also shown in Figure 2. Significantly higher proportions of participants in each treatment group achieved a PASI75 response at week 16 compared to the placebo group.

[0247] As shown in the response signals, a significantly higher proportion of participants in each dose group achieved a PASI75 response at week 16 compared to the placebo group (9.3%) (37.2% in the 25 mg QD, 58.1% in the 50 mg QD, 51.2% in the 25 mg BID, 65.1% in the 100 mg QD, and 78.6% in the 100 mg BID; p=0.002 for the 25 mg QD and p<0.001 for all other dose groups).

[0248] As shown in Figure 2, a significant response signal was detected for the primary endpoint (PASI75 response at week 16).

[0249] [Table 4] a Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders. b Treatment differences and 95% confidence intervals were calculated using Mantel-Haenszel (MH) weightings, adjusted for baseline weight categories (≤90kg, >90kg). c The p-values ​​are based on the Cochran-Mantel-Haenszel (CMH) chi-squared test, stratified by baseline weight category (≤90kg, >90kg).

[0250] Secondary efficacy endpoint: No adjustment was made for multiplicity for the secondary endpoints in this study. All statistical tests were performed at a two-sided significance level of 0.05. The nominal p-values ​​are presented.

[0251] All selected secondary endpoints demonstrated achieved statistical significance at a nominal significance level of 0.05 (two-sided) at week 16. At week 16, the proportion of participants achieving a clear (0) or minimum (1) IGA score, a clear (0) IGA score, a PASI90 response, a PASI100 response (Figure 3), or a DLQI score of 0 or 1 was significantly higher in each peptide dose group compared to placebo. At week 16, participants in each peptide dose group showed significantly greater improvement (reduction) from baseline than participants treated with placebo, as measured by PASI total score, BSA, PSSD symptom score, and PSSD sign score. In longitudinal analyses, PASI and IGA response rates showed clear separation between peptide doses from placebo as early as week 4 and generally continued to increase until week 16. In most dose groups, the response rates for PASI75, PASI90, and PASI100 continued to increase without any clear plateau until week 16 (Figure 4).

[0252] Table 3 and Figure 3 summarize the percentages of participants who achieved complete IGA score disappearance (0), complete IGA score disappearance (0) or minimum (1), PASI100, and PASI90 response at week 16.

[0253] [Table 5] a Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders. b Treatment differences and 95% confidence intervals were calculated using Mantel-Henzel (MH) weighting, adjusted for baseline weight categories (≤90kg, >90kg). c The p-value is based on the Cochran-Mantel-Haenzel (CMH) chi-squared test, stratified by baseline weight category (≤90kg, >90kg).

[0254] Timeline up to week 16 Time-series analysis of PASI75, PASI90, PASI100, IGA0 / 1, and IGA0: Figure 4 summarizes the proportion of participants achieving PASI75, PASI90, PASI100, IGA0 / 1, and IGA0 over time from week 1 to week 16, along with their corresponding 95% CIs. Clear separation between peptide dose and placebo (0.0%) in the proportion of participants achieved a PASI75 response initiated at week 4 in the 50 mg QD (16.3%), 100 mg QD (16.3%), and 100 mg BID (23.8%) groups. After week 4, the PASI75 response continued to improve in the treatment groups until week 16. The PASI75 response was generally stable or increasing in all groups from week 12 to week 16. Similar response patterns were observed for PASI90 and IGA0 / 1 responses, respectively. Regarding PASI100 response, a clear separation between peptide dose and placebo (0.0%) in the proportion of participants achieved a PASI100 response (11.9%) initiated at week 8 in the 100 mg BID group, and the PASI100 response rate in the 100 mg BID group continued to increase up to week 16 (40.5%). A similar response pattern was observed for the endpoint of the proportion of participants achieving an IGA score of (0).

[0255] Safety: Safety was evaluated among all randomized and treated participants who received at least one dose of the investigational drug (partially or completely) according to the assigned treatment they received during the trial. This is also referred to as the safety analysis set.

[0256] Overall, the IL-23 receptor antagonist peptide was well tolerated by all participants in the IL-23 receptor antagonist peptide treatment groups during the study, and the proportion of subjects experiencing one or more adverse events (AEs) was similar between the IL-23 receptor antagonist peptide group and the placebo group. There was no evidence of a dose-dependent increase in the occurrence of AEs across the peptide treatment groups. There were three SAEs that occurred in the study (n=1 each: attempted suicide, COVID-19, and infected cyst). No dose-dependent relationship was observed.

[0257] A small number of laboratory anomalies occurred during the trial and were similar between the placebo and treatment groups. There was no evidence of a dose-dependent increase in the occurrence of anomalies. There were no deaths, MACEs, or malignancies during the trial.

[0258] Table 4 provides a summary of key safety outcomes up to the end of the study.

[0259] [Table 6] a This includes all IL-23 peptide treatment sequences (25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Subjects are counted only once for any given event, regardless of the number of times the event was actually experienced. Adverse events are coded using MedDRA Version 25.1. * MACE: Myocardial infarction (MI), stroke, or cardiovascular death.

[0260] Pharmacokinetics: The evaluable pharmacokinetic (PK) analysis set included all randomized subjects who received at least one full dose of IL-23 receptor antagonist peptide and had at least one valid blood sample drawn for PK analysis after its initial administration of IL-23 receptor antagonist peptide. Plasma concentrations of IL-23 receptor antagonist peptide from week 1 to week 16 are summarized in Table 5. The number of participants whose IL-23 receptor antagonist peptide plasma concentration from week 1 to week 16 was < LLOQ (0.02 ng / mL) is summarized in Table 6.

[0261] [Table 7-1]

[0262] [Table 7-2]

[0263] [Table 7-3]

[0264] [Table 7-4]

[0265] [Table 7-5]

[0266] [Table 7-6]

[0267] a All randomized subjects who received at least one complete dose and had at least one valid blood sample drawn for PK analysis after the initial dose. bFor QD dosing, the peak is defined as any sample between 0.25 hours and <6 hours from the last AM dose, the intermediate is between 6 hours and <20 hours from the last AM dose, and the trough is at least 20 hours from the last AM dose. c For BID dosing, the peak is defined as any sample between 0.25 hours and <4 hours from the last dose, the intermediate is between 4 hours and <8 hours from the last dose, and the trough is at least 8 hours from the last dose. Note: The subjects may include multiple samples collected within the same time window, where N is the number of samples included in the summary. Note: Data from participants who discontinued the study drug will be excluded from that point onward. In addition, data from participants who received incomplete / inaccurate doses or skipped doses based on two previous doses prior to PK sample collection, or from participants who skipped doses before PK sample collection, will be excluded for those visits.

[0268] [Table 8] a All randomized subjects who received at least one complete dose and had at least one valid blood sample drawn for PK analysis after the initial dose. b For QD dosing, the peak is defined as any sample between 0.25 hours and <6 hours from the last AM dose, the intermediate is between 6 hours and <20 hours from the last AM dose, and the trough is at least 20 hours from the last AM dose. c For BID dosing, the peak is defined as any sample between 0.25 hours and <4 hours from the last dose, the intermediate is between 4 hours and <8 hours from the last dose, and the trough is at least 8 hours from the last dose. Note: Data from participants who discontinued the study drug will be excluded from that point onward. In addition, data from participants who received incomplete / inaccurate doses or skipped doses based on two previous doses prior to PK sample collection, or from participants who skipped doses before PK sample collection, will be excluded for those visits. Main: LLOQ = lowest quantitative level (0.02ng / mL)

[0269] Following oral administration of IL-23 receptor antagonist peptide, the median plasma drug concentration increased in a dose-dependent manner. The median trough concentrations of IL-23 receptor antagonist peptide over time remained generally similar, with no significant drug accumulation between week 1 and week 16. This is consistent with the final elimination half-life of IL-23 receptor antagonist peptide (approximately 9–12 hours) and the achievement of steady-state conditions by week 1 of treatment. The median trough plasma concentrations of IL-23 receptor antagonist peptide over time are graphically shown in Figure 5.

[0270] At week 16, the median peak plasma concentrations of IL-23 receptor antagonist peptide were 0.295 ng / mL for 25 mg QD, 0.917 ng / mL for 50 mg QD, 0.796 ng / mL for 25 mg BID, 1.165 ng / mL for 100 mg QD, and 1.970 ng / mL for the 100 mg BID dose (Table 5). At week 16, the median trough plasma concentrations of IL-23 receptor antagonist peptide were 0.057 ng / mL for 25 mg QD, 0.089 ng / mL for 50 mg QD, 0.134 ng / mL for 25 mg BID, 0.132 ng / mL for 100 mg QD, and 0.451 ng / mL for the 100 mg BID dose (Table 5). The median plasma concentrations of IL-23 receptor antagonist peptide were significantly higher in the BID dosing regimen for the same total daily dose given in the QD regimen, as shown in Figure 5, with the trough concentration of 25 mg BID being equivalent to that of 100 mg QD. For the QD dosing regimen, peak concentrations were defined as any PK sample taken between 0.25 hours and <6 hours after the last morning dose, and trough concentrations were at least 20 hours after the last morning dose. For the BID dosing regimen, peak concentrations were defined as any PK sample taken between 0.25 hours and <4 hours after the last dose, and trough concentrations were at least 8 hours after the last dose.

[0271] To evaluate the effect of body weight on IL-23 receptor antagonist peptide (IL-23) PK, plasma concentrations of IL-23 receptor antagonist peptide up to week 16 were compared between two subgroups based on baseline body weight ≤90 kg (Table 7) and >90 kg (Table 8). Line plots of baseline ≤median and >median body weight for trough concentrations of IL-23 receptor antagonist peptide up to week 16 were created for each treatment group to evaluate the effect of body weight on IL-23 receptor antagonist peptide PK (Figure 6). Based on the tabular and graphical presentation of IL-23 receptor antagonist peptide plasma concentration data by median baseline body weight, it is not consistently clear that body weight has a significant impact on systemic drug exposure.

[0272] [Table 9-1]

[0273] [Table 9-2]

[0274] [Table 9-3]

[0275] [Table 9-4]

[0276] [Table 9-5]

[0277] [Table 9-6] a All randomized subjects who received at least one complete dose and had at least one valid blood sample drawn for PK analysis after the initial dose. b For QD dosing, the peak is defined as any sample between 0.25 hours and <6 hours from the last AM dose, the intermediate is between 6 hours and <20 hours from the last AM dose, and the trough is at least 20 hours from the last AM dose. c For BID dosing, the peak is defined as any sample between 0.25 hours and <4 hours from the last dose, the intermediate is between 4 hours and <8 hours from the last dose, and the trough is at least 8 hours from the last dose. Note: The subjects may include multiple samples collected within the same time window, where N is the number of samples included in the summary. Note: Data from participants who discontinued the study drug will be excluded from that point onward. In addition, data from participants who received incomplete / inaccurate doses or skipped doses based on two previous doses prior to PK sample collection, or from participants who skipped doses before PK sample collection, will be excluded for those visits.

[0278] [Table 10-1]

[0279] [Table 10-2]

[0280] [Table 10-3]

[0281] [Table 10-4]

[0282] [Table 10-5]

[0283] [Table 10-6] a All randomized subjects who received at least one complete dose and had at least one valid blood sample drawn for PK analysis after the initial dose. b For QD dosing, the peak is defined as any sample between 0.25 hours and <6 hours from the last AM dose, the intermediate is between 6 hours and <20 hours from the last AM dose, and the trough is at least 20 hours from the last AM dose. cFor BID dosing, the peak is defined as any sample between 0.25 hours and <4 hours from the last dose, the intermediate is between 4 hours and <8 hours from the last dose, and the trough is at least 8 hours from the last dose. Note: The subjects may include multiple samples collected within the same time window, where N is the number of samples included in the summary. Note: Data from participants who discontinued the study drug will be excluded from that point onward. In addition, data from participants who received incomplete / inaccurate doses or skipped doses based on two previous doses prior to PK sample collection, or from participants who skipped doses before PK sample collection, will be excluded for those visits.

[0284] Tables 9 (trough concentration), 10 (intermediate concentration), and 11 (peak concentration) summarize the clinical response rates at week 16 based on the quartile of plasma IL-23 receptor antagonist peptide concentration at week 16. Figures 7 and 8 show bar plots of the percentage of participants who achieved a PASI75, PASI90, and PASI100 response, or an IGA score of 0 / 1 or 0 at week 16, based on the trough plasma concentration of IL-23 receptor antagonist peptide at week 16. Figures 9 and 10 show bar plots of the percentage of participants who achieved a PASI75, PASI90, and PASI100 response, or an IGA score of 0 / 1 or 0 at week 16, based on the intermediate plasma IL-23 receptor antagonist peptide concentration at week 16. Figures 11 and 12 show bar plots of the percentage of participants who achieved a PASI75, PASI90, and PASI100 response, or an IGA score of 0 / 1 or 0 at week 16, based on the peak plasma IL-23 receptor antagonist peptide concentration at week 16.

[0285] [Table 11-1]

[0286] [Table 11-2] a All randomized subjects who received at least one complete dose and had at least one valid blood sample drawn for PK analysis after the initial dose. Note: For QD (Quick Day) administration, the trough is at least 20 hours after the last AM (Acute Morning) dose. For BID (Broad Day) administration, the trough is at least 8 hours after the last dose. Note: Sample results from participants who discontinued the study drug will be excluded from that point onward. In addition, sample results from participants who received incomplete / inaccurate doses or skipped doses based on two previous doses prior to PK sample collection, or data from participants who skipped doses before PK sample collection, will be excluded for that visit.

[0287] [Table 12-1]

[0288] [Table 12-2] a All randomized subjects who received at least one complete dose and had at least one valid blood sample drawn for PK analysis after the initial dose. Note: For QD (Quick Day) administration, the interim dose is 6 to <20 hours after the last AM (Acute Morning) dose. For BID (Best Day) administration, the interim dose is 4 to <8 hours after the last dose. Note: Sample results from participants who discontinued the study drug will be excluded from that point onward. In addition, sample results from participants who received incomplete / inaccurate doses or skipped doses based on two previous doses prior to PK sample collection, or data from participants who skipped doses before PK sample collection, will be excluded for that visit.

[0289] [Table 13-1]

[0290] [Table 13-2] a All randomized subjects who received at least one complete dose and had at least one valid blood sample drawn for PK analysis after the initial dose. Note: For QD dosing, the peak is defined as any sample between 0.25 hours and <6 hours from the last AM dose. For BID dosing, the peak is defined as any sample between 0.25 hours and <4 hours from the last dose. Note: Sample results from participants who discontinued the study drug will be excluded from that point onward. In addition, sample results from participants who received incomplete / inaccurate doses or skipped doses based on two previous doses prior to PK sample collection, or data from participants who skipped doses before PK sample collection, will be excluded for that visit.

[0291] Pharmacodynamics A set of evaluable pharmacodynamic (PD) analyses included all randomized subjects. A strong systemic PD response, significantly differentiating treatment from placebo, was observed at all doses of the IL-23 receptor antagonist peptide. The IL-23 receptor antagonist peptide significantly attenuated serum levels of the psoriasis-related biomarker BD-2 (Figure 13). Statistically significant reductions in BD-2 serum levels were observable in all treatment groups as early as week 4, and administration of 100 mg BID resulted in a statistically significant reduction in BD-2 compared to all other doses from week 8 onward.

[0292] A statistically significant decrease in serum IL-22 levels was observed in all treatment groups compared to placebo, and the 100 mg BID treatment group again showed a statistically significant decrease from week 12 onward compared to all other doses (Figure 14). Statistically significant decreases in serum levels of IL-17A (Figure 15) and IL-17F (Figure 16) were also observed in all treatment groups compared to placebo.

[0293] To evaluate psoriasis-related systemic biomarkers (beta-defensin 2 (BD-2), IL-17A, IL-17F, and IL-22), serum protein concentrations were measured using validated immunoassays. The IL-17A (catalog no. 03-0159-00) and IL-17F (catalog no. 03-0164-00) assays used are commercially available SMC®-based, highly sensitive immunoassays produced by EMD Millipore Corporation. Analysis was performed on the Erenna® instrument platform according to the manufacturer's protocol, except for the use of 11 μL of Elution Buffer B. The IL-22 assay is also based on the SMC® platform and performed on the Erenna instrument, although the assay was internally developed as a coated plate-based assay. Development and optimization of the BD-2 assay were performed at Meso Scale Discovery, an electrochemiluminescence-based platform division of Meso Scale Diagnostics LLC (MSD). For all assays, concentration adjustments were made for measurements lower than the empirically defined LLOQ value or empirically defined ULOQ value. Assay QC validated the performance of the generated standard curves (mean concentration recovery and CV of technical replicates) and control samples (inter-assay plate agreement (CV)).

[0294] Immunogenicity: Table 12 summarizes the incidence of anti-drug antibodies (ADAs) to the IL-23 receptor antagonist peptide up to week 16. The overall incidence of ADA was low, with 3 out of 209 participants (1.4%) testing positive for ADA before the initial dose of the IL-23 receptor antagonist peptide (baseline), and subsequently testing negative. All 3 participants were randomized to the IL-23 receptor antagonist peptide 50 mg QD treatment group. Of the additional 209 participants, 8 (3.8%) had one ADA-positive sample after dose. The antibody response to the IL-23 receptor antagonist peptide was low titer (1:50, minimum detectable titer in the assay), transient, and ADA positivity was observed at a single point in time during the study in all participants who reported a positive ADA result. There was no clear association between positive ADA results and the dose level or time in the study.

[0295] [Table 14] a Includes all treatment columns (25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). b Subjects who tested positive for antibodies at baseline, regardless of their condition after the initial dose. c Subjects positive for treatment-boosted antibodies include those who were positive at baseline and whose titer doubled at any given time. Subjects with baseline samples who did not show a double titer increase after treatment are not considered treatment-boosted. d This includes subjects who were positive for antibodies at baseline but whose titer did not double after the first dose, remained the same after treatment, or whose ADA titer decreased or disappeared after administration. eSubjects who tested positive for antibodies expressed under treatment include all treatment-boosted or treatment-induced subjects who were positive at any point after the initial dose up to the 16-week or 20-week follow-up visit. Subjects with a baseline-positive sample who did not show a twofold increase in titer after treatment are not considered treatment-boosted. f Subjects who tested positive under treatment at any point before the 16th week or the 20th week follow-up visit will be excluded.

[0296] Table 13 summarizes the incidence of neutralizing antibodies (NAbs) against the IL-23 receptor antagonist peptide up to week 16. All ADA-positive samples were negative in the NAb assay. There was no clear correlation between ADA positivity and efficacy.

[0297] [Table 15] a Includes all treatment columns (25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). b Subjects who tested positive for antibodies expressed under treatment include all treatment-boosted or treatment-induced subjects who were positive at any point after the first dose up to week 16 or week 20 of follow-up. Subjects with a baseline-positive sample who did not show a twofold increase in titer after treatment are not considered treatment-boosted. c Evaluable subjects are those who test positive for antibodies expressed under treatment, without detectable interference in the neutralizing antibody assay. d Regardless of the antibody status after the initial dose, subjects who tested positive for neutralizing antibodies at baseline were included. e Neutralizing antibodies expressed from antibody targets under positive treatment are considered positive targets. f Neutralizing antibodies at any given point in time are excluded from the study.

[0298] Baseline disease characteristics Baseline psoriasis disease characteristics (full analysis set) of participants who received at least one study drug were consistent with the population with moderate to severe psoriasis (Table 14). Baseline disease characteristics were generally comparable across treatment groups, with some variability observed. The mean duration of psoriasis disease was 18.2 (12.79) years. The mean percentage of body surface areas (BSAs) involved was 22.8 (12.99), and the median PASI total score was 19.05 (5.831). In addition, 79.2% of participants had an IGA=3, and 20.8% had severe disease as defined by a baseline IGA score of 4.

[0299] The mean (SD) baseline DLQI, PSSD symptom, and sign scores were 13.5 (7.08), 51.8 (23.84), and 64.6 (18.25), respectively (Tables 14, 15, and 16).

[0300] [Table 16] a Includes all peptide treatment sequences (25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID).

[0301] [Table 17] a Includes all peptide treatment sequences (25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID).

[0302] [Table 18] Conventional non-biological whole body Novel non-biological whole-body systems biological therapy Whole-body therapy (conventional non-biological whole-body therapy, novel non-biological whole-body therapy, 1,25-vitamin D3 and analogues, phototherapy, biological agents) a Includes all peptide treatment sequences (25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID).

[0303] Scalp psoriasis response In the above trials, a significant dose-response was observed for the primary endpoint of PASI75. The response rates for all doses (PASI75, PASI90, PASI100, IGA score 0 / 1, IGA score 0, and ss-IGA score 0 / 1, with an improvement of ≥2 grades from baseline) were significantly higher than placebo at week 16 (nominal p<0.05 for all comparisons) (Table 17). The compound of formula (I) demonstrated significantly higher efficacy compared to placebo in patients with moderate to severe plaque psoriasis, including scalp psoriasis, and was well tolerated in all treatment groups. Percentage of patients who achieved scalp-specific (ss)-IGA score 0 / 1 and ss-IGA score 0 at week 16 and had at least a 2-grade improvement from baseline. The response rates for scalp-specific (ss)-IGA scores of 0 / 1 and 0, as well as the response rates with at least two grades of improvement from baseline for all doses, were significantly higher than placebo at week 16, as shown in Figure 17.

[0304] [Table 19] IGA = Overall assessment by the principal investigator, PASI = Area and severity index of psoriasis, ss-IGA = Overall assessment by the principal investigator of scalp-specific treatment.

[0305] Serum levels of psoriasis disease biomarkers BD-2, IL-22, IL-17A, and IL-17F In patients receiving either placebo or the compound of formula (I), serum levels of psoriasis disease biomarkers BD-2, IL-22, IL-17A, and IL-17F were analyzed relative to baseline and compared to clinical response. A linear mixed-effects model was used to analyze treatment interactions over time, baseline serum protein levels, and patient random effects.

[0306] We demonstrated that systemic pharmacodynamic changes, indicated by changes in serum levels of biomarkers such as the antimicrobial peptide BD-2, correlate with the PASI response after therapeutic treatment. Analyzing serum levels of these biomarkers related to the pathophysiology of psoriasis, we found that a doubling of BD2 at all doses was significantly distinguishable from placebo, starting at week 4, as shown in Figure 18. The doubling of BD-2 increased with increasing clinical response. A progressive increase in the doubling of serum BD-2 levels was observed with increasing clinical response, regardless of time point or dose, demonstrating a correlation between serum BD-2 decay and PASI response. Treatment with the compound of formula (I) drove a significant decay of serum IL-22 at all doses, distinguishable from placebo, starting at week 4, as shown in Figure 19, and was statistically significant compared to placebo. The pharmacodynamic response to serum IL-22 levels correlated with clinical outcome. As shown in Figure 20, compared to placebo, IL-17 cytokine isoforms accompanied by a significant attenuation of serum IL-17A and IL-17F levels, resulting in a statistically significant higher decrease. The treatment did not increase serum levels of IL-23 in psoriasis patients.

[0307] Example 2. Daily administration for 52 weeks in adult human subjects with expanded moderate to severe psoriasis vulgaris. The IL-23 receptor antagonist peptide used in this embodiment refers to the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, specifically the hydrochloride salt of the compound of formula (I) in crystalline form.

[0308] The following is a multicenter, long-term continuous administration (LTE), double-blind, dose-range, parallel-group intervention study in participants from Example 1 to evaluate the efficacy and safety of long-term continuous administration of hydrochloride of compound (I) for the treatment of moderate to severe plaque psoriasis. Patients from Example 1 continued to receive the same dose of compound (I) over an additional 36-week treatment period, with a 4-week safety follow-up period following the last dose of compound (I). Patients randomized to placebo in Example 1 received a dose of 100 mg QD of compound (I) starting at week 16 of Example 1 (Figure 21). A summary of the treatment groups is shown in Table 18.

[0309] [Table 20] a Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. b Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). c The total duration of treatment is defined as (last dose day of the study drug - first dose day of the study drug) + 1. d Total number of active tablets taken × Tablet strength (25 mg or 100 mg) / (Last dose day - First dose day + 1).

[0310] Example 1 began with 255 participants randomized to one of six treatment groups: placebo (n=43), 25 mg QD (n=43), 25 mg BID (n=41), 50 mg QD (n=43), 100 mg QD (n=43), and 100 mg BID (n=43). At week 16, 227 participants continued treatment and received at least one additional dose: placebo → 100 mg QD (n=25), 25 mg QD (n=35), 25 mg BID (n=40), 50 mg QD (n=39), 100 mg QD (n=40), and 100 mg BID (n=38). The proportion of participants discontinuing treatment was highest in the 25 mg BID group (n=10, 25.0%). The most common reason for discontinuing treatment was lack of efficacy (n=19, 8.4%), which tended to be higher in the 25 mg QD (n=4, 11.4%) and 25 mg BID (n=5, 12.5%) groups (Table 19).

[0311] [Table 21] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). The complete analysis set consists of randomized participants from Example 1 who continued to Example 2 and received at least one trial intervention (including partial doses) during the long-term follow-up period.

[0312] Of the participants who received the compound of formula (I), a total of 21.5% (53 / 247) discontinued the study intervention by week 52. The most common reason for discontinuation was lack of efficacy (8.1%, n=20, Table 20).

[0313] [Table 22] a Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. b Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID).

[0314] Primary endpoints The primary efficacy endpoint was defined as the proportion of participants achieving a PASI75 response at week 52, which is defined as a reduction of at least 75% from baseline PASI in Example 1. For the primary analysis, a combined strategy (non-responder complementation) was applied to address intermediate events #1 (discontinuation of the study intervention due to AEs of lack of efficacy or exacerbation of psoriasis) and #2 (initiation of protocol-prohibited medication or therapy that may improve psoriasis). A treatment strategy (observational data) was applied to intermediate event #3 (discontinuation of the study intervention for other reasons). Participants for whom data were missing after the application of ICE were considered non-responders.

[0315] Since there was no control arm (at 16 weeks), this primary analysis summarized only the proportion of participants who achieved a PASI75 response and its 95% confidence interval at week 52 for each intermediate group.

[0316] Table 21 summarizes the percentage of participants who achieved a PASI75 response by week 52. In addition, Figure 22, Table 22, and Table 23 summarize the percentage of participants who achieved a PASI75 response over time from week 1 to week 52 of the trial.

[0317] [Table 23] a 95% CID was calculated using the Wald method. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0318] [Table 24-1]

[0319] [Table 24-2]

[0320] [Table 24-3]

[0321] [Table 24-4]

[0322] [Table 24-5] a The mean LS is based on an MMRM model using the following covariates: treatment group, visit, treatment group based on visit interaction, baseline weight category (≤90kg, >90kg), baseline weight category based on visit interaction, baseline PAS total score, and baseline PAS total score based on visit interaction. b For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. Subjects with ICE1-2 showed zero change from baseline after the event. The observed data were used for subjects with ICE3.

[0323] [Table 25] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. b The 95% confidence interval (CI) was calculated using the Wald method. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0324] Secondary endpoint Secondary endpoints included additional changes from baseline in PASI, IGA, and PSSD at week 52 in Example 1, including the proportion of subjects who achieved PASI90, PASI100, a clear (0) or minimum (1) IGA score, a PSSD symptom score of 0, and a PSSD sign score of 0.

[0325] Similar results were observed for the PASI and IGA2 secondary endpoints at week 52 (Tables 24 and 25). Efficacy results based on other PASI and IGA2 endpoints were comparable to the PASI75 response over time (Figure 22). PASI and IGA response rates were generally maintained from week 16 to week 52, with the highest response rates observed in the 100 mg BID group (Figure 23).

[0326] [Table 26] a The 95% confidence interval (CI) was calculated using the Wald method. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0327] [Table 27] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. b The 95% confidence interval (CI) was calculated using the Wald method. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0328] In Example 1, the proportion of participants with an initial baseline score of ≥1 who had a PSSD symptom score of 0 and a PSSD sign score of 0 at week 52 is summarized in Tables 26 and 27.

[0329] [Table 28] a The 95% confidence interval (CI) was calculated using the Wald method. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0330] [Table 29] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. b The 95% confidence interval (CI) was calculated using the Wald method. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0331] Tables 28-30 summarize the changes from baseline in the total PASI score, PSSD symptom score, and PSSD sign score at week 52.

[0332] [Table 30] aFor subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. b The mean LS is based on an MMRM model using the following covariates: treatment group, visit, treatment group based on visit interaction, baseline weight category (≤90kg, >90kg), baseline weight category based on visit interaction, baseline PAS total score, and baseline PAS total score based on visit interaction. Subjects with ICE1-2 showed zero change from baseline after the event. The observed data were used for subjects with ICE3.

[0333] [Table 31] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. b The mean LS is based on an MMRM model using the following covariates: treatment group, visit, treatment group based on visit interaction, baseline weight category (≤90kg, >90kg), baseline weight category based on visit interaction, baseline PSSD symptom score, and baseline PSSD symptom score based on visit interaction. Subjects with ICE1-2 showed zero change from baseline after the event. The observed data were used for subjects with ICE3.

[0334] [Table 32] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. bThe mean LS is based on an MMRM model using the following covariates: treatment group, visit, treatment group based on visit interaction, baseline weight category (≤90kg, >90kg), baseline weight category based on visit interaction, baseline PSSD sign score, and baseline PSSD sign score based on visit interaction. Subjects with ICE1-2 showed zero change from baseline after the event. The observed data were used for subjects with ICE3.

[0335] The proportion of participants achieving PASI75, PASI90, PASI100, IGA0 / 1, and IGA0 over time from week 1 to week 52, along with their corresponding 95% confidence intervals (CIs), are summarized in Figures 22, 23, Table 31, and Table 32. The mean life-span (LS) and corresponding 95% CIs for the change from baseline in the total PASI score are shown in Figure 24 and Table 22.

[0336] [Table 33-1]

[0337] [Table 33-2]

[0338] [Table 33-3] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0339] [Table 34-1]

[0340] [Table 34-2]

[0341] [Table 34-3] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0342] Overall, the response rate was maintained for the 100 mg BID dose over the 52-week treatment period, and several endpoints showed slight improvement after week 16 (most notably PASI90 and IGA0 / 1). Changes from baseline endpoints (e.g., changes in PASI score over time) showed continued improvement up to week 52.

[0343] The proportion of participants with a baseline symptom score ≥ 1 who achieved a PSSD symptom score of absent (0) over time, and the proportion of participants with a baseline sign score ≥ 1 who achieved a PSSD sign score of absent (0) over time, are summarized in Figure 25, Table 33, and Table 34.

[0344] [Table 35] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0345] [Table 36] a For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. Subjects with ICE1-2 were assumed to be non-responders after the event. Observed data were used for subjects with ICE3. After accounting for ICE, subjects with missing data were considered non-responders.

[0346] The mean life expectancy (LS) and corresponding 95% confidence intervals (CIs) for changes from baseline in the PSSD symptom score and PSSD sign score are shown in Figures 26, 27, Table 35, and Table 36, respectively. In general, the response patterns were similar to those observed in PASI up to week 52.

[0347] [Table 37-1]

[0348] [Table 37-2]

[0349] [Table 37-3]

[0350] [Table 37-4]

[0351] [Table 37-5] aThe mean LS is based on an MMRM model using the following covariates: treatment group, visit, treatment group based on visit interaction, baseline weight category (≤90kg, >90kg), baseline weight category based on visit interaction, baseline PSSD symptom score, and baseline PSSD symptom score based on visit interaction. b For subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. Subjects with ICE1-2 showed zero change from baseline after the event. The observed data were used for subjects with ICE3.

[0352] [Table 38-1]

[0353] [Table 38-2]

[0354] [Table 38-3]

[0355] [Table 38-4]

[0356] [Table 38-5] a The mean LS is based on an MMRM model using the following covariates: treatment group, visit, treatment group based on visit interaction, baseline weight category (≤90kg, >90kg), baseline weight category based on visit interaction, baseline PSSD sign score, and baseline PSSD sign score based on visit interaction. bFor subjects randomized to placebo at week 0, only those who crossed over to treatment with the compound of formula (I) from week 16 onward are included. Subjects with ICE1-2 showed zero change from baseline after the event. The observed data were used for subjects with ICE3.

[0357] safety Similar to Example 1, the compound of formula (I) was well tolerated by participants in all treatment groups during the study, and the proportion of subjects experiencing one or more adverse events (AEs) was similar between the group treated with the compound of formula (I) and the placebo group. In addition, no dose-dependent increase in the incidence of AEs was observed across the treatment groups.

[0358] The cumulative 56-week safety data, including that for Example 1, are shown in Tables 37 to 47. The LTE safety analysis was based on randomized participants in Example 1 who participated in the trial during the long-term duration and received at least one trial intervention dose (including partial doses) during the trial period.

[0359] [Table 39-1]

[0360] [Table 39-2] a Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. b Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: A target is counted only once for any given event, regardless of how many times the event is actually experienced. Adverse events are coded using MedDRA Version 25.1.

[0361] Table 40-1

[0362] Table 40-2

[0363] Table 40-3

[0364] Table 40-4

[0365] Table 40-5

[0366] Table 40-6

[0367] Table 40-7

[0368] Table 40-8

[0369] Table 40-9

[0370] Table 40-10

[0371] Table 40-11 a Only the placebo crossover subjects were included in the placebo → 100 mg QD sequence after crossover for treatment with the compound of formula (I). b All sequences of treatment with the compound of formula (I) were included (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: Subjects were counted only once for any given event, regardless of the number of times they actually experienced the event. Adverse events were coded using MedDRA Version 25.1.

[0372]

Table 41-1

[0373]

Table 41-2

[0374]

Table 42-1

[0375]

Table 42-2

[0376]

Table 43-1

[0377]

Table 43-2

[0378]

Table 44

[0379] [Table 45-1]

[0380] [Table 45-2]

[0381] [Table 45-3] a Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. b Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID).

[0382] [Table 46-1]

[0383] [Table 46-2]

[0384] [Table 46-3]

[0385] [Table 46-4]

[0386] [Table 46-5]

[0387] [Table 46-6]

[0388] [Table 46-7] a Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. b Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID).

[0389] [Table 47-1]

[0390] [Table 47-2] Key: ALT = Alanine aminotransferase, AST = Aspartate aminotransferase, ULN = Upper limit of normal range a Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. b Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: The maximum post-baseline value is used to determine the rising category.

[0391] [Table 48-1]

[0392] [Table 48-2]

[0393] [Table 48-3] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). b Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. Note: For the change from baseline, N represents the number of subjects with missing data at both the baseline and post-baseline points in time.

[0394] [Table 49] a Only those targeted for placebo crossover were included in the QD column for the crossover treatment with the compound of formula (I), specifically the placebo → 100 mg QD. b Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID).

[0395] Important safety events are shown in Table 48 (with supporting information in Tables 49-54). The proportion of participants experiencing one or more AEs was 58.6% in the combination group administered with the compound of formula (I), and there was no evidence of a dose-dependent increase in the occurrence of specific AEs across treatment groups (Tables 33 and 49).

[0396] [Table 50-1]

[0397] [Table 50-2] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). For each given event, it is counted only once, regardless of how many times the event was actually experienced. Adverse events are coded using MedDRA Version 25.1.

[0398] [Table 51-1]

[0399] [Table 51-2]

[0400] [Table 51-3]

[0401] [Table 51-4]

[0402] [Table 51-5]

[0403] [Table 51-6]

[0404] [Table 51-7]

[0405] [Table 51-8] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: A target is counted only once for any given event, regardless of how many times the event is actually experienced. Adverse events are coded using MedDRA Version 25.1.

[0406] [Table 52-1]

[0407] [Table 52-2] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: A target is counted only once for any given event, regardless of how many times the event is actually experienced. Adverse events are coded using MedDRA Version 25.1.

[0408] [Table 53-1]

[0409] [Table 53-2] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: A target is counted only once for any given event, regardless of how many times the event is actually experienced. Adverse events are coded using MedDRA Version 25.1.

[0410] [Table 54-1]

[0411] [Table 54-2] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: A target is counted only once for any given event, regardless of how many times the event is actually experienced. Adverse events are coded using MedDRA Version 25.1.

[0412] [Table 55] a Includes all columns of treatment with the compound of formula (I) (placebo → 100 mg QD, 25 mg QD, 50 mg QD, 25 mg BID, 100 mg QD, and 100 mg BID). Note: A target is counted only once for any given event, regardless of how many times the event is actually experienced. Adverse events are coded using MedDRA Version 25.1.

[0413] [Table 56]

[0414] In all groups, the most frequent organ-specific category involved in AEs was infections and parasitic illnesses (41.9%). Across treatment groups, there was no clear evidence of a dose-dependent increase in the incidence of AEs in this SOC.

[0415] The most common adverse events (AEs) in this SOC were nasopharyngitis (18.1%), upper respiratory tract infection (9.7%), and COVID-19 (5.3%) in the combined group receiving the compound of formula (I) (Tables 48 and 49). AEs reported by at least 5% of participants in any treatment group are summarized in Tables 48 and 50. Again, the most common AEs in the combined group of participants administered the compound of formula (I) were nasopharyngitis, upper respiratory tract infection, and COVID-19.

[0416] The proportion of participants who experienced one or more serious adverse events (SAEs) after receiving compound (I) was low (4.0%), with eight participants each experiencing one SAE and one participant experiencing two SAEs (Tables 48 and 51). All SAEs were single and considered unrelated to the investigator's study intervention.

[0417] The proportion of participants who discontinued the study intervention due to one or more adverse events (AEs) was low (n=4). All events were specific in nature and did not show an apparent dose-dependent increase (Tables 48 and 52). The number of participants with abnormal hematological and chemical laboratory values ​​with CTCAE toxicity grade ≥3 remained low until the end of the study (Tables 43-46). There was no apparent dose-dependent increase in the incidence of laboratory abnormalities.

[0418] No deaths were reported during the LTE trial period. One case of basal cell carcinoma was reported in the 50 mg QD group. In the 50 mg QD arm (with a history of myocardial infarction), there was one case of SAE due to exacerbation of coronary artery disease, and in the placebo group and the 100 mg QD group, there was one case of SAE due to cerebrovascular accident.

[0419] Example 3. Daily administration of a single dose for 16 weeks in adult human subjects with moderate to severe plaque psoriasis. The IL-23 receptor antagonist peptide used in this embodiment refers to the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, specifically the hydrochloride salt of the compound of formula (I) in crystalline form.

[0420] The following describes a multicenter, randomized, double-blind, placebo-controlled trial evaluating the efficacy and safety of the hydrochloride of compound (I) for the treatment of moderate to severe plaque psoriasis.

[0421] [Table 57-1]

[0422] [Table 57-2]

[0423] Overall design This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter intervention trial with randomized discontinuation and treatment in subjects with moderate to severe psoriasis vulgaris. The trial enrolls 600 target subjects, randomized in a 2:1 ratio to either treatment or placebo, in each age group consisting of approximately 10% adolescent participants and approximately 90% adults. A schematic diagram of this trial is shown in Figure 28.

[0424] Participants will be instructed to receive the experimental intervention at approximately the same time each day upon waking, in a fasting state, using approximately 240 mL of non-carbonated water.

[0425] dose Examples 1 and 2 demonstrated the clinical trial results for all five dosing regimens evaluated in this study (25 mg QD, 25 mg BID, 50 mg QD, 100 mg QD, 100 mg BID). The steady-state mean concentration (C) of IL-23 receptor antagonist peptide in the serum of the subjects. avg ) and trough (C trough Using the concentration and efficacy endpoint (percentage of participants with an IGA score of 0 or 1 or PASI 75 / 90 / 100), a higher clinical effect was observed. trough C avg It was found to be more closely related to this.

[0426] The population PK model was developed using the results from Examples 1 and 2, incorporating body weight with a standard relative growth index, and centered at approximately 90 kg, with the population PK model results shown in Figures 29–32. Covariate analysis of renal and hepatic functional variables was performed, and neither was found to be significant. Based on this model, post-hoc C2 of the IL-23 receptor antagonist peptide was performed. trough and C avg The value was obtained. Next, the obtained C trough and C avg Using the values, ordinal logistic Emax regression models were fitted for PASI75 (Figures 29 and 30) and IGA0 / 1 (Figures 31 and 32) to obtain exposure-response (ER) models. In the ER models for both PASI75 and IGA0 / 1, C avg C trough It is found to be a better model parameter for clinical response. Therefore, the 200 mg QD regimen is modeled to achieve a similar clinical response rate to that of the 100 mg BID regimen, with the ease of single-dose administration.

[0427] Adult participants: IL-23 receptor antagonist peptide 200 mg daily Weeks 0-24: Participants receive 200 mg of IL-23 receptor antagonist peptide once daily (QD). Weeks 24-52: Participants who are PASI75 responders will be re-randomized in a 1:1 ratio to either continue receiving 200 mg of IL-23 receptor antagonist peptide daily or switch to placebo. Participants who switch to placebo will receive 200 mg of IL-23 receptor antagonist peptide once daily at week 24 if there is a loss of PASI improvement of ≥50%, or at week 52 if no loss of response is observed. All participants will be treated with 200 mg of IL-23 receptor antagonist peptide at week 52. Participants who are PASI75 non-responders at week 24 will continue receiving 200 mg of IL-23 receptor antagonist peptide until week 52.

[0428] Weeks 52-156: Participants receive 200 mg of IL-23 receptor antagonist peptide daily until week 156.

[0429] Placebo vs. IL-23 receptor antagonist peptide 200 mg daily Weeks 0 to 16: Participants receive a placebo once a day until week 16.

[0430] Weeks 16 to 156: Participants will cross over to receive 200 mg of IL-23 receptor antagonist peptide once daily until week 156.

[0431] Adolescent participants: IL-23 receptor antagonist peptide 200 mg daily Weeks 0-156: Participants were treated once daily with 200 mg of IL-23 receptor antagonist peptide.

[0432] The young adult will not participate in re-randomization regardless of their PASI score at week 24.

[0433] Placebo vs. IL-23 receptor antagonist peptide 200 mg daily Weeks 0 to 16: Participants receive a placebo once a day until week 16.

[0434] Weeks 16 to 156: Participants will cross over to receive 200 mg of IL-23 receptor antagonist peptide once daily until week 156.

[0435] The trial includes a 5-week screening period, a placebo-controlled period up to week 16, and a randomization discontinuation and retreatment period from week 24 to week 52, at which point patients will transition to an open-label IL-23 receptor antagonist peptide until week 156. A 2-week safety follow-up is included for participants who discontinue the trial intervention during the study or at the end of the treatment period.

[0436] Efficacy, safety, PK, immunogenicity, and biomarkers will be evaluated. In addition, (where permitted by local regulations) there will be three optional sub-studies in consenting subjects: pharmacological genomics, blood samples, skin biopsies, and photographic collections.

[0437] Inclusion Criteria Each participant was 12 years of age or older and met all of the following criteria. (a) Having a diagnosis of psoriasis vulgaris with or without PsA for at least 26 weeks prior to the first dose of the study intervention, (b) Having total BSA ≥ 10% at screening and baseline, (c) Having a total PASI ≥ 12 at screening and baseline, (d) Having a total IGA ≥ 3 at screening and baseline, (e) For psoriasis vulgaris, phototherapy or systemic treatment is a candidate.

[0438] For subjects aged ≥12 to <18 years, a baseline weight requirement of 40 kg or more is necessary.

[0439] Exclusion criteria A potential target is excluded if the target meets any of the following criteria: (a) Having a non-plaque form of psoriasis (e.g., erythrodermic psoriasis, guttate psoriasis, or pustular psoriasis), (b) Having current drug-induced psoriasis (e.g., a new onset or exacerbation of psoriasis caused by beta-blockers, calcium channel blockers, or lithium), (c) Having a known allergy, hypersensitivity, or intolerance to IL-23 receptor peptide or its excipients, (d) Having undergone a major surgical procedure (e.g., requiring general anesthesia) within 8 weeks of screening, or not having fully recovered from a surgical procedure, or having a planned surgical procedure during the time of the examination, (e) Having a transplanted organ > 12 weeks prior to the first dose (excluding corneal transplants) (f) The patient had a history of drug or alcohol abuse within one year prior to screening.

[0440] The target cases are those in which the subjects are (a) If you have previously received IL-23 receptor antagonist peptide, (b) If you have experienced major efficacy failure (no response within 16 weeks) to one or more IL-23-targeting agents, or have had a clinically significant adverse event (AE) to one or more IL-23-targeting agents, (c) If you have received any B-cell depleting agent (including, but not limited to, rituximab or alemtuzumab) within 26 weeks of the first dose of the trial intervention, (d) If, within 12 weeks of the first dose of the study intervention or 5 half-lives, whichever is longer, you have received natalizumab, belimumab, or any T-cell modulating biological therapy or agent (including, but not limited to, abatacept or vizilizumab), (e) If, within four weeks of the first dose of the study intervention, you have received any systemic immunosuppressant (including, but not limited to, methotrexate (MTX), azathioprine, cyclosporine A, corticosteroids, cyclophosphamide, tofacitinib, apremilast, and duclavacitinib), (f) Except for the Bacillus Calmet Guérin (BCG) vaccine listed below, if you have received or are expected to receive any live viral or bacterial vaccine within 12 weeks prior to the first dose of the trial intervention, (g) If you have received the BCG vaccine within 12 months of the first dose of the trial intervention, (j) If, within four weeks of the first dose of the study intervention, you have received any phototherapy or any systemic drug administration that may affect psoriasis or PASI or IGA assessment (including, but not limited to, oral or injectable corticosteroids, acitretin, retinoids, 1,25-dihydroxyvitamin D3 and analogues, herbal remedies or traditional Taiwanese, Korean or Chinese medicines), (k) If you have received any topical therapy that may affect psoriasis or PASI or IGA assessment (including, but not limited to, corticosteroids, calcineurin inhibitors, vitamin D analogues, vitamin A analogues, retinoids, tar, anthraline, calcipotriene, tazarotene, methoxsalen, trimethylpsoralen, fumarate, PDE4 inhibitors, aryl hydrocarbon receptor modulators, and traditional Taiwanese, Korean, or Chinese medicines) within two weeks of the first dose of the study intervention.

[0441] Furthermore, subjects will be excluded if their screening laboratory test results show any of the following: (a) Hemoglobin < 10 ng / dL, (b) White blood cells<3.5×10 3 / μL, (c) Neutrophils<1.5×10 3 / μL, (d) Platelets<100×10 3 / μL, (e)eGFR<60mL / min / 1.73m 2 , (f) Aspartate aminotransferase > 2 × ULN, (g) Alanine aminotransferase > 2 × ULN.

[0442] Those who test positive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV) during screening will be further excluded.

[0443] Additionally, participants who have undergone a chest X-ray or CT scan within the past 12 weeks and show evidence of ongoing infection or malignancy will be excluded (chest X-rays are optional for participants under 18 years of age at the time of screening).

[0444] The following individuals will be additionally excluded if they meet one or more of the following criteria: (a) Having a history of chronic or recurrent infections, including but not limited to chronic kidney infection, chronic chest infection, recurrent urinary tract infection, severe mycosis, or open, purulent, or infected skin wounds or ulcers, (b) If you have a history of an infected articular prosthesis, or if the prosthesis has not been removed or replaced, you are receiving antibiotics for a suspected infection of the articular prosthesis. (c) Having or suspected immunodeficiency, including, but not limited to, a history of invasive opportunistic infections (e.g., active TB, nontuberculous mycobacterial infection, histoplasmosis, listeriosis, coccidioidomycosis, pneumocystis, aspergillosis, HIV, etc.) or otherwise unusually frequent or long-term recurrent infections. (e) Having a serious infection (e.g., generalized herpes zoster, sepsis, pneumonia, or pyelonephritis), or having been hospitalized or administered IV antibiotics within the 8 weeks prior to screening, (f) The subject has tested positive for COVID-19 or been exposed to COVID-19 within four weeks prior to the first dose (unless the subject is asymptomatic and has had a negative test for at least two weeks after the onset of symptoms or exposure, (g) Having a current malignancy or a history of malignancy within 5 years prior to screening (excluding non-melanoma skin cancer or cervical cancer that has been adequately treated and has no evidence of recurrence for at least 12 weeks prior to the first dose), (h) Having a history of lymphoproliferative disorders including lymphoma, monoclonal immunoglobulinemia of unknown significance, or signs and symptoms of lymphoproliferative disorders, (i) Has a known active tuberculosis infection.

[0445] Intervention group Each participant in the group will be administered a tablet containing either an IL-23 receptor antagonist peptide or a placebo. Participants will take the tablet with approximately 240 mL of non-carbonated water and will remain fasted throughout the entire study (including the day of arrival at the facility). Fasting is defined as refraining from food intake for at least two hours before the study intervention and refraining from food and liquid intake for at least 30 minutes after the study intervention.

[0446] This trial will utilize central randomization. Participants will be assigned to one of two intervention groups based on an algorithm developed prior to the trial. Permutation block randomization will be used, stratifying participants by age group (adults <18 years and adults ≥18 years), baseline weight categories for adults (≤90kg, >90kg), and geographical area. Based on the algorithm, participants will be assigned a unique intervention code that directs them to the intervention assignment and matching trial intervention kit.

[0447] At week 24, adult participants who are PASI75 responders and were randomized to IL-23 receptor antagonist peptide 200 mg once daily will be re-randomized in a 1:1 ratio to either placebo or IL-23 receptor antagonist peptide 200 mg once daily. Participants will be assigned to a treatment group using permutation block randomization, and randomization will be stratified by geographical region and PASI90 response status at week 24.

[0448] Test evaluation Efficacy, PK, immunogenicity, biomarkers, pharmacogenomics, photographs, and safety criteria will be measured during treatment. Participants will be provided with an electronic device to input patient-reported outcome (PRO) data at each trial visit. All visit-specific PRO assessments, with the exception of urine pregnancy tests and urinalysis, will be performed / completed before any other tests, procedures, or clinical assessments to prevent interference with the participants' perception.

[0449] An electrocardiogram (ECG) should precede vital signs, and both procedures should be completed before any invasive procedures. Vital signs should be recorded from the arm opposite to the one from which the blood sample was taken.

[0450] All samples (including safety, efficacy, PK, photographs, and biomarkers) are obtained after PRO and ECG evaluation.

[0451] The Area and Severity Index (PASI), Body Surface Area (BSA), and Investigator's Global Assessment (IGA) are obtained at weeks 0, 2, 3, 8, 12, 16, 20, 24, 28, 32, 36, 44, and 52. The Area and Severity Index (NAPSI), Physician's Global Assessment of Fingernails (f-PGA), Physician's Static Global Assessment of Genital Area (s-PGA-G), Physician's Global Assessment of Hands and / or Feet (hf-PGA), and Scalp-Specific Physician's Global Assessment (ss-IGA) are obtained at weeks 0, 8, 16, 24, 36, and 52.

[0452] Adverse events are reported and followed up by the investigator. Clinically relevant changes occurring during the study are recorded. Any clinically significant abnormalities persisting at the end of the study / early withdrawal are followed up by the investigator, if possible, until improvement or clinical stability is achieved. Safety and tolerability assessments include physical examination, vital signs, electrocardiogram, clinical safety laboratory assessment, review of concomitant medications, pregnancy testing, suicidal ideation assessment using the Columbia Suicide Severity Scale, and tuberculosis assessment.

[0453] Key endpoint analysis The primary efficacy endpoint is the proportion of participants who achieve a PASI90 response, defined as a reduction of at least 90% from baseline in the total PASI score, or who achieve an IGA0 or 1 and at least two grades of improvement in the IGA score after 16 weeks.

[0454] For the primary analysis, a combined strategy (non-responder complementation) will be applied to address intermediate events #1 (discontinuation of the study intervention due to AEs such as lack of efficacy or worsening of psoriasis) and #2 (initiation of protocol-prohibited medication or therapy that may improve psoriasis). A treatment strategy (observational data) will be applied to intermediate event #3 (discontinuation of the study intervention for other reasons). Participants for whom data is missing after the application of ICE will also be considered non-responders.

[0455] Using the MCP Mod, we will test whether there is a positive overall therapeutic effect based on the candidate response model.

[0456] Safety: Safety will be evaluated among all randomized and treated participants who received at least one dose of the investigational drug (partially or completely) according to the assigned treatment they received during the clinical trial. This is also referred to as the safety analysis set.

[0457] The present invention described above, in practice and as examples, is described in some detail for the purpose of clarity of understanding, but it will be understood by those skilled in the art that certain changes and modifications may be made within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference as it is incorporated individually by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

[0458] Each aspect of the Invention as defined in this section or any other section may incorporate definitions and limitations, such as those described throughout the initial filing disclosure, specification, and claims.

[0459] Example 4. Preparation of the crystalline form of the hydrochloride salt of the peptide of SEQ ID NO: 1. Ac-[Pen] * -NT-[W(7-Me)]-[Lys(Ac)]-[Pen] * -Phe[4-(2-aminoethoxy)]-[2-Nal]-[THP]-EN-[3-Pal]-Sarc-NH2(where, [Pen] * -[Pen] * (forms a disulfide bond) (SEQ ID NO: 1):

[0460] [ka]

[0461] 18.9 kg of Rink amide AM resin (substituted: 0.95 mmol / g) was packed into a 1000 L SPPS reactor and SPPS was performed. Each SPPS cycle consisted of Fmoc cleavage, coupling with each constituent unit, and essential capping. For Fmoc cleavage, the resin was treated with 20% piperidine in DM (10 ml / g of resin each) at 25°C for 5 ± 2 minutes and 10 ± 2 minutes. Coupling was performed using DMF (10 ml / g of resin) as the solvent, using the constituent units, coupling reagents, and conditions shown in Table 55. For capping, the resin was treated with acidic anhydride and pyridine in DMF for 20 minutes (volume ratio DMF / Ac2O / pyridine 50:1:1, DMF:10 ml / g of resin). Diisopropyl carbonate (DIC) was added in two parts, with the second part added approximately 20-30 minutes after the first part.

[0462] [Table 58]

[0463] The peptide resin was subjected to final acetylation with acidic anhydride and pyridine in DMF for 20 minutes (volume ratio DMF / Ac2O / pyridine 10:1:1; DMF:10 ml / g resin). After drying at 25-35°C, 72.8 kg of linear peptide-Rink amide AM resin was obtained.

[0464] TFA cutting In a jacketed reactor, 100 g of the above resin was added at 18°C ​​to a 700 mL cutting cocktail consisting of 630 mL of TFA, 35 mL of TIS, 17.5 mL of EDT, and 17.5 mL of water. Upon addition of the resin, the temperature rose to 30°C, and the mixture was stirred at 30°C for a further 35 minutes. The mixture was cooled to 20°C, the resin was filtered off, and each sample was washed twice with 100 mL of TFA. The filtrates were combined and cooled to -15°C. For precipitation, 4.0 L of diisopropyl ether was added within 20 minutes while maintaining the solution / suspension temperature at 7°C. After the complete addition of the diisopropyl ether, the temperature was raised to 22°C, and the suspension was stirred for 2.5 hours.

[0465] Next, the suspension was transferred to a filter dryer, and the precipitated crude product was filtered off at ambient temperature. Then, each filter cake was washed three times with 300 mL of diisopropyl ether and dried overnight in a vacuum at 30°C to obtain 52.87 g of linear peptide as the TFA salt.

[0466] Purification by oxidation and preparative HPLC 28 g of linear peptide as TFA salt was dissolved in 280 mL of 30% AcOH in water at ambient temperature. 3.71 g of iodine and 7.17 g of potassium iodide were dissolved in 280 mL of water. Both the peptide and the iodine / iodide solution were added in parallel to a vigorously stirred mixture of 2.2 L of 30% AcOH in water at ambient temperature within 60 minutes. After both solutions had been completely added, a brown oxidized mixture was obtained. After stirring at ambient temperature for 30 minutes, IPC showed almost complete conversion of the starting materials. 1.5 hours after the complete addition of the peptide and iodine solutions, 3.5 g of vitamin C was added. The resulting yellow solution was then stirred for 10 minutes. The oxidized mixture was filtered over a frit glass funnel and applied to a preparative RP-HPLC column. The chromatography conditions were the same as those used in Example 4. All fractions were adjusted to pH 7 with 18% HCl in water. The fractions collected during preparative RP-HPLC were analyzed by UHPLC. The fraction containing >98% of the product was pooled for subsequent isolation.

[0467] Isolation A 420 mL product pool was obtained after oxidation and preparative HPLC purification. Test lyophilization determined the product concentration of this solution to be approximately 29 g / L, which corresponds to a theoretical yield of approximately 12.2 g.

[0468] From the total pool volume, 120 mL was transferred to a round-bottom flask, and the initial pH of 7.51 was adjusted to pH 3.00 with 4.5 mL of 1 M HCl aqueous solution. Acetonitrile was evaporated from the product solution under vacuum at 40°C until the water began to evaporate. After evaporation, 80 mL of the product aqueous solution remained (pH 2.54), of which 40 mL was transferred to a reactor connected to a heating / cooling system and used for subsequent isolation.

[0469] Next, the pH of the solution was adjusted to pH 3.75 by adding 1.0 mL of 0.5 M NH4HCO3 within 65 minutes. A 1% (w / w) compound of formula (I) was added as a seeding material to the clear yellow solution, and the resulting dilute suspension was stirred at 25°C for 60 minutes. Next, the pH of the suspension was adjusted to pH 4.50 by adding 2.9 mL of 0.5 M NH4HCO3 within 125 minutes. After stirring the suspension at 25°C for 30 minutes, the pH decreased to pH 4.12. Next, the pH was readjusted to 4.50 by adding 0.2 mL of 0.5 M NH4HCO3. After stirring at 25°C for 16 hours, a concentrated suspension remained, which was filtered over a glass Nutsche filter (G4) (filtration time 1 minute) and washed with 1.59 mL of water (1 volume equivalent; filtration time 1 minute) without stirring. The washed filter cake was dried in a vacuum oven at 25°C for 16 hours. The dried product was finally removed from the filter.

[0470] In total, 1.77 g of compound (partial HCl salt) of formula (I) was isolated from a 60 mL product pool, which is equivalent to 12.4 g of compound (I) from the entire 420 mL product pool. The isolated material was found to have a purity of 99.4% (HPLC), a chloride content of 1.6% (titration), and a water content of 3.6% (KF).

[0471] The crystallinity of the partial hydrochloride salt of the compound of formula (I) was confirmed by X-ray powder diffraction (XRPD) patterns. The following two-theta peaks were observed: 4.2920, 6.9201, 7.6600, 8.5693, 9.2667, 9.9817, 10.7256, 11.5429, 11.9937, 13.0633, 13.3317, 13.9650, 14.7879, 15.8430, 17.1481, 17.6468, 18.1402, 18.6158, 19.3291, 20.4899, 20.7090, or 21.7813 + / - 0.2 degree two-theta.

[0472] Example 5. Synthesis procedure for the crystalline hydrochloride of the peptide of SEQ ID NO: 1 30 g of the crystalline hydrochloride of the compound of formula (I) prepared according to Example 4 was dissolved in 120 mL of methanol and 51.4 mL of water. Dissolution was carried out in EasyMax 402 with stirring at 40°C. 57.1 mL of 1 M sodium chloride was added to the EasyMax reactor over 1 hour. Next, 300 mg of a seed of the hydrochloride of the compound of formula (I) prepared according to Example 4 was added to the solution. The slurry was then aged at 40°C with stirring for 8 hours. The slurry was cooled to 5°C at a cooling rate of 0.1 K / min. An additional 114.31 mL of 1 M sodium chloride was added to the EasyMax reactor over 4 hours, and the slurry was aged for an additional 5 hours. The solid was isolated by vacuum filtration and washed twice with 30 mL of water and twice with 30 mL of isopropanol. The solid was air-dried.

[0473] The isolated solid of the crystalline hydrochloride salt form of the compound of formula (I) had a purity of 99.3 area% (UPLC) and a water content of 6.33 w / w% (KF). The chloride content of the isolated crystalline hydrochloride salt form of the compound of formula (I) was assayed by ion chromatography and found to be 0.64 molar equivalents relative to the compound of formula (I). The crystallinity of the crystalline hydrochloride salt form of the compound of formula (I) was confirmed by the XRPD pattern (Figure 33). The following two-theta peaks were observed: 3.8, 4.2, 6.9, 7.6, 8.5, 9.3, 9.4, 10.0, 10.8, 11.6, 12.0, 12.2, 12.8, 13.1, 13.3, 13.8, 13.9, 14.2, 14.4, 14.7, 15.3, 15.7, 16.2, 16.4, 17.2, 17.6, 18.2, 18.7, 19.2, 19.6, 19.9, 20.5, and 20.8 degrees two-theta + / - 0.2 degrees two-theta.

[0474] The present invention described above, in practice and as examples, is described in some detail for the purpose of clarity of understanding, but it will be understood by those skilled in the art that certain changes and modifications may be made within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference as it is incorporated individually by reference. In the event of any conflict between this application and the references provided herein, this application shall prevail.

[0475] Each aspect of the Invention as defined in this section or any other section may incorporate definitions and limitations, such as those described throughout the initial filing disclosure, specification, and claims.

Claims

1. A method for treating psoriasis in a person in need of treatment for psoriasis, wherein the patient in need of administration is given formula (I): 【Chemistry 1】 compounds or This includes administering a pharmaceutically acceptable salt or solvate thereof, After treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the subject, (i) A reduction of 75% or more in the Area and Severity Index of Psoriasis (PASI) compared to the baseline PASI. (ii) Investigator's Global Assessment (IGA) score of 2 or less after treatment, (iii) A decrease of 1 or more from baseline in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score, and A method for determining whether a person is a responder to treatment by at least one measure of psoriasis response to treatment, selected from the group consisting of (iv) a decrease in the Dermatological Quality of Life Index (DLQI) score.

2. A method for treating psoriasis in a person in need of treatment for psoriasis, wherein formula (I): 【Chemistry 2】 This includes administering the compound or a pharmaceutically acceptable salt or solvate thereof. A method for achieving a reduction of 75% or more in the area and severity index (PASI) score of psoriasis compared to the baseline PASI score.

3. The method according to claim 1 or 2, wherein the subject achieves a measure of psoriasis response which is a reduction of at least about 90% in the PASI score compared to the baseline PASI score.

4. The method according to claim 3, wherein the subject achieves a measure of psoriasis response which is a reduction of approximately 100% of the PASI score compared to the baseline PASI score.

5. The method according to claim 1, wherein the subject achieves a measure of psoriasis response which is a decrease of at least two points in the IGA score.

6. The method according to claim 1 or 5, wherein the subject achieves an Investigator General Assessment (IGA) score of 2 or less.

7. The method according to claim 6, wherein the subject achieves an IGA score of 1 or less.

8. The method according to claim 7, wherein the subject achieves an IGA score of 0.

9. The method according to claim 1 or 5, wherein the patient achieves an Investigator's Global Assessment (IGA) score of 2 or less after treatment.

10. The method according to claim 9, wherein the patient achieves an IGA score of 1 or less after treatment.

11. The method according to claim 10, wherein the patient achieves an IGA score of 0 after treatment.

12. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least two weeks after the start of treatment.

13. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least four weeks after the start of treatment.

14. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least eight weeks after the start of treatment.

15. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least 16 weeks after the start of treatment.

16. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least 20 weeks after the start of treatment.

17. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least 24 weeks after the start of treatment.

18. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least 28 weeks after the start of treatment.

19. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least 32 weeks after the start of treatment.

20. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least 40 weeks after the start of treatment.

21. The method according to claim 1 or 2, wherein the measure of the psoriasis response is measured at least 52 weeks after the start of treatment.

22. The method according to claim 1 or 2, wherein the psoriasis is psoriasis vulgaris.

23. The method according to claim 22, wherein the psoriasis is moderate to severe plaque psoriasis.

24. The method according to claim 1 or 2, wherein the subject is a candidate for phototherapy or systemic therapy.

25. The method according to claim 1 or 2, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is the hydrochloride salt of the compound of formula (I) or its solvate.

26. The method according to claim 1 or 2, comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

27. The method according to either claim 1 or 2, comprising administering the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof on a daily basis.

28. The method according to claim 1 or 2, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 5 mg to about 800 mg.

29. The method according to claim 28, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 25 mg to about 500 mg.

30. The method according to claim 29, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 50 mg to about 500 mg.

31. The method according to claim 30, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 25 mg.

32. The method according to claim 30, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 50 mg.

33. The method according to claim 30, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 100 mg.

34. The method according to claim 30, comprising administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg.

35. The method according to claim 1 or 2, wherein the patient has at least 10% body surface area (BSA) before treatment.

36. The method according to claim 1 or 2, wherein the patient has a PASI score of approximately 12 to 72 prior to treatment.

37. The method according to claim 1 or 2, wherein the subject has at least three Investigator General Assessments (IGAs) prior to treatment.

38. The method according to claim 1 or 2, wherein the subject has at least one Psoriasis Symptoms and Signs Diary (PSSD) symptom score prior to treatment.

39. The method according to claim 1 or 2, wherein the subject has a dermatological quality of life index (DLQI) score greater than 1 before treatment.

40. The method according to claim 1 or 2, wherein the subject has not been treated with a biological agent for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

41. The method according to claim 1 or 2, wherein the subject has not been treated with any IL-23 receptor antagonist for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

42. A pharmaceutical product for treating subjects diagnosed with psoriasis, formula (I): 【Transformation 3】 A pharmaceutical product comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, which, when administered to the subject in an amount of at least 25 mg, causes an average reduction of at least 75% in the Area and Severity Index (PASI) of psoriasis, as measured from the baseline PASI score.

43. The pharmaceutical product according to claim 42, wherein the subject achieves at least about 90% reduction in the area and severity index score of psoriasis compared to the baseline.

44. The pharmaceutical product according to claim 43, wherein the subject achieves a reduction of approximately 100% in the area and severity index score of psoriasis compared to the baseline.

45. The pharmaceutical product according to claim 42, wherein the patient achieves an Investigator's Global Assessment (IGA) score of 2 or less after treatment.

46. The pharmaceutical product according to any one of claims 42 to 45, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 25 mg to about 800 mg.

47. The pharmaceutical product according to claim 46, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 50 mg to about 800 mg.

48. The pharmaceutical product according to claim 47, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 50 mg to about 500 mg.

49. The pharmaceutical product according to claim 46, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 25 mg.

50. The pharmaceutical product according to claim 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 50 mg.

51. The pharmaceutical product according to claim 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is in an amount of about 100 mg.

52. The pharmaceutical product according to claim 48, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of about 200 mg.

53. A method for treating psoriasis in a person in need of treatment for psoriasis, wherein the patient in need of administration is given formula (I): 【Chemistry 4】 A method comprising administering a compound or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg.

54. The method according to claim 53, wherein the method comprises administering the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg once daily.

55. The method described above is (i) A reduction of 75% or more in the Area and Severity Index of Psoriasis (PASI) compared to the baseline PASI. (ii) Investigator's Global Assessment (IGA) score of 2 or less after treatment, (iii) A decrease of 1 or more from baseline in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score, and The method according to claim 53, further comprising the step of achieving one or more selected from the group consisting of (iv) a reduction in the Dermatological Quality of Life Index (DLQI) score.

56. The method according to any one of claims 53 to 55, wherein the psoriasis is psoriasis vulgaris.

57. The method according to claim 56, wherein the psoriasis is moderate to severe plaque psoriasis.

58. The method according to any one of claims 53 to 55, wherein the subject is a candidate for phototherapy or systemic therapy.

59. The method according to any one of claims 53 to 55, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is the hydrochloride salt of the compound of formula (I) or its solvate.

60. The method according to any one of claims 53 to 55, comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

61. The method according to any one of claims 53 to 65, comprising administering the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof on a daily basis.

62. The method according to any one of claims 53 to 55, wherein the patient has at least 10% of body surface area (BSA) before treatment.

63. The method according to any one of claims 53 to 55, wherein the patient has a PASI score of approximately 12 to 72 prior to treatment.

64. The method according to any one of claims 53 to 55, wherein the subject has at least three Investigator General Assessments (IGAs) prior to treatment.

65. The method according to any one of claims 53 to 55, wherein the subject has at least one psoriasis symptom and sign diary (PSSD) symptom score prior to treatment.

66. The method according to any one of claims 53 to 55, wherein the subject has at least one PSSD sign score before treatment.

67. The method according to any one of claims 53 to 55, wherein the subject has a dermatological quality of life index (DLQI) score greater than 1 before treatment.

68. The method according to any one of claims 53 to 55, wherein the subject has not been treated with a biological agent for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

69. The method according to any one of claims 53 to 55, wherein the subject has not been treated with any IL-23 receptor antagonist for psoriasis prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

70. A method for treating a patient population diagnosed with psoriasis, wherein the patient population is given formula (I): 【Transformation 5】 A method comprising administering a compound or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg.

71. The method according to claim 70, wherein the method comprises administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof in an amount of about 200 mg daily.

72. The method described above is (i) A mean reduction of 75% or more in the area and severity index (PASI) of psoriasis in the patient population compared to the baseline PASI. (ii) The mean Investigator's Global Assessment (IGA) score of 2 or less after treatment in the patient population, (iii) In the aforementioned patient population, a mean decrease of 1 or more from baseline in the Psoriasis Symptoms and Signs Diary (PSSD) symptom score, and The method according to claim 70, further comprising the step of achieving one or more selected from the group consisting of (iv) a reduction in the Dermatological Quality of Life Index (DLQI) score in at least 50% of the patient population.

73. The method according to any one of claims 70 to 72, wherein the psoriasis is psoriasis vulgaris.

74. The method according to claim 73, wherein the psoriasis is moderate to severe plaque psoriasis.

75. The method according to any one of claims 70 to 72, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is the hydrochloride salt of the compound of formula (I) or its solvate.

76. The method according to any one of claims 70 to 72, comprising orally administering a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.

77. The method according to any one of claims 70 to 72, comprising administering the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof on a daily basis.

78. The method according to any one of claims 70 to 72, wherein the patients in the patient population have at least 10% body surface area (BSA) before treatment.

79. The method according to any one of claims 70 to 72, wherein the patients in the patient population have a PASI score of approximately 12 to 72 before treatment.

80. The method according to any one of claims 70 to 72, wherein the patients in the patient population have at least three Investigator General Assessments (IGAs) prior to treatment.

81. The method according to any one of claims 70 to 72, wherein the patients in the patient population have at least one Psoriasis Symptoms and Signs Diary (PSSD) symptom score prior to treatment.

82. The method according to any one of claims 70 to 72, wherein, prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the patients in the patient population have not been treated with a biological agent for psoriasis.

83. The method according to any one of claims 70 to 72, wherein, prior to the initiation of treatment with the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, the patients in the patient population have not been treated for psoriasis with any IL-23 receptor antagonist.

84. The method according to any one of claims 70 to 72, wherein the subject is a patient.

85. The method according to claim 84, wherein the subject is an adult or adolescent patient.

86. The method according to any one of claims 70 to 85, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is a hydrochloride salt.

87. The method according to any one of claims 70 to 86, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is a hydrochloride salt in a crystalline form.

88. A pharmaceutical product for treating subjects with psoriasis, comprising formula (I): 【Transformation 6】 A pharmaceutical product comprising the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof is present in an amount of approximately 200 mg.

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